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This work demonstrates gastric mucin-triggered nanocarrier disassembly for release of antisense oligonucleotides and consequent unassisted cellular entry as a novel oral delivery strategy. A fluorescence activation-based reporter system was used to investigate the interaction and mucin-mediated disassembly of chitosan-based nanocarriers containing a 13-mer DNA oligonucleotide with a flanked locked RNA nucleic acid gapmer design. Gastric mucins were shown to trigger gapmer release from nanocarriers that was dependent on the interaction time, mucin concentration and N : P ratio with a maximal release at N : P 10. In contrast to siRNA, naked gapmers exhibited uptake into mucus producing HT-MTX mono-cultures and HT-MTX co-cultured with the carcinoma epithelial cell line Caco-2. Importantly, in vivo gapmer uptake was observed in epithelial tissue 30 min post-injection in murine intestinal loops. The findings present a mucosal design-based system tailored for local delivery of oligonucleotides that may maximize the effectiveness of gene silencing therapeutics within tumours at mucosal sites.

Objective: Colonoscopy with biopsy sampling is often performed to detect collagenous colitis (CC) and lymphocytic colitis (LC) in patients with chronic non-bloody diarrhea. However, the diagnostic yield is low and incurs high costs. Fecal calprotectin (FC) and myeloperoxidase (MPO) indicate intestinal inflammation in ulcerative colitis (UC) and Crohn's disease (CD). In CC, elevated fecal levels of eosinophil protein X (EPX) and eosinophil cationic protein (ECP) have been reported. We aimed to evaluate if F-EPX, F-ECP, FC, and F-MPO could predict the diagnostic outcome in patients with chronic non-bloody diarrhea referred to colonoscopy. We also evaluated serum (S) EPX and ECP in this regard., Methods: Of 67 included patients, 63 (94%) underwent colonoscopy with biopsy sampling. Fecal EPX, F-ECP, FC, F-MPO, S-EPX, and S-ECP were analyzed., Results: Diagnostic outcome: normal: n = 46 (73%), CC: n = 9 (14%), LC: n = 4 (6%), UC: n = 2 (3%), CD: n = 2 (3%). Higher levels of F-EPX and F-ECP were found in CC compared to a normal diagnostic outcome (p = 0.01). No change was noted in any of the fecal markers in LC. When all of the fecal markers were normal the probability of a normal diagnostic outcome was 92%. We found no differences in S-EPX and S-ECP between the groups., Conclusion: Elevated F-EPX and F-ECP could predict CC. None of the fecal markers predicted LC. Serum-EPX and S-ECP are not useful for the diagnosis of CC, LC, UC, or CD. With normal levels in all of the analyzed fecal markers, there is a low probability of a pathologic diagnostic outcome.

Objective: Treatment of early-onset schizophrenia spectrum psychosis (EOS) is hampered by limited data on clinical presentation and illness course. We aimed to systematically review the clinical characteristics, diagnostic trajectories, and predictors of illness severity and outcomes of EOS., Methods: We conducted a systematic PubMed, PsycINFO, and Embase literature review including studies published from January 1, 1990 to August 8, 2014 of EOS patients with 1) ≥50% nonaffective psychosis cases; 2) mean age of subjects <19 years; 3) clinical samples recruited through mental health services; 4) cross-sectional or prospective design; 5) ≥20 participants at baseline; 6) standardized/validated diagnostic instruments; and 7) quantitative psychotic symptom frequency or severity data. Exploratory analyses assessed associations among relevant clinical variables., Results: Across 35 studies covering 28 independent samples (n = 1506, age = 15.6 years, age at illness onset = 14.5 years, males = 62.3%, schizophrenia-spectrum disorders = 89.0%), the most frequent psychotic symptoms were auditory hallucinations (81.9%), delusions (77.5%; mainly persecutory [48.5%], referential [35.1%], and grandiose [25.5%]), thought disorder (65.5%), bizarre/disorganized behavior (52.8%), and flat or blunted affect/negative symptoms (52.3%/50.4%). Mean baseline Positive and Negative Syndrome Scale (PANSS)-total, positive, and negative symptom scores were 84.5 ± 10.9, 19.3 ± 4.4 and 20.8 ± 2.9. Mean baseline Clinical Global Impressions-Severity and Children's Global Assessment Scale/Global Assessment of Functioning (CGAS/GAF) scores were 5.0 ± 0.7 and 35.5 ± 9.1. Comorbidity was frequent, particularly posttraumatic stress disorder (34.3%), attention-deficit/hyperactivity and/or disruptive behavior disorders (33.5%), and substance abuse/dependence (32.0%). Longer duration of untreated psychosis (DUP) predicted less CGAS/GAF improvement (p < 0.0001), and poor premorbid adjustment and a diagnosis of schizophrenia predicted less PANSS negative symptom improvement (p = 0.0048) at follow-up. Five studies directly comparing early-onset with adult-onset psychosis found longer DUP in EOP samples (18.7 ± 6.2 vs. 5.4 ± 3.1 months, p = 0.0027)., Conclusions: EOS patients suffer substantial impairment from significant levels of positive and negative symptoms. Although symptoms and functioning improve significantly over time, pre-/and comorbid conditions are frequent, and longer DUP and poorer premorbid adjustment is associated with poorer illness outcome.

Objective: To evaluate the efficacy of fixed combination aerosol foam calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD)., Design: Patients were randomized (100:101:101) to receive Cal/BD foam, Cal foam, or BD foam once daily for four weeks., Setting: Twenty-eight United States centers., Participants: 302 patients (≥18 years) with Psoriasis vulgaris (plaque Psoriasis; ≥mild disease severity by physicians global assessment)., Measurements: Treatment success of the body ("clear"/"almost clear" from baseline moderate/severe disease; "clear" from baseline mild disease). Involved scalp treatment success was an additional endpoint., Results: Most patients (76%) had moderate Psoriasis of the body (66% for scalp). At Week 4, 45 percent of Cal/BD foam patients achieved treatment success, significantly more than Cal foam (14.9%; OR 4.34 [95%CI 2.16,8.72] P<0.001) or BD foam (30.7%; 1.81 [1.00,3.26] P=0.047). Fifty-three percent of Cal/BD foam patients achieved treatment success of the scalp, significantly greater than Cal foam (35.6%; 1.91 [1.09,3.35] P=0.021), but not BD foam (47.5%; 1.24 [0.71,2.16] P=0.45). Mean modified Psoriasis area and severity index (population baseline 7.6) improved in all groups, with statistically significant differences in Week 4 Cal/BD foam score (2.37) versus Cal foam (4.39; mean difference -2.03 [-2.63][-1.43] P<0.001) and BD foam (3.37; -1.19 [-1.80][-0.59] P<0.001). Four (Cal/BD), 10 (Cal), and 8 (BD) adverse drug reactions were reported., Conclusion: Cal/BD foam was significantly more effective than Cal foam and BD foam in providing treatment success at Week 4 and effective on involved scalp., Trial Registration: NCT01536938.

Background: An aerosol foam formulation of fixed combination calcipotriene 0.005% (as hydrate; Cal) plus betamethasone dipropionate 0.064% (BD) was developed to improve psoriasis treatment., Objectives: To compare the efficacy and safety of Cal/BD aerosol foam with Cal/BD ointment after 4 weeks., Methods: In this Phase II, multicenter, investigator-blind, 4-week trial, adult patients with psoriasis vulgaris were randomized to Cal/BD aerosol foam, Cal/BD ointment, aerosol foam vehicle or ointment vehicle (3:3:1:1). The primary efficacy endpoint was the proportion of patients at week 4 who achieved treatment success (clear or almost clear with at least a two-step improvement) according to the physician's global assessment of disease severity., Results: In total, 376 patients were randomized. At week 4, significantly more patients using Cal/BD aerosol foam achieved treatment success (54.6% versus 43.0% [ointment]; p = 0.025); mean modified (excluding the head, which was not treated) psoriasis area and severity index score was significantly different between Cal/BD aerosol foam and Cal/BD ointment (mean difference -0.6; p = 0.005). Rapid, continuous itch relief occurred with both active treatments. One adverse drug reaction was reported with Cal/BD aerosol foam (application site itch)., Conclusions: Cal/BD aerosol foam demonstrates significantly greater efficacy and similar tolerability compared with Cal/BD ointment for psoriasis treatment.

Objective: This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis., Design: A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase., Results: Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious., Conclusions: Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation., Trial Registration Numbers: http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Fixed combination calcipotriol 50 µg/g (Cal; as hydrate) plus betamethasone 0.5 mg/g (as dipropionate; BD) has been formulated in an innovative aerosol foam., Objective: To assess systemic safety of Cal/BD aerosol foam., Methods: In a multicentre, single-arm, open-label, maximal-use systemic-exposure trial, adult patients with moderate to severe, extensive psoriasis (15%-30% of body surface area, including ≥30% of scalp) applied Cal/BD foam once daily. Endpoints were week 4 abnormal adrenocorticotropic hormone (ACTH) challenge test and change in albumin-corrected serum calcium, 24-hour urinary calcium excretion, and urinary calcium-creatinine ratio., Results: 35 patients reaching week 4 exhibited normal ACTH responses. At week 4, changes in calcium homeostasis were minor and not clinically relevant; no patients experienced elevations above normal. Disease severity generally improved, and 49% of patients achieved treatment success according to the Physician's Global Assessment of Disease Severity., Conclusion: No clinically relevant HPA axis or calcium homeostasis impact was observed with 4 weeks of once-daily Cal/BD foam in patients with extensive psoriasis vulgaris., (© The Author(s) 2015.)

Introduction: An innovative aerosol foam formulation of calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) designed to improve treatment outcomes., Objective: To compare the efficacy and safety of Cal/BD aerosol foam with aerosol foam vehicle in patients with psoriasis., Design: Phase III, double-blind, randomized PSO-FAST (Cal/BD foam in PSOriasis vulgaris, a Four-week, vehicle-controlled, efficacy And Safety Trial) study recruited patients with ≥ mild severity psoriasis of the trunk and/or limbs from 27 US outpatient sites (NCT01866163). Patients were randomized (3:1) to Cal/BD foam or vehicle once-daily for 4 weeks., Primary Outcome: proportion of patients at week 4 who achieved treatment success according to physician's global assessment., Secondary Outcomes: modified (excluding head) psoriasis area and severity index (mPASI) and patient's assessment of itch (visual analog scale). Safety was monitored by adverse events/calcium homeostasis., Results: 426 patients enrolled between June and October 2013 (Cal/BD foam, n=323; vehicle, n=103). At week 4, significantly more patients using Cal/BD foam achieved treatment success versus vehicle (53.3 versus 4.8%; OR 30.3, 95% CI 9.7,94.3; P < .001) and mean mPASI score was significantly lower for patients using Cal/BD foam than vehicle (2.0 versus 5.5; adjusted difference -3.3, P <.001). Significantly greater itch relief was observed for patients using Cal/BD foam than vehicle (P = .010 at day 3, P < .001 from day 5). Adverse drug reactions were reported in 10 Cal/BD foam patients (3.1%) and two vehicle patients (1.9%); events occurred in one patient each except application site pain (Cal/BD foam, two patients; vehicle, one patient). There were no clinically significant changes in calcium homeostasis., Conclusions: Cal/BD foam was efficacious, achieved rapid itch relief and was well tolerated in patients with body psoriasis. This innovative aerosol foam formulation is expected to become a valuable treatment option.

In adults with schizophrenia, early response/non-response (ER/ENR) to antipsychotics at 2 weeks robustly predicts ultimate response/non-response (UR/UNR). However, less data about the predictive value of ER/ENR exist in adolescents with schizophrenia. Post hoc analysis of a 6-week trial in adolescents aged 13-17 with schizophrenia were randomized 2:1 to olanzapine or placebo. ER was defined as ≥20 % reduction in Brief Psychiatric Rating Scale-children (BPRS-C) total score at week 2 (ER2) or 3 (ER3); UR was defined with increasing stringency as total BPRS-C score reduction ≥20, ≥30, ≥40 or ≥50 %; remission was defined cross-sectionally using Andreasen et al. (2005) criteria. By week 2 (n = 69) and 3 (n = 66), olanzapine-treated youth achieved 73.3 and 85.5 % of their overall BPRS-C score reduction at 6 weeks last observation carried forward. ER and ENR patients did not differ significantly regarding baseline demographic, illness and treatment variables. ER 2 (frequency = 68.1 %) and ER 3 (frequency = 65.2 %) significantly predicted UR and remission (p = 0.0044-p < 0.0001), with ER3 having more predictive power. A ≥ 20 % BPRS-C reduction threshold for ER had best predictive validity (area under the curve = 0.88-0.92). At 6 weeks, patients with ER had significantly greater improvements in BPRS-C, Clinical Global Impressions Improvement and Severity scores, greater cross-sectional remission and less all-cause discontinuation (p = 0.047-p < 0.0001). Adverse event profiles were similar in the ER and ENR groups. Adolescents with schizophrenia experienced the majority of symptomatic improvement early during olanzapine treatment. ER predicted UR and remission, with ER3 having best predictive power. A ≥ 20 % improvement threshold for defining ER was confirmed as a robust outcome indicator.

Aims: We studied whether variants previously associated with congenital long QT syndrome (cLQTS) have an effect on the QTc interval in a Danish population sample. Furthermore, we assessed whether carriers of variants in cLQTS-associated genes are more prone to experience syncope compared with non-carriers and whether carriers have an increased mortality compared with non-carriers., Methods and Results: All genetic variants previously associated with cLQTS were surveyed using the Human Gene Mutation Database. We screened a Danish population-based sample with available whole-exome sequencing data (n = 870) and genotype array data (n = 6161) for putative cLQTS genetic variants. In total, 33 of 1358 variants previously reported to associate with cLQTS were identified. Of these, 10 variants were found in 8 or more individuals. Electrocardiogram results showed normal mean QTc intervals in carriers compared with non-carriers. Syncope data analysis between variant and non-variant carriers showed that 4 of 227 (1.8%) and 95 of 5861 (1.6%) individuals, respectively, had experienced syncope during follow-up (P = 0.80). There was no significant difference in overall mortality rates between carriers [7/217 (3.2%)] and non-carriers [301/6453 (4.7%)] (P = 0.24)., Conclusion: We present QTc data and register data, indicating that 26 cLQTS-associated variants neither had any effect on the QTc intervals nor on syncope propensity or overall mortality. Based on the frequency of individual gene variants, we suggest that the 10 variants frequently identified, assumed to relate to cLQTS, are less likely to associate with a dominant monogenic form of the disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Patient-centered communication is a core competency in modern health care and associated with higher levels of patient satisfaction, improved patient health outcomes, and lower levels of burnout among physicians. The objective of the present study was to develop a questionnaire assessing medical student and physician self-efficacy in patient-centeredness (SEPCQ) and explore its psychometric properties., Methods: A preliminary 88-item questionnaire (SEPCQ-88) was developed based on a review of the literature and medical student portfolios and completed by 448 medical students from Aarhus University. Exploratory Principal Component analysis resulted in a 27-item version (SEPCQ-27) with three underlying self-efficacy factors: 1) Exploring the patient perspective, 2) Sharing information and power, and 3) Dealing with communicative challenges. The SEPCQ-27 was completed by an independent sample of 291 medical students from 2 medical schools and 101 hospital physicians., Results: Internal consistencies of total and subscales were acceptable for both students and physicians (Cronbach's alpha (range): 0.74-0.95). There were no overall indications of gender-related differential item function (DIF), and a Confirmatory Factor Analysis (CFA) indicated good fit (CFI = 0.98; NNFI = 0.98; RMSEA = 0.05; SRMR = 0.07). Responsiveness was indicated by increases in SEPCQ scores after a course in communication and peer-supervision (Cohen's d (range): 0.21 to 0.73; p: 0.053 to 0.001). Furthermore, positive associations were found between increases in SEPCQ-scores and course-related motivation to learn (medical students) and between SEPCQ scores and years of clinical experience (physicians)., Conclusions: The final SEPCQ-27 showed satisfactory psychometric properties, and preliminary support was found for its construct validity, indicating that the SEPCQ-27 may be a valuable measure in future patient centered communication training and research.

Brain activation reduces balance between cerebral consumption of oxygen versus carbohydrate as expressed by the so-called cerebral oxygen-carbohydrate-index (OCI). We evaluated whether preparation for surgery, anaesthesia including tracheal intubation and surgery affect OCI. In patients undergoing aortic surgery, arterial to internal jugular venous (a-v) concentration differences for oxygen versus lactate and glucose were determined from before anaesthesia to when the patient left the recovery room. Intravenous anaesthesia was supplemented with thoracic epidural anaesthesia for open aortic surgery (n = 5) and infiltration with bupivacaine for endovascular procedures (n = 14). The a-v difference for O2 decreased throughout anaesthesia and in the recovery room (1.6 ± 1.9 versus 3.2 ± 0.8 mmol l(-1), mean ± SD), and while a-v glucose decreased during surgery and into the recovery (0.4 ± 0.2 versus 0.7 ± 0.2 mmol l(-1) , P<0.05), a-v lactate did not change significantly (0.03 ± 0.16 versus -0.03 ± 0.09 mmol l(-1)). Thus, OCI decreased from 5.2 ± 1.8 before induction of anaesthesia to 3.2 ± 1.0 following tracheal intubation (P<0.05) because of the decrease in a-v O2 with a recovery for OCI to 4.6 ± 1.4 during surgery and to 5.6 ± 1.7 in the recovery room. In conclusion, preparation for surgery and tracheal intubation decrease OCI that recovers during surgery under the influence of sensory blockade., (© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Aims: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration., Methods and Results: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF <1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10A SNP V1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K) OR (95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments for NaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970)., Conclusion: Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10A V1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background and Objective: The antipsoriatic effect of an innovative aerosol foam formulation of fixed combination calcipotriol 50 μg/g (as hydrate; Cal) and betamethasone 0.5 mg/g (as dipropionate; BD) was explored in order to compare the effect with that of the first-line treatment Cal/BD ointment., Methods: This was a Phase IIa, single-centre, investigator-blinded, exploratory study, with intra-individual comparison using a modified psoriasis plaque test. Patients were treated once daily (6 days/week) for 4 weeks with Cal/BD foam, Cal/BD ointment, BD foam and Cal/BD foam vehicle, randomized to four plaque test sites (5 cm(2) each). The primary efficacy endpoint was change in total clinical score (TCS; sum of erythema, scaling and lesional thickness). Secondary endpoints included ultrasonographic changes in total skin thickness and echo-poor band thickness, and adverse events., Results: Twenty-four patients, median age 52.5 years (range 21-75), completed this study. At week 4, test sites treated with Cal/BD foam had a significantly greater decrease in mean (±SD) TCS (-6.00 ± 1.27) versus those treated with Cal/BD ointment (-5.25 ± 1.78; difference -0.75; 95 % CI -1.46 to -0.04; p = 0.038), BD foam (-4.96 ± 1.85; difference -1.04; 95 % CI -1.75 to -0.33; p = 0.005) or foam vehicle (-1.88 ± 1.12; difference -4.13; 95 % CI -4.83 to -3.42; p < 0.001). Total skin thickness and echo-poor band thickness of Cal/BD foam-treated sites were reduced to a greater extent than those treated with comparators. Eleven patients reported 17 adverse events, the most frequent being headache (five patients). There were no lesional/perilesional adverse events or adverse drug-related events., Conclusions: Cal/BD foam demonstrated a significant improvement in antipsoriatic effect over Cal/BD ointment, BD foam and foam vehicle alone.

Neuropeptide Y (NPY) causes anxiolytic- and antidepressant-like effects after central administration in rodents. These effects could theoretically be utilized in future gene therapy for anxiety and depression using viral vectors for induction of overexpression of NPY in specific brain regions. Using a recombinant adeno-associated viral (rAAV) vector, we addressed this idea by testing effects on anxiolytic- and depression-like behaviours in adult mice after overexpression of NPY transgene in the amygdala and/or hippocampus, two brain regions implicated in emotional behaviours. In the amygdala, injections of rAAV-NPY caused significant anxiolytic-like effect in the open field, elevated plus maze, and light-dark transition tests. In the hippocampus, rAAV-NPY treatment was associated with anxiolytic-like effect only in the elevated plus maze. No additive effect was observed after combined rAAV-NPY injection into both the amygdala and hippocampus where anxiolytic-like effect was found in the elevated plus maze and light-dark transition tests. Antidepressant-like effects were not detected in any of the rAAV-NPY injected groups. Immobility was even increased in the tail suspension and forced swim tests after intra-amygdaloid rAAV-NPY. Taken together, the present data show that rAAV-NPY treatment may confer non-additive anxiolytic-like effect after injection into the amygdala or hippocampus, being most pronounced in the amygdala., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections., Methods/design: The TEA trial is a Danish investigator-initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naïve or treated for a limited period are, 1:1 randomised to a 12- week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014., Discussion: Antipsychotics are currently the only available pharmacologic treatments for psychotic disorders. However, information about head-to-head differences in efficacy and tolerability of antipsychotics are scarce in children and adolescents. The TEA trial aims at expanding the evidence base for the use of antipsychotics in early onset psychosis in order to inform more rational treatment decisions in this vulnerable population. Here, we account for the trial design, address methodological challenges, and discuss the estimation of sample size., Trial Registration: ClinicalTrials.gov: NCT01119014.

Background: Chronic non-bloody diarrhoea affects up to 5% of the population. Microscopic colitis is one of the most common causes, encompassing the subtypes collagenous colitis and lymphocytic colitis. The diagnosis of microscopic colitis is made by histological examination of colonic mucosal biopsy specimens. The aim of this investigation was to determine whether laboratory parameters or questions about disease history or concomitant disease could be helpful in discriminating patients with MC from those with a histologically normal colonic mucosa., Findings: Patients admitted for colonoscopy because of chronic non-bloody diarrhoea (>2 loose stools for >3 weeks) at endoscopy units in Malmö during 2007 and 2009, were enrolled. A total number of 78 patients were included (60 women, 18 men, median age 59, IQR 45-69 years). Out of these 78, 15 patients (19%) had microscopic colitis (CC; n = 10, LC; n = 5). MC was especially prevalent in patients above the age of 50 (25%). No differences were found between those with normal histology and MC in laboratory analyses (inflammatory and liver parameters). Neither were differences shown in questions regarding symptoms, environmental factors or concomitant diseases except for an association with celiac disease (p = 0.019) and a trend maybe indicating an inverse association with appendectomy (p = 0.057)., Conclusions: Microscopic colitis is associated with female gender, celiac disease and consumption of NSAIDs. Trends were observed indicating that age above 50 years, acute onset and absence of appendectomy may be associated with MC. No associations were observed with other symptoms, calprotectin levels or liver parameters.

The objective of the article is to characterize the models used by pharmacists to obtain medication history and medication review in Danish hospitals. The models are characterized based on the sources used to create an overview of the patient's medication as well as the time spent per patient. Currently pharmacists perform medication review at 16 departments. The sources frequently used are the patient journal (81%) and clinical data (81%). The patient contributes to the medication review in 25%.

The identification of individuals at high risk of developing atrial fibrillation (AF) is important to prevent potentially lethal and invalidating complications of this arrhythmia. Recently, several studies have investigated the association between PR-interval and the risk of AF and have tested the value of PR-interval in personalized risk scores for AF. However, the results of these studies are generally conflicting. When looking for an association between a prolonged PR-interval (first-degree atrioventricular [AV] block vs. normal PR-interval) and an increased risk of AF, not all studies were able to find a consistent and statistically significant association. In two recent studies, however, the investigators were able to show an increased risk of AF for individuals with PR-intervals in the short range compared with individuals in the middle range. The existence of a true U-shaped relationship could potentially explain part of the conflicting results from investigators only looking for an increased risk for longer PR-intervals. However, regardless of these speculations, the association seems relatively weak. The significance of PR-interval in risk prediction of AF has been tested in three independent risk scores where model selection primarily was based on improvement in c-statistics. In one risk score, PR-interval improved the predictive value of the risk model, whereas it did not in the other two risk scores. Further studies are warranted before any final conclusion can be drawn, although based on the current evidence, it is reasonable to conclude that the predictive value of PR-interval in AF risk prediction is limited.

Objective: The use of early response/nonresponse (ER/ENR) to antipsychotics as a predictor for ultimate response/nonresponse (UR/UNR) may help decrease inefficacious treatment continuation. However, data have been limited to adults, and ER/ENR has only been determined using time-consuming psychopathology rating scales. In the current study, we assessed if early improvement on the Clinical Global Impressions-Improvement (CGI-I) scale predicted UR/UNR in psychiatrically ill youth started on antipsychotic treatment., Methods: Seventy-nine youth aged 6-19 years, with schizophrenia spectrum disorders, treated naturalistically with aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone and evaluated monthly, were divided into ER/ENR groups at week 4, using at least "minimally improved" on the CGI-I scale. Prediction using week 4 ER/ENR status for UR (CGI-I=at least "much improved"), effectiveness and adverse effect outcomes at 8-12 weeks were assessed., Results: At 4 weeks, 45.6% of subjects were ER and 54.4% were ENR without differences regarding baseline demographic, illness, and treatment variables, except for higher age (p=0.034) and maximum risperidone dose (p=0.0043) in ENR. ER/ENR status at 4 weeks predicted UR/UNR at week 12 significantly (p<0.0001): Sensitivity=68.9%, specificity=85.3%, positive predictive value=86.1%, negative predictive value=67.4%. At weeks 4, 8, and 12, ER patients improved significantly more on the CGI-I, CGI-Severity, and Children's Global Assessment of Functioning scales, and more ER patients reached UR compared with ENR patients (83.3% vs. 34.9%, all p<0.0001). ENR patients had more extrapyramidal side effects (EPS) at weeks 4, 8, and 12 (p=0.0019-0.0079). UR was independently associated with ER (odds ratio [OR]=18.09; 95% confidence interval [CI]=4.71-91.68, p<0.0001) and psychosis not otherwise specified (NOS) (OR=4.82 [CI: 1.31-21.41], p=0.017) (r(2)=0.273, p<0.0001)., Conclusions: Older age and EPS were associated with ENR; ENR and schizophrenia were associated with UNR in naturalistically treated youth with schizophrenia spectrum disorders. Early CGI-I-based treatment decisions require further consideration and study.

More than 300 variants in 12 genes have been associated with Brugada syndrome (BrS) which has a prevalence ranging between 1:2000 and 1:100,000. Until recently, there has been little knowledge regarding the distribution of genetic variations in the general population. This problem was partly solved, when exome data from the NHLI GO Exome Sequencing Project (ESP) was published. In this study, we aimed to report the prevalence of previously BrS-associated variants in the ESP population. We performed a search in ESP for variants previously associated with BrS. In addition, four variants in ESP were genotyped in a second Danish control population (n = 536) with available electrocardiograms. In ESP, we identified 38 of 355 (10%) variants, distributed on 272 heterozygote carriers and two homozygote carriers. The genes investigated were on average screened in 6258 individuals. This corresponds to a surprisingly high genotype prevalence of 1:23 (274:6258). Genotyping the four common ESP-derived variants CACNA2D1 S709N, SCN5A F2004L, CACNB2 S143F, and CACNB2 T450I in the Danish controls, we found a genotype prevalence comparable with that found in ESP. We suggest that exome data are used in research, as an additive tool to predict the pathogenicity of variants in patients suspected for BrS., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The two-compound topical suspension/gel containing calcipotriene plus betamethasone dipropionate is effective and safe in the treatment of psoriasis on the body and scalp within the general psoriasis patient population., Objective: To evaluate the systemic effects of once-daily use of two-compound topical suspension/gel on the hypothalamic-pituitary-adrenal (HPA) axis and calcium homeostasis in subjects with extensive psoriasis vulgaris., Methods: An open-label, single-group, 8-week trial in 43 subjects with extensive psoriasis covering 15-30% of the body surface area. Blood and 24-hour urine samples were collected and a standard-dose adrenocorticotropic hormone (ACTH) stimulation test was performed at baseline, weeks 4 and 8. Primary endpoints were serum cortisol 30 minutes after ACTH injection (HPA axis response abnormal at serum cortisol ≤18 μg/dL) and changes from baseline in albumin-corrected serum calcium (sCa), 24-hour urinary calcium excretion (24hCa) and urine calcium:creatinine ratio (Ca:Crea)., Results: Two (4.7%) subjects showed signs of adrenal suppression based on the ACTH stimulation test results at week 4; both were withdrawn from treatment and had normal serum cortisol 30-minute values at follow-up 4 weeks later. None of the subjects who continued treatment to week 8 showed signs of adrenal suppression. There were no clinically relevant mean changes from baseline to weeks 4 and 8 in sCa, 24hCa or Ca:Crea and no subject had sCa above the reference range., Conclusion: The two-compound topical suspension/gel containing calcipotriene plus betamethasone dipropionate may be applied once daily to extensive psoriasis vulgaris without generally causing adrenal suppression or disturbance of calcium homeostasis, consistent with previous findings. In a small number of patients with extensive psoriasis treated with large volumes of topical suspension, adrenal suppression may be observed. In the real-world setting, it is anticipated that systemic side-effects would occur in only a few cases within the general psoriasis patient population. ClinicalTrials.gov Identifier:

Introduction: The objective of this study was to compare medication reconciliation and medication review based on number, type and severity of discrepancies and drug-related problems (DRPs), denoted errors., Material and Methods: This was a retrospective study conducted at the Department of Cardiology, Hillerød Hospital. Medication reconciliation compared the prescriptions in patient records, an electronic medication system (EMS) and in discharge summaries (DS). The medication review was based on the EMS. The two methods were performed on the same data material. To assess the clinical importance of the errors, a four-point scale was applied., Results: A total of 75 patient records were included. In all, 198 discrepancies were identified by medication reconciliation, 2.6 per patient. The most frequent discrepancies were omission of a drug in the DS and discrepancy between the drugs noted in the patient record and the EMS. 15% of the discrepancies were potentially serious or fatal, 62% were potentially significant and 23% were potentially non-significant. A total of 129 DRPs were identified by medication review, 1.7 per patient. The most frequent DRPs were sub therapeutic dosage, inappropriate dosage regimen and untreated medical condition. 35% of the DRPs were potentially serious or fatal, 29% were potentially significant and 36% were potentially non-significant., Conclusion: Medication reconciliation identified a higher number of errors than medication review, but the number of serious errors identified by medication review was higher than that identified by medication reconciliation. The two methods identified different types of errors and should be used concurrently to supplement each other., Funding: not relevant., Trial Registration: not relevant.

Objective: Collagenous colitis (CC) and lymphocytic colitis (LC) are two subtypes of microscopic colitis (MC). Even though they most often are described as different entities they share many clinical and histological features. The aim of this study was to investigate the occurrence of conversion between CC and LC in a larger cohort of patients., Materials and Methods: All 664 patients in our Pathology register with a diagnosis of CC and LC were scrutinized and those where additional endoscopies had been carried out were included, and their biopsies were re-examined., Results: Sixty-five patients (55 women, 10 men, median age 58 years; range 29-86) fulfilled our criteria for inclusion. The primary diagnosis was CC in 47 patients (39 women, 8 men, median age 58 years; range 29-86) and LC in 18 patients (16 women, 2 men, median age 58 years; range 33-74). Conversion occurred in nine of the 65 patients (14%, all women, median age 59 years; range 41-72), three from CC to LC and six from LC to CC., Conclusion: This study has found that patients can show histological features consistent with both CC and LC over time. These patients could represent a subgroup with a true conversion between two separate entities. Alternatively, MC could be a spectral disease where the varying histological features are manifestations of the natural fluctuation. A third possibility could be that the histological changes reflect different manifestations during the disease course and consequently, the diagnostic criteria could be too vague.

Lack of medication reconciliation (MR) during transition in care is a major source to preventable, adverse drug events (PADE). At admission it is crucial that a thorough medication history is obtained in order to prevent discrepancies in the medication list. Still, discrepancies occur and one third of them have the potential to harm the patient. Systematic MR has proved to prevent PADE. The process of implementing MR is complex. Preliminary results from The Danish Safer Hospital Programme show, that comprehensive intervention is the key to success. Further research into interventions and implementation of MR in a clinical setting is needed.

The aim of this study was to examine the effects of the OPG-RANKL-TRAIL system on proliferation, regulation of calcification-associated genes and calcification of human vascular smooth muscle cells (HVSMCs). Small interfering (si)RNA-mediated knockdown of OPG was followed by treatment of HVSMCs with recombinant RANKL or TRAIL. Regulation of a calcification-associated gene set was assayed by pathway analysis of microarray results. The lack of OPG in HVSMCs or treatment with RANKL or TRAIL did not affect proliferation of HVSMCs. In addition, OPG, RANKL or TRAIL did not modify the regulation of a calcification-associated gene set. Finally, in the long term calcification assay, we found that cells isolated from seven different human donors showed a great variability in the response to RANKL and insulin. However, overall RANKL and/or insulin did not affect the development of calcification of HVSMCs. These studies indicate that OPG knockdown does not alter the calcification process in HVSMCs., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aim: To estimate the incidence of collagenous colitis (CC) in southern Sweden during 2001-2010., Methods: Cases were identified by searching for CC in the diagnostic registers at the Pathology Departments in the county of Skåne. The catchment area comprised the south-west part of the county (394 307 inhabitants in 2010) and is a mixed urban and rural type with limited migration. CC patients that had undergone colonoscopy during the defined period and were living in this area were included in the study regardless of where in Skåne they had been diagnosed. Medical records were scrutinized and uncertain cases were reassessed to ensure that only newly diagnosed CC cases were included. The diagnosis of CC was based on both clinical and histopathological criteria. The clinical criterion was non-bloody watery diarrhoea. The histopathological criteria were a chronic inflammatory infiltrate in the lamina propria, a thickened subepithelial collagen layer ≥ 10 micrometers (μm) and epithelial damage such as flattening and detachment., Results: During the ten year period from 2001-2010, 198 CC patients in the south-west part of the county of Skåne in southern Sweden were newly diagnosed. Of these, 146 were women and 52 were men, i.e., a female: male ratio of 2.8:1. The median age at diagnosis was 71 years (range 28-95/inter-quartile range 59-81); for women median age was 71 (range 28-95) years and was 73 (range 48-92) years for men. The mean annual incidence was 5.4/10(5) inhabitants. During the time periods 2001-2005 and 2006-2010, the mean annual incidence rates were 5.4/10(5) for both periods [95% confidence interval (CI): 4.3-6.5 in 2001-2005 and 4.4-6.4 in 2006-2010, respectively, and 4.7-6.2 for the whole period]. Although the incidence varied over the years (minimum 3.7 to maximum 6.7/10(5)) no increase or decrease in the incidence could be identified. The odds ratio (OR) for CC in women compared to men was estimated to be 2.8 (95% CI: 2.0-3.7). The OR for women 65 years of age or above compared to below 65 years of age was 6.9 (95% CI: 5.0-9.7), and for women 65 years of age or above compared to the whole group the OR was 4.7 (95% CI: 3.6-6.0). The OR for age in general, i.e., above or 65 years of age compared to those younger than 65 was 8.3 (95% CI: 6.2-11.1). During the last decade incidence figures for CC have also been reported from Calgary, Canada during 2002-2004 (4.6/10(5)) and from Terrassa, Spain during 2004-2008 (2.6/10(5)). Our incidence figures from southern Sweden during 2001-2010 (5.4/10(5)) as well as the incidence figures presented in the studies during the 1990s (Terrassa, Spain during 1993-1997 (2.3/10(5)), Olmsted, United States during 1985-2001 (3.1/10(5)), Örebro, Sweden during 1993-1998 (4.9/10(5)), and Iceland during 1995-1999 (5.2/10(5)) are all in line with a north-south gradient, something that has been suggested before both for CC and inflammatory bowel disease., Conclusion: The observed incidence of CC is comparable with previous reports from northern Europe and America. The incidence is stable but the female: male ratio seems to be decreasing.

Neuropeptide Y (NPY) has been implicated in anxiolytic- and antidepressant-like behaviour as well as seizure-suppressant effects in rodents. Although these effects appear to be predominantly mediated via other NPY receptors (Y1 and/or Y2), several studies have also indicated a role for Y5 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY, Y1 or Y2 receptors in the hippocampus or amygdala has previously been shown to modulate emotional behaviour and seizures in rodents. The present study explored the potential effects of gene therapy with the Y5 receptor, by testing effects of recombinant adeno-associated viral vector (rAAV) encoding Y5 (rAAV-Y5) in anxiety- and depression-like behaviour as well as in kainate-induced seizures in adult mice. The rAAV-Y5 vector injected into the hippocampus and amygdala induced a pronounced and sustained increase in Y5 receptor mRNA expression and functional Y5 receptor binding, but no significant effects were found with regard to anxiety- and depression-like behaviours or seizure susceptibility. Instead, rAAV-mediated Y5 receptor transgene overexpression resulted in moderate hyperactivity in the open field test. These results do not support a potential role for single transgene overexpression of Y5 receptors for modulating anxiety-/depression-like behaviours or seizures in adult mice. Whether the induction of hyperactivity by rAAV-Y5 could be relevant for other conditions remains to be studied., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aim: Solitary Median Maxillary Central Incisor (SMMCI) is a developmental anomaly in the permanent dentition with one single central incisor in the maxilla, positioned exactly in the midline. This condition has been associated with extra- and intraoral malformations in the frontonasal segment of the cranium and face. It is not known whether the centrally located permanent incisor is always preceded by a centrally located primary incisor. The aim was to analyse whether a permanent single central incisor in SMMCI is always preceded by a primary single central incisor and to study extra- and intraoral phenotypic traits of the condition., Study Design: cross-sectional radiographic study of 11 children, visual analysis of photos and dental and panoramic radiographs., Results: Nine of the 11 cases exhibited a primary SMMCI with one symmetrical crown and root. Two cases exhibited two separate primary central incisor crowns with fused roots. The phenotypical traits (indistinct philtrum, lack of normal upper lip contour, missing superior labial frenulum and distinct mid-palatal ridge) were findings observed in young children with a primary SMMCI., Conclusion: The present study concludes and stresses the necessity of diagnosing of the SMMCI condition early in life. Furthermore, paediatric dentists are recommended to be aware of the condition and to refer these patients to interdisciplinary diagnostics and treatment.

Neuropeptide Y (NPY) exerts anxiolytic- and antidepressant-like effects in rodents that appear to be mediated via Y1 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY in the hippocampus or amygdala has previously been shown to confer anxiolytic-like effect in rodents. The present study explored an alternative and more specific approach: overexpression of Y1 receptors. Using a recombinant adeno-associated viral vector (rAAV) encoding the Y1 gene (rAAV-Y1), we, for the first time, induced overexpression of functional transgene Y1 receptors in the hippocampus of adult mice and tested the animals in anxiety- and depression-like behavior. Hippocampal Y1 receptors have been suggested to mediate seizure-promoting effect, so the effects of rAAV-induced Y1 receptor overexpression were also tested in kainate-induced seizures. Y1 receptor transgene overexpression was found to be associated with modest anxiolytic-like effect in the open field and elevated plus maze tests, but no effect was seen on depression-like behavior using the tail suspension and forced swim tests. However, the rAAV-Y1 vector modestly aggravated kainate-induced seizures. These data indicate that rAAV-induced overexpression of Y1 receptors in the hippocampus could confer anxiolytic-like effect accompanied by a moderate proconvulsant adverse effect. Further studies are clearly needed to determine whether Y1 gene therapy might have a future role in the treatment of anxiety disorders., (Copyright © 2011 Wiley Periodicals, Inc.)

Delirium is a common and often under-recognised neuropsychiatric disorder in paediatric critical care, secondary to a general medical condition. Paediatric delirium (PD) is associated with high morbidity and mortality and prolonged stay at the intensive care unit. This review introduces the reader to PD and focuses on diagnostic tools, prognosis and treatment. The literature about PD is sparse. In order to make recommendations about PD based on evidence more clinical studies are urgently needed.

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). We suggested that plasma osteoprotegerin (OPG), a strong, independent predictor of cardiovascular disease, could discriminate between anti-diabetic treatments depending on their benefits regarding cardiovascular disease. The South Danish Diabetes Study, an investigator-driven, randomized, controlled clinical trial lasting 2 years, was used to test this hypothesis in patient groups with different medication strategies (insulin aspart or NPH insulin, added either metformin/placebo or rosiglitazone/placebo). A total of 371 individuals were eligible for the study. Basic variables were analysed along with measurement of plasma OPG and HbA(1c) at the beginning and end of the study. Only rosiglitazone treatment caused a significant decrease in plasma OPG concentrations (p = 0.003), while no significant change was seen in the other treatment groups. The effect of rosiglitazone on plasma OPG remained significant in a univariate analysis adjusted for change in HbA(1c) (p = 0.013). Of note, the change in plasma OPG significantly correlated with HbA(1c) improvement in rosiglitazone-treated patients (R = 0.29, p = 0.0002), while this correlation was poor in those not receiving rosiglitazone (R = 0.06, p =0.48). Treatment with rosiglitazone among patients with T2DM reduces the concentration of plasma OPG. This is not seen with metformin despite similar reductions in HbA(1c) . Alteration in the OPG/RANKL pathway by glitazones may have implications for the understanding of both cardiovascular effects and bone side effects of the drug., (© 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.)

We conducted a comparison of the preoperative airway and teeth status assessment with a dedicated postoperative assessment. We included 211 patients with a preoperative airway and teeth assessment performed by the designated physicians at the department of anaesthesia. 27% of the patients had an incomplete preoperative assessment. 66% were not informed about the risk of damages to the teeth and 16% of the patients were postoperatively considered to have periodontitis compared to only 3% preoperatively. Postoperatively we found, that many more patients had an overall poor dental status.

Inherited ion-channel disorders can lead to life-threatening cardiac arrhythmias. A recent, rare entity has been discovered and termed short QT syndrome due to its electrocardiac features in conjunction with atrial and ventricular tachyarrhythmias as well as syncope and sudden cardiac death. The basis of the new syndrome is genetic and this review covers the genes responsible for the condition as well as the pathophysiology and diagnostic challenges involved in the syndrome. Furthermore, treatment for this new arrhythmic syndrome is reviewed.

Stressful life events and chronic stress are implicated in the development of depressive disorder in humans. Neuropeptide Y (NPY) and galanin have been shown to modulate the stress response, and exert antidepressant-like effects in rodents. To further investigate these neuropeptides in depression-like behaviour, NPY and galanin gene expression was studied in brains of mice subjected to chronic restraint stress (CRS) and concomitant treatment with the antidepressant fluoxetine (FLX). CRS caused a significant increase in depression-like behaviour that was associated with increased NPY mRNA levels in the medial amygdala. Concomitant FLX treatment reverted depression-like effects of CRS and led to significant increases in levels of NPY and galanin mRNA in the dentate gyrus, amygdala, and piriform cortex. These findings suggest that effects on NPY and galanin gene expression could play a role in the antidepressant effects of FLX., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Partially hydrolyzed guar gum (PHGG) is a water-soluble fiber if added to oral rehydration solution (ORS) and undergoes fermentation in the colon liberating short chain fatty acids (SCFAs). SCFAs potentiate the effect of ORS, reducing the severity of diarrhea., Aim: To examine the effect of PHGG-added ORS in reducing the stool output and duration of diarrhea in adult cholera., Methods: 195 male patients were studied in a randomized controlled trial: (a) 65 received ORS + 25 g PHGG; (b) 65 received ORS + 50 g PHGG, and (c) 65 received ORS alone (control). Major outcomes were stool weight and duration of diarrhea., Results: No significant differences were found in mean +/- SD stool weight (g/kg b.w.) during the first and second 24 h. In the subgroup analysis (excluding very high purging patients, stool weight in the first 24 h was >10 kg), the stool weight (g/kg b.w.) was significantly reduced in the first 24 h in both groups receiving PHGG (PHGG 25 g, 136 +/- 68 vs. PHGG 50 g, 144 +/- 49 vs. control, 176 +/- 43, p = 0.01)., Conclusion: PHGG-added ORS might have a beneficial effect in moderately purging adult cholera. However, further studies are warranted to confirm the preliminary findings., (2008 S. Karger AG, Basel.)

Although electroconvulsive seizures (ECS) are widely used as a treatment for severe depression, the working mechanism of ECS remains unclear. Repeated ECS causes anticonvulsant effects that have been proposed to underlie the therapeutic effect of ECS, and neuropeptide Y (NPY) is a potential candidate for mediating this anticonvulsant effect. Repeated ECS results in prominent increases in NPY synthesis. In contrast, NPY-sensitive receptor binding is decreased, so it is unclear whether ECS causes a net increase in NPY signalling. Agonist-stimulated [35S]GTPgammaS binding is a method for detecting functional activation of G-protein-coupled receptors. The present study in mice examined the effects of daily ECS for 14 days on NPY-stimulated [35S]GTPgammaS functional binding and compared this with gene expression of NPY and NPY receptors as well as [125I]peptide YY (PYY) binding in hippocampus of the same animals. Significant increases in NPY mRNA and concomitant reductions in NPY-sensitive binding were found in the dentate gyrus, hippocampal CA1, and neocortex of ECS treated mice, which is consistent with previous rat data. These changes remained significant 1 week after repeated ECS. Significant increases in NPY Y1, Y2, and Y5 mRNA were found in the dentate gyrus after ECS. Surprisingly, unaltered levels of functional NPY receptor binding accompanied the decreased NPY-sensitive binding. This suggests that mechanisms coupling NPY receptor stimulation to G-protein activation could be augmented after repeated ECS. Thus increased synthesis of NPY after repeated ECS should result in a net increase in NPY signalling in spite of reduced levels of NPY-sensitive binding., (Copyright 2006 Wiley-Liss, Inc.)

Microscopic colitis, encompassing collagenous and lymphocytic colitis, is a fairly common cause of chronic watery diarrhoea, especially in elderly women. In recent epidemiological studies the annual incidence of each disorder was 4-6/100.000 inhabitants. The aetiology is unknown. The main clinical symptoms are watery diarrhoea, weight loss and abdominal pain. Laboratory analyses are nondiagnostic, and the diagnoses rely on histopathological examination of colonic mucosal biopsies. There is an association to autoimmune diseases such as thyroid disorders, diabetes mellitus, celiac disease and arthritis. Budesonide is the best-documented treatment of collagenous colitis. It is superior to placebo in short-term therapy, but the long-term efficacy is not well studied. The evidence for other therapeutic alternatives such as loperamide, cholestyramine, bismuth subsalicylate, or 5-aminosalicylates is weak. In unresponsive severe disease azathioprine or methotrexate may be tried. There are at present no controlled data on the treatment of lymphocytic colitis. The long-term prognosis of microscopic colitis is good, serious complications are rare and there is no increased mortality.

Glucagon has a short plasma t(1/2) in vivo, with renal extraction playing a major role in its elimination. Glucagon is degraded by neutral endopeptidase (NEP) 24.11 in vitro, but the physiological relevance of NEP 24.11 in glucagon metabolism is unknown. Therefore, the influence of candoxatril, a selective NEP inhibitor, on plasma levels of endogenous and exogenous glucagon was examined in anesthetized pigs. Candoxatril increased endogenous glucagon concentrations, from 6.3 +/- 2.5 to 20.7 +/- 6.3 pmol/l [COOH-terminal (C)-RIA, P < 0.05]. During glucagon infusion, candoxatril increased the t(1/2) determined by C-RIA (from 3.0 +/- 0.5 to 17.0 +/- 2.5 min, P < 0.005) and midregion (M)-RIA (2.8 +/- 0.5 to 17.0 +/- 3.0 min, P < 0.01) and reduced metabolic clearance rates (MCR; 19.1 +/- 3.2 to 9.4 +/- 2.0 ml.kg(-1).min(-1), P < 0.02, C-RIA; 19.2 +/- 4.8 to 9.0 +/- 2.3 ml.kg(-1).min(-1), P < 0.05, M-RIA). However, neither t(1/2) nor MCR determined by NH2-terminal (N)-RIA were significantly affected (t(1/2), 2.7 +/- 0.4 to 4.5 +/- 1.6 min; MCR, 30.3 +/- 6.4 to 28.5 +/- 9.0 ml.kg(-1).min(-1)), suggesting that candoxatril had no effect on NH2-terminal degradation but leads to the accumulation of NH2-terminally truncated forms of glucagon. Determination of arteriovenous glucagon concentration differences revealed that renal glucagon extraction was reduced (but not eliminated) by candoxatril (from 40.4 +/- 3.8 to 18.6 +/- 4.1%, P < 0.02, C-RIA; 29.2 +/- 3.1 to 14.7 +/- 2.2%, P < 0.02, M-RIA; 26.5 +/- 4.0 to 19.7 +/- 3.5%, P < 0.06, N-RIA). Femoral extraction was reduced by candoxatril when determined by C-RIA (from 22.7 +/- 2.4 to 8.0 +/- 5.1%, P < 0.05) but was not changed significantly when determined using M- or N-RIAs (10.0 +/- 2.8 to 4.7 +/- 3.7%, M-RIA; 10.5 +/- 2.5 to 7.8 +/- 4.2%, N-RIA). This study provides evidence that NEP 24.11 is an important mediator of the degradation of both endogenous and exogenous glucagon in vivo.

Background: Lymphocytic colitis is characterised by chronic diarrhoea and specific microscopic changes in a macroscopically normal colonic mucosa. We report clinical features and treatment outcome in a large patient cohort., Methods: Patients were searched for in 24 Swedish gastroenterology clinics. The biopsy material was reassessed using strict histopathological criteria. Clinical data were obtained from medical notes., Results: Lymphocytic colitis was diagnosed in 199 cases. The female:male ratio was 2.4:1. Median age at diagnosis was 59 (48-70) years. The most frequent symptoms were diarrhoea (96%), abdominal pain (47%), and weight loss (41%). The course was chronic intermittent in 30% of patients, chronic continuous in 7%, and a single attack in 63%, and in these cases the disease duration was 6 (4-11) months. Seventy nine (40%) patients reported associated diseases, of which thyroid disorders, coeliac disease, and diabetes mellitus were the most common. In 34 first or second degree relatives of 24 (12%) patients, a family history of ulcerative colitis, Crohn's disease, collagenous colitis, or coeliac disease was reported. Drug induced disease was suspected in 19 (10%) patients. A non-significant peak of disease onset was seen in December-January. More than 80% of treated patients improved on corticosteroids, including budesonide., Conclusions: A family history of other bowel disorders is a new finding. The sudden onset and single attack of limited duration may support a possible infectious cause in some cases. Drugs may cause lymphocytic colitis.

Glucagon metabolism under basal (endogenous) conditions and during intravenous glucagon infusion was studied in anesthetized pigs by use of midregion (M), COOH-terminal (C), and NH2-terminal (N)-RIAs. Arteriovenous concentration differences revealed a negative extraction of endogenous glucagon immunoreactivity across the portal bed (-35.4 +/- 11.0, -40.3 +/- 9.6, -35.6 +/- 16.9%, M-, C-, N-RIA, respectively), reflecting net secretion of pancreatic glucagon and intestinal glicentin and oxyntomodulin, but under exogenous conditions, a net extraction occurred (11.6 +/- 3.6 and 18.6 +/- 5.7%, C- and N-RIA, respectively). Hindlimb extraction of endogenous (17.4 +/- 3.7%, C-RIA) and exogenous (29.1 +/- 4.8 and 19.8 +/- 5.1%, C- and M-RIA) glucagon was detected, indicating M and C cleavage of the molecule. Renal extraction of glucagon was detected by all assays under endogenous (19.4 +/- 6.7, 33.9 +/- 7.1, 29.5 +/- 6.7%, M-, C-, N-RIA) and exogenous conditions (46.9 +/- 4.8, 46.4 +/- 6.0, 47.0 +/- 7.7%; M-, C-, N-RIA), indicating substantial elimination of the peptide. Hepatic glucagon extraction was undetectable under basal conditions and detected only by M-RIA (10.0 +/- 3.8%) during glucagon infusion, indicating limited midregional cleavage of the molecule. The plasma half-life determined by C- and N-RIAs (2.7 +/- 0.2 and 2.3 +/- 0.2 min) were similar, but both were shorter than when determined by M-RIA (3.2 +/- 0.2 min, P < 0.02). Metabolic clearance rates were similar regardless of assay (14.4 +/- 1.1, 13.6 +/- 1.7, 17.0 +/- 1.7 ml x kg-1 x min-1, M-, C-, N-RIA). Porcine plasma degraded glucagon, but this was not significantly affected by the dipeptidyl peptidase IV (DPP IV) inhibitor valine-pyrrolidide, and in anesthetized pigs, glucagon's metabolic stability was unchanged by DPP IV inhibition. We conclude that tissue-specific metabolism of glucagon occurs, with the kidney being the main site of removal and the liver playing little, if any, role. Furthermore, valine-pyrrolidide has no effect on glucagon stability, suggesting that DPP IV is unimportant in glucagon metabolism in vivo, in contrast to its significant role in the metabolism of the other proglucagon-derived peptides and glucose-dependent insulinotropic polypeptide.

Objective: To study the role of cyclooxygenase (COX) inhibition on the development of advanced atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice., Design: Sixty apoE(-/-) mice were divided into three groups: a control group, a group fed standard mouse chow supplemented with 0.0067% (wt/wt) MF Tricyclic (selective COX-2 inhibitor), and a group fed the diet supplemented with 0.0134% (wt/wt) sulindac (non-selective COX inhibitor). Four months later, the mice were killed and the atherosclerotic plaque area in the aortic root was measured., Results: Mean body weights did not differ at any time. The MF Tricyclic and sulindac groups had drug plasma levels of 1.31 +/- 0.11 and 0.84 +/- 0.23 micro g/ml, respectively. Plasma total cholesterol and triglyceride values were similar in all three groups. A small difference in plasma levels of high-density lipoprotein cholesterol was found between the groups (p = 0.03). Advanced atherosclerotic plaques were present in mice from all three groups, but there was no difference in mean plaque size between the groups (p = 0.9)., Conclusion: Neither selective COX-2 nor non-selective COX inhibition influenced the development of advanced atherosclerosis in apoE(-/-) mice.

Collagenous colitis and lymphocytic colitis are newly described colitides that are only diagnosable microscopically; therefore, both are known under the umbrella term 'microscopic colitis'. This is a short review of the clinical findings, and epidemiological and basic observations of these relatively little described colitides belonging to the group of inflammatory bowel diseases.

Background: Interest in fructooligosaccharides as a health-promoting food component is increasing. Fructooligosaccharides are mainly indigestible and large amounts in the colon may provoke gastrointestinal symptoms., Objective: The symptoms of irritable bowel syndrome (IBS) may be provoked by large quantities of carbohydrates in the colon. The objective of this study was to determine whether regular consumption of fructooligosaccharides worsens gastrointestinal symptoms in patients with IBS., Design: A multicenter, prospective, randomized, double-blind, placebo-controlled parallel group comparison was conducted at 24 sites. The study consisted of a 2-wk, single-blind run-in phase and a 12-wk, double-blind comparative phase. Subjects were randomly assigned to receive 20 g fructooligosaccharides powder/d (n = 52) or a placebo (n = 46). Efficacy was based on the patients' overall response to treatment at completion of the study and on the severity and duration of individual symptoms (abdominal distension, abdominal rumbling, abnormal flatulence, and abdominal pain)., Results: Data from 96 patients (16 men and 80 women) were analyzed. After 4-6 wk of treatment, IBS symptoms improved more in the placebo group than in the fructooligosaccharide group. After completion of the study, there were no significant differences between the 2 groups: symptoms improved in 58% of the fructooligosaccharide group and in 65% of the placebo group and symptoms worsened in 8% of the fructooligosaccharide group and in 13% of the placebo group., Conclusion: Although symptoms worsened in patients with IBS at the onset of treatment with 20 g fructooligosaccharides/d, continuous treatment for 12 wk resulted in no worsening of symptoms.

Low-radiation-dose computed tomography (low-dose CT) is a new, promising technology presently used in screening for lung cancer in some medical centres in the USA and Japan. The three population-based studies of the efficacy of screening with low-dose CT published to date all show that more than 85% of the lung cancers detected by low-dose CT are in stage I, offering improved possibility for curative treatment. The number of false positive scans, was up to 20%. The radiation dose per low-dose CT scan was approximately the dose of a mammography (1 mSv). In two studies, low-dose CT failed to detect some centrally located tumours. None of the studies are capable of evaluating changes in lung cancer mortality in a screened population compared to those of a control population. There is, therefore, a need for further assessments of positive as well as negative effects of population-based screening with low-dose CT.