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Abstract Background To investigate how callers understand the information given by telephone by registered nurses in a casualty clinic, to what degree the advice was followed, and the final outcome of the condition for the patients. Methods The study was conducted at a large out-of-hours inter-municipality casualty clinic in Norway during April and May 2010. Telephone interviews were performed with 100 callers/patients who had received information and advice by a nurse as a sole response. Six topics from the interview guide were compared with the telephone record files to check whether the caller had understood the advice. In addition, questions were asked about how the caller followed the advice provided and the patient's outcome. Results 99 out of 100 interviewed callers stated that they had understood the nurse's advice, but interpreted from the telephone records, the total agreement for all six topics was 82.6%. 93 callers/patients stated that they followed the advice and 11 re-contacted the casualty clinic. 22 contacted their GP for the same complaints the same week, of whom five patients received medical treatment and one was hospitalised. There were significant difference between the native-Norwegian and the non-native Norwegian regarding whether they trusted the nurse (p = 0.017), and if they got relevant answers to their questions (p = 0.005). Conclusion Callers to the out-of-hours service seem to understand the advice given by the registered nurses, and a large majority of the patients did not contact their GP or other health services again with the same complaints. Practice Implication Medical and communicative training must be an important part of the continuous improvement strategy within the out-of-hour services.

Abstract Background In Norway, no valid activity statistics from the primary health care out-of-hours services or the pre-hospital emergency health care system have previously been available. Methods The National Centre for Emergency Primary Health Care has initiated an enterprise called "The Watchtowers" which consists of a representative sample of seven casualty clinics covering 18 Norwegian municipalities. The purpose of the project is to provide routine information over several years, which will enable monitoring, evaluation and comparison of the activities in the out-of-hours services. This paper presents data from 2007, the first full calendar year for the Watchtowers, analyzes some differences in user patterns for the seven casualty clinics involved, and estimates national figures for the use of casualty clinics and out-of-hours services in Norway. Results A total of 85 288 contacts were recorded during 2007 [399 per 1 000 inhabitants] of which 64 846 contacts were considered non-urgent [76.6%]. There were 53 467 consultations by a doctor [250 per 1 000], 8 073 telephone consultations by doctor [38 per 1 000], 2 783 home visits and call-outs by doctor [13 per 1000] and 20 502 contacts managed by nurses on their own [96 per 1000]. The most common mode of contact was by telephone. Women, young children and elderly had the highest rates of contact. Conclusion Norway has a high rate of contacts to the out-of-hours services compared with some other countries with available data. Valid national figures and future research of these services are important both for local services and policy makers.

Abstract Background The municipalities are responsible for the emergency primary health care services in Norway. These services include casualty clinics, primary doctors on-call and local emergency medical communication centres (LEMC). The National centre for emergency primary health care has initiated an enterprise called "The Watchtowers", comprising emergency primary health care districts, to provide routine information (patients' way of contact, level of urgency and first action taken by the out-of-hours services) over several years based on a minimal dataset. This will enable monitoring, evaluation and comparison of the respective activities in the emergency primary health care services. The aim of this study was to assess incidence of emergency contacts (potential life-threatening situations, red responses) to the emergency primary health care service. Methods A representative sample of Norwegian emergency primary health care districts, "The Watchtowers" recorded all contacts and first action taken during the year of 2007. All the variables were continuously registered in a data program by the attending nurses and sent by email to the National Centre for Emergency Primary Health Care at a monthly basis. Results During 2007 the Watchtowers registered 85 288 contacts, of which 1 946 (2.3%) were defined as emergency contacts (red responses), corresponding to a rate of 9 per 1 000 inhabitants per year. 65% of the instances were initiated by patient, next of kin or health personnel by calling local emergency medical communication centres or meeting directly at the casualty clinics. In 48% of the red responses, the first action taken was a call-out of doctor and ambulance. On a national basis we can estimate approximately 42 500 red responses per year in the EPH in Norway. Conclusion The emergency primary health care services constitute an important part of the emergency system in Norway. Patients call the LEMC or meet directly at casualty clinics with medical problems that initially are classified as a potentially life-threatening situation, a red response.

Abstract Background In Norway there is a shortage of valid health activity statistics from the primary care out-of-hours services and the pre-hospital emergency health care system. There is little systematic information available because data registration is lacking or is only recorded periodically, and definitions of variables are not consistent. Method A representative sample of Norwegian municipalities and out-of-hours districts was contracted to establish a sentinel network, "The Watchtowers", and procedures were developed for collecting continuous data from out-of-hours services. All contacts, either per telephone or direct attendance, are recorded during day and night. The variables are registered in a computer program developed by the National Centre for Emergency Primary Health Care, and sent by email in Excel-file format to the Centre on a monthly basis. Results The selection process yielded a group of 18 municipalities, with a fair degree of representativeness for Norwegian municipalities as a whole. The sample has 212,921 inhabitants, which constitutes 4.6% of the total Norwegian population. During a pilot period lasting three months the Watchtowers recorded all individual contacts. The procedures for registration, submitting and checking data worked satisfactorily. There was little data missing, and during the last three months of 2006 a total of 23,346 contacts were registered. Conclusion We have been able to establish a sentinel network with a fair degree of representativeness for Norwegian out-of-hours districts and municipalities. The data collected reflect national activities from casualty clinics in Norway. Such data are useful for both research and system improvements.

The development of new large molecule drug therapies along with the innovation of biologic-device combination products such as prefilled syringes, autoinjectors and pen injectors have significantly impacted the treatment of new diseases and has improved the process of administering parenteral medicines. To support the regulatory approval of a new biologic-device combination products or subsequent chemistry, manufacturing and control changes impacting a combination product, sponsor companies must thoroughly assess the potential impact to product quality, safety and efficacy. In this report, a risk-based process to determine the potential impact to product quality, safety, and efficacy as well as corresponding regulatory actions supporting a chemistry, manufacturing and control change is presented. The risk assessment includes the standardized assessment of a) chemistry, manufacturing and control risk factors, potential responses and appropriately weighted scoring; b) pharmacokinetic risk factors, potential responses and appropriately weighted scoring; and c) the use of a 2-dimensional risk grid to combine the chemistry, manufacturing and control risks and pharmacokinetic risks to provide a regulatory recommendation. Three case studies (two clinical case studies and a post-approval case study) are provided to demonstrate the assessment process and capabilities., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Cyclodextrins (CDs) are important molecular hosts for hydrophobic guests in water and extensively employed in the pharmaceutical, food and cosmetic industries to encapsulate drugs, flavours and aromas. Compared with α- and β-CD, the wide-scale use of γ-CD is currently limited due to costly production processes. We show how the yield of γ-CD in the enzymatic synthesis of CDs can be increased 5-fold by adding a tetra- ortho -isopropoxy-substituted azobenzene template irradiated at 625 nm (to obtain the cis -( Z )-isomer) to direct the synthesis. Following the enzymatic reaction, the template can then be readily recovered from the product mixture for use in subsequent reaction cycles. Heating induces thermal cis -( Z ) to trans -( E ) relaxation and consequent dissociation from γ-CD whereupon the template can then be precipitated by acidification. For this study we designed and synthesised a set of three water-soluble azobenzene templates with different ortho -substituents and characterised their photoswitching behaviour using UV/vis and NMR spectroscopy. The templates were tested in cyclodextrin glucanotransferase-mediated dynamic combinatorial libraries (DCLs) of cyclodextrins while irradiating at different wavelengths to control the cis / trans ratios. To rationalise the behaviour of the DCLs, NMR titrations were carried out to investigate the binding interactions between α-, β- and γ-CD and the cis and trans isomers of each template., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The U.S. Food and Drug Administration and European Commission have developed successful orphan drug legislation to promote the research, development, and marketing approval of drugs to treat rare diseases. Central to these regulations are the concepts of structural similarity and clinical superiority/significant benefit to achieve orphan drug exclusivity. However, differences in health authority expectations remain regarding the qualification for an orphan drug designation, defining structural similarity, and demonstrating clinical superiority/significant benefit. These differences can create sponsor company uncertainty regarding the approvability of products (e.g., blocking risk by an existing orphan product) and divergent orphan drug decisions among health authorities. A comprehensive assessment of current regulations, case studies in exclusivities, and recommendations for improvement are presented., (© 2022. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

This review summarises the present knowledge of acute compartment syndrome, which is a time-critical diagnosis threatening both life and limb of the affected patients. Acute compartment syndrome is a clinical diagnosis, which in equivocal cases can be supported by direct intra-compartmental pressure measurement and laboratory values. Imaging can detect fractures; and non-invasive monitoring is under investigation but has not yet found clinical use. The treatment is a surgical fasciotomy, and this should be performed acutely. If diagnosis is made more than 24-48 hours after onset of symptoms, non-operative treatment should be considered.

Radioactive particles originating from nuclear fuel reprocessing at the United Kingdom Atomic Energy Authority's Dounreay Facility were inadvertently released to the environment in the late 1950s to 1970s and have subsequently been found on site grounds and local beaches. Previous assessments of risk associated with encountering a particle have been based on conservative assumptions related to particle composition and speciation. To reduce uncertainties associated with environmental impact assessments from Dounreay particles, further characterization is relevant. Results of particles available for this study showed variation between Dounreay Fast Reactor (DFR) and Materials Test Reactor (MTR) particles, reflecting differences in fuel design, release scenarios, and subsequent environmental influence. Analyses of DFR particles showed they are small (100-300 μm) and contain spatially correlated U and Nb. Molybdenum, part of the DFR fuel, was identified at atomic concentrations below 1%. Based on SR-based micrometer-scale X-ray Absorption Near Edge Structure spectroscopy (μ-XANES), U may be present as U(IV), and, based on a measured Nb/U atom ratio of ~2, stoichiometric considerations are commensurable with the presence of UNb 2 O 7 . The MTR particles were larger (740-2000 μm) and contained U and Al inhomogeneously distributed. Neodymium (Nd) was identified in atomic concentrations of around 1-2%, suggesting it was part of the fuel design. The presence of U(IV) in MTR particles, as indicated by μ-XANES analysis, may be related to oxidation of particle surfaces, as could be expected due to corrosion of UAl x fuel particles in air. High 235 U/ 238 U atom ratios in individual DFR (3.2 ± 0.8) and MTR (2.6 ± 0.4) particles reflected the presence of highly enriched uranium. The DFR particles featured lower 137 Cs activity levels (2.00-9.58 kBq/particle) than the MTR (43.2-641 kBq 137 Cs/particle) particles. The activities of the dose contributing radionuclides 90 Sr/ 90 Y were proportional to 137 Cs ( 90 Sr/ 137 Cs activity ratio ≈ 0.8) and particle activities were roughly proportional to the size. Based on direct beta measurements, gamma spectrometry, and the VARSKIN6 model, contact dose rates were calculated to be approximately 74 mGy/h for the highest activity MTR particle, in agreement with previously published estimates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Multispecies experiments like microcosms and mesocosms are widely used in many fields of research but not in radioecology. In radioecology, size limitations are important as large experimental volumes involve problems with waste (radionuclides), or shielding, absorption and available space in gamma fields (often within a climate chamber). We have therefore performed a literature review (ISI Web of Science, n = 406) of the design and properties of multispecies effect studies <100 L in size and with three or more mentioned taxa in other research fields to assess their suitability to radioecology. Studies with more mentioned taxa assess structural ecosystem parameters more often than studies with fewer mentioned taxa, while the opposite trend is seen for indirect effects/interactions. Studies of indirect effects benefit from more replicates and longer experiments. Almost all studies assess some ecosystem level parameter but only a quarter take a holistic approach assessing both structural and functional as well as indirect effects. We find that most cosms are custom-made systems, rather than standardised designs. Unmanipulated cosms consist of excised portions of the natural environment with a higher number of mentioned taxa, high ecological complexity and high realism, but have a relatively low replicability. In contrast, standardised cosms with fewer mentioned taxa have less ecological complexity but much higher replicability. This literature review shows that smaller cosm sizes have similar ecological complexity (e.g. number of taxa and trophic levels) and experimental duration as larger sized cosms, allowing for ecologically-relevant investigations, despite their small size. We encourage multispecies radioecology studies, preferably with environmental relevant doses and sufficient detail on dosimetry., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ecosystem response to gamma radiation exposure depends on the different species sensitivities and the multitude of direct and indirect pathways by which individual organisms can be affected, including the potential for complex interactions across multiple trophic levels. In this study, multi-species microcosms were used to investigate effects of ionizing radiation in a model freshwater ecosystem, including endpoints at both structural and functional levels and ecological interactions. Microcosms were exposed for 22 days to a gradient of gamma radiation with four dose rates from 0.72 to 19 mGy h -1 , which are within the range of those seen at contaminated sites. Results showed significant dose related effects on photosynthetic parameters for all macrophyte species. No significant effects of radiation were observed for the consumers in the microcosms, however trends indicate the potential for longer-term effects. We also witnessed a different response of Daphnia magna and Lemna minor compared to previous single-species studies, illustrating the importance of multispecies studies, which aim to encompass systems more realistic to natural ecosystems. Microcosms allowed us to isolate specific relationships between interacting species in an ecosystem and test the effects, both direct and indirect, of radiation on them. In addition, the ecological pathways and processes, and the experimental design itself, was central to understanding the results we witnessed. This type of study is important for radioecology research that has been very much limited to high dose rates and single species studies. This approach to radioecology has been strongly promoted in recent decades and, to our knowledge, this is the first microcosm study performed at dose rates similar to those at contaminated field sites., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The FIGARO low dose 60 Co gamma irradiation facility at the Norwegian University of Life Sciences, Ås, Norway, is dedicated to the study of effects on living organisms from acute or chronic ionizing radiation exposures, either alone or in combination with other stressors such as UV radiation, metals or radionuclides. Here, we present a framework of working guidelines and computer software for characterization of absorbed dose rates and accumulated doses to organisms exposed within the continuous gamma field at FIGARO. The aims of the framework are to ensure gamma exposures are well characterized, that results from exposures are correctly interpreted in terms of absorbed dose rates and accumulated doses, and that sufficient information is available so that exposures can be reproduced later or at other facilities., Methods: The software of the framework includes a Geant4 application for Monte Carlo radiation transport simulations and tools for dose planning, recording and reporting. The working guidelines are prepared for expert users who provide simulated, calculated or estimated absorbed dose rates and for regular users who conduct exposure experiments and are responsible for record keeping. To demonstrate the developed framework, we use a case study where 14 freshwater microcosms are exposed to four levels of gamma dose rates at FIGARO., Conclusion: The framework guides users towards good dosimetry practices. Lessons learned could be transferable to other gamma irradiation facilities.

Pathogenic mutations in the appetite-regulating melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity with limited treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause weight loss by reducing appetite. We assessed the effect of the GLP-1 RA liraglutide 3.0 mg for 16 weeks in 14 obese individuals with pathogenic MC4R mutations (BMI 37.5 ± 6.8) and 28 matched control participants without MC4R mutation (BMI 36.8 ± 4.8). Liraglutide decreased body weight by 6.8 kg ± 1.8 kg in individuals with pathogenic MC4R mutations and by 6.1 kg ± 1.2 kg in control participants. Total body fat, waist circumference, and fasting and postprandial glucose concentrations similarly decreased in both groups. Thus, liraglutide induced an equal, clinically significant weight loss of 6% in both groups, indicating that the appetite-reducing effect of liraglutide is preserved in MC4R causal obesity and that liraglutide acts independently of the MC4R pathway. Thus, liraglutide could be an effective treatment of the most common form of monogenic obesity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the Barents Sea region new petroleum fields are discovered yearly and extraction of petroleum products is expected to increase in the upcoming years. Despite enhanced technology and stricter governmental legislation, establishment of the petroleum industry in the Barents Sea may potentially introduce a new source of contamination to the area, as some discharges of produced water will be allowed. Whether the presence of produced water poses a risk to the Arctic marine life remains to be investigated. The aim of this study was to examine effects of exposure to several compounds found in produced water-a mixture of selected organic compounds (APW), radium-226 ((226)Ra), barium (Ba), and a scale inhibitor-on the copepod species Calanus finmarchicus. Experiments were performed using exposure concentrations at realistic levels based on those detected in the vicinity of known discharge points. The influence of lethal and sublethal effects on early life stages was determined and significantly lower survival in the APW exposure groups was found. In the Ba treatment the life stage development did not proceed to the same advanced stages as observed in the control (filtered sea water). The scale inhibitor and (226)Ra treatments showed no significant difference from control. In addition, adult females were exposed to APW, (226)Ra, and a mixture of the two. Both individual-level effects (egg production and feeding) and molecular-level effects (gene expression) were assessed. On the individual level endpoints, only treatments including APW produced an effect compared to control. However, on the molecular level the possibility that also (226)Ra induced toxicologically relevant effects cannot be ruled out.

Three experiments were conducted to determine the effects of feeder adjustment and diet form on growth performance of nursery (Exp. 1 and 2) and finishing (Exp. 3) pigs. Treatments were arranged as a 2 × 3 factorial with the main effects of feeder adjustment and diet form. The 2 feeder adjustments were a narrow and wide feeder adjustment (minimum gap opening of 1.27 and 2.54 cm, respectively). The 3 diet forms were meal, poor-quality pellets (70% pellets and 30% fines for Exp. 1 and 2 and 50% pellets and 50% fines for Exp. 3), and screened pellets with minimal fines (3 to 10%). In Exp. 1, 210 pigs (initially 11.9 kg BW) were used in a 21-d trial with 7 pigs per pen and 5 pens per treatment. No feeder adjustment × diet form interactions were observed. There were no differences in ADG, ADFI, or G:F due to feeder adjustment. Pigs fed the meal diet had increased ( < 0.05) ADG and ADFI compared with pigs fed the poor-quality or screened pellets. Pigs fed meal or poor-quality pellets had decreased ( < 0.05) G:F compared with pigs fed screened pellets. In Exp. 2, 1,005 nursery pigs (initially 14.1 kg BW) were used in a 28-d trial with 26 to 28 pigs per pen and 6 pens per treatment. Pigs fed from the narrow feeder adjustment had decreased ( < 0.05) ADG and ADFI compared with pigs fed from the wide adjustment with no differences in G:F. Pigs fed the meal diet had decreased ( < 0.05) ADG compared with pigs fed poor-quality or screened pellets. Pigs fed meal or poor-quality pellets had decreased ( < 0.05) G:F compared with pigs fed screened pellets. In Exp. 3, 246 pigs (initially 56.8 kg BW) were used in a 69-d trial with 5 pens per treatment and 6 or 7 pigs per pen. Overall, ADFI decreased ( < 0.05) and G:F increased ( < 0.05) for pigs fed from the narrow adjusted feeders compared with the wide adjustment with no differences in ADG. Overall, pigs fed meal diets tended to have decreased ( < 0.10) ADG and had decreased ( < 0.05) G:F compared with pigs fed screened pellets; ADG and G:F in those fed poor-quality pellets were intermediate. Feeding meal or poor-quality pellets increased ( < 0.05) ADFI compared with pigs fed screened pellets. In conclusion, feeding nursery pigs from a wide feeder gap may increase ADG and ADFI with no negative effects on G:F. For finishing pigs, reducing feeder gap reduced feed disappearance and improved G:F. In all experiments, the greatest G:F improvements from pelleting were observed when the percentage of fines was minimized.

Background: Electroporation, a method for increasing the permeability of membranes to ions and small molecules, is used in the clinic with chemotherapeutic drugs for cancer treatment (electrochemotherapy). Electroporation with calcium causes ATP (adenosine triphosphate) depletion and cancer cell death and could be a novel cancer treatment. This study aims at understanding the relationship between applied electric field, calcium concentration, ATP depletion and efficacy., Methods: In three human cell lines--H69 (small-cell lung cancer), SW780 (bladder cancer), and U937 (leukaemia), viability was determined after treatment with 1, 3, or 5 mM calcium and eight 99 μs pulses with 0.8, 1.0, 1.2, 1.4 or 1.6 kV/cm. Fitting analysis was applied to quantify the cell-killing efficacy in presence of calcium. Post-treatment intracellular ATP was measured in H69 and SW780 cells. Post-treatment intracellular ATP was observed with fluorescence confocal microscopy of quinacrine-labelled U937 cells., Results: Both H69 and SW780 cells showed dose-dependent (calcium concentration and electric field) decrease in intracellular ATP (p<0.05) and reduced viability. The 50% effective cell kill was found at 3.71 kV/cm (H69) and 3.28 kV/cm (SW780), reduced to 1.40 and 1.15 kV/cm (respectively) with 1 mM calcium (lower EC50 for higher calcium concentrations). Quinacrine fluorescence intensity of calcium-electroporated U937 cells was one third lower than in controls (p<0.0001)., Conclusions: Calcium electroporation dose-dependently reduced cell survival and intracellular ATP. Increasing extracellular calcium allows the use of a lower electric field., General Significance: This study supports the use of calcium electroporation for treatment of cancer and possibly lowering the applied electric field in future trials.

Four experiments were conducted to investigate the effects of deoxynivalenol (DON) from naturally contaminated dried distillers grains with solubles (DDGS) and the efficacy of feed additives in nursery pig diets. In Exp. 1, 180 pigs (10.3 ± 0.2 kg BW) were fed 1 of 5 diets for 21 d. Diets were 1) Positive Control (PC; < 0.5 mg/kg DON), 2) Negative Control (NC; 4 mg/kg DON), 3) NC + 0.10% Biofix (Biomin Inc., Herzogenburg, Austria), 4) NC + 0.15% Cel-can (VAST Inc., Mason City, IA) and 0.50% bentonite clay, and 5) NC + 0.25% Defusion Plus (Cargill Animal Nutrition, Minneapolis, MN). Pigs fed the NC diet had poorer ( < 0.01) ADG than those fed the PC. Pigs fed Defusion Plus had improved ( < 0.03) ADG over those fed NC, whereas pigs fed Biofix or Cel-can with bentonite clay had reduced ADG ( < 0.01) compared with those fed PC. In Exp. 2, 340 pigs (11.7 ± 0.1 kg BW) were fed 1 of 8 diets for 21 d. Diets were 1) PC (< 0.5 mg/kg DON), 2) Low NC (1.5 mg/kg DON), 3) Low NC + 0.15% Biofix, 4) Low NC + 0.30% Biofix, 5) High NC (3.0 mg/kg DON), 6) High NC + 0.30% Biofix, 7) High NC + 0.45% Biofix, and 8) Diet 7 with 5% added water. Increasing the DON level reduced (linear; < 0.05) ADG, ADFI, and pig BW, and Biofix did not improve performance. In Exp. 3, 1,008 pigs (12.5 ± 0.3 kg BW) were fed 6 treatments for 24 d. Diets were 1) PC ( < 0.5 mg/kg DON), 2) NC (3 mg/kg DON), 3) NC + 0.25% Defusion, 4) NC + 0.50% Defusion, 5) Diet 3 with supplemental nutrients, and 6) Diet 5, pelleted. Pigs fed the NC had decreased ( < 0.01) ADG and ADFI, but adding Defusion improved (linear; < 0.04) ADG and ADFI over pigs fed NC. Pelleting improved ( < 0.01) both ADG and G:F, resulting in ADG above PC pigs. In Exp. 4, 980 pigs (12.0 ± 0.3 kg BW) were fed 1 of 7 diets in a 28-d trial in a 2 × 3 + 1 factorial arrangement. The 7 treatments were based on 3 diets fed in meal or pellet form: 1) PC (< 0.5 mg/kg DON), 2) NC (3 mg/kg DON), and 3) NC + 0.25% Defusion. Treatment 7 was Diet 3 with supplemental nutrients in pellet form. No interactions were observed between pelleting and Defusion. Pigs fed the NC had decreased ( < 0.01) ADG and ADFI, and pelleting improved ( < 0.01) ADG to PC levels, driven by improved ( < 0.01) G:F. Adding nutrients or Defusion had no effect. Overall, these studies show that Defusion and pelleting can help overcome some of the negative effects of DON, whereas other feed additives and additional nutrients do not.

Four experiments were conducted to investigate the effects of varying concentrations of supplemental vitamin D3 on pig growth, feed preference, serum 25-hydroxycholecalciferol [25(OH)D3] , and bone mineralization of nursing and weanling pigs. In Exp. 1, 270 pigs (1.71 ± 0.01 kg BW) were administered 1 of 3 oral vitamin D3 dosages (none, 40,000, or 80,000 IU vitamin D3) on d 1 or 2 of age. Increasing oral vitamin D3 increased serum 25(OH)D3 on d 10 and 20 (quadratic, P < 0.01) and d 30 (linear, P < 0.01). No differences were observed in ADG before weaning or for nursery ADG, ADFI, or G:F. Vitamin D3 concentration had no effect on bone ash concentration or bone histological traits evaluated on d 19 or 35. In Exp. 2, 398 barrows (initially 7 d of age) were used in a 2 × 2 split plot design to determine the influence of vitamin D3 before (none or 40,000 IU vitamin D3 in an oral dose) or after weaning (1,378 or 13,780 IU vitamin D3/kg in nursery diets from d 21 to 31 of age) in a 45-d trial. Before weaning (7 to 21 d of age), oral vitamin D3 dose did not influence growth but increased (P < 0.01) serum 25(OH)D3 at weaning (d 21) and tended (P = 0.08) to increase 25(OH)D3 on d 31. Increasing dietary vitamin D3 concentration from d 21 to 31 increased (P < 0.01) serum 25(OH)D3 on d 31. Neither the oral vitamin D3 dose nor nursery vitamin D3 supplements influenced nursery ADG, ADFI, or G:F. In Exp. 3, 864 pigs (initially 21 d of age) were allotted to 1 of 2 water solubilized vitamin D3 treatments (none or 16,516 IU/L vitamin D3 provided in the drinking water from d 0 to 10) in a 30-d study. Providing vitamin D3 increased serum 25(OH)D3 concentrations on d 10, 20, and 30; however, vitamin D3 supplementation did not affect overall (d 0 to 30) ADG, ADFI, or G:F. In Exp. 4, 72 pigs were used in a feed preference study consisting of 2 feed preference comparisons. Pigs did not differentiate diets containing either 1,378 or 13,780 IU vitamin D3/kg but consumed less (P < 0.01) of a diet containing 44,100 IU vitamin D3/kg compared with the diet containing 1,378 IU vitamin D3/kg. Overall, these studies demonstrate that supplementing vitamin D3 above basal concentrations used in these studies is effective at increasing circulating 25(OH)D3, but the supplement did not influence growth or bone mineralization. Also, concentrations of vitamin D3 of 44,100 IU/kg of the diet may negatively affect feed preference of nursery pigs.

Purpose: We evaluated the long-term outcome of bladder autoaugmentation in children with neurogenic bladder dysfunction., Materials and Methods: Data were compiled from the records of 25 children with a median age of 9.3 years (range 0.9 to 14.2) who underwent detrusor myotomy between 1992 and 2008. All patients were diagnosed with small bladder capacity, low compliance and high end filling pressures, and were unresponsive to clean intermittent catheterization and anticholinergics., Results: Median followup was 6.8 years (range 0.1 to 15.6). Median postoperative bladder capacity was unchanged or decreased to 95 ml (range 25 to 274) during the first 3 months compared to a median preoperative capacity of 103 ml (14 to 250). At 5 months postoperatively median bladder capacity increased significantly to 176 ml (range 70 to 420, p<0.01). This increase remained significant during the rest of followup. Median bladder compliance doubled after 1 year to 10 ml/cm H2O (range 1 to 31, p<0.05) compared to the preoperative level, and further increased to 17 ml/cm H2O (5 to 55) at 5 years (p<0.05). Median maximal detrusor pressure was 43 cm H2O (range 8 to 140) preoperatively. This value decreased significantly postoperatively (p<0.01) and at final followup it was 26 cm H2O (range 6 to 97). Kidney function developed normally in all patients except 1 with persistent uremia. Reflux was alleviated in 7 of 9 cases. Of the patients 18 became continent on clean intermittent catheterization., Conclusions: Bladder autoaugmentation in children with neurogenic bladder dysfunction offers, after a transient decrease in bladder capacity, a long lasting increase in capacity and compliance, while the end filling pressure decreases., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

The cDNA for a novel truncated progesterone receptor (PR-M) was previously cloned from human adipose and aortic cDNA libraries. The predicted protein sequence contains 16 unique N-terminal amino acids, encoded by a sequence in the distal third intron of the progesterone receptor PR gene, followed by the same amino acid sequence encoded by exons 4 through 8 of the nuclear PR. Thus, PR-M lacks the N terminus A/B domains and the C domain for DNA binding, whereas containing the hinge and hormone-binding domains. In this report, we have localized PR-M to mitochondria using immunofluorescent localization of a PR-M-green fluorescent protein (GFP) fusion protein and in Western blot analyses of purified human heart mitochondrial protein. Removal of the putative N-terminal mitochondrial localization signal obviated association of PR-M with mitochondria, whereas addition of the mitochondrial localization signal to green fluorescent protein resulted in mitochondrial localization. Immunoelectron microscopy and Western blot analysis after mitochondrial fractionation identified PR-M in the outer mitochondrial membrane. Antibody specificity was shown by mass spectrometry identification of a PR peptide in a mitochondrial membrane protein isolation. Cell models of overexpression and gene silencing of PR-M demonstrated a progestin-induced increase in mitochondrial membrane potential and an increase in oxygen consumption consistent with an increase in cellular respiration. This is the first example of a truncated steroid receptor, lacking a DNA-binding domain that localizes to the mitochondrion and initiates direct non-nuclear progesterone action. We hypothesize that progesterone may directly affect cellular energy production to meet the increased metabolic demands of pregnancy.

Objective: To measure the psychological distress associated with a split-thickness skin graft (STSG)., Method: A retrospective postal questionnaire survey of 102 patients who had undergone a STSG procedure within the last 3.5 years. Outcomes measures included the Hospital Anxiety and Depression Scale (HADS), Derriford Appearance Scale (DAS-59) and subjective rating scales (SRS) of noticeability and worry about the grafted and donor area., Resutls: Scores on the SRS correlated positively with HADS and DAS-59 scores. Rates of anxiety were higher than depression (19% vs 13%, respectively). Greater than 10% of the sample experienced significant appearance-related distress when compared to standardised test norms. Concerns about the grafted area were higher than for the donor site, but those concerned about the graft were also likely to be concerned about the donor area. Aged (< 60 years) and reason for surgery (trauma as opposed to cancer) were associated with significantly higher scores on appearance measures., Conclusion: STSG is not associated with high levels of psychological distress, However, there is a small but significant monitory who experience appearance-related distress, low mood and anxiety who would benefit from targeted psychological intervention, Demographic factors, such as age or gender, and length of time since surgery, are not useful discriminators in identifying vulnerable individuals. Simple SRS of visibility and worry correlate significantly with standardised psychological measures. These can be used as a short and effective screening tool to identify individuals who would benefit from postoperative psychological input. DECLARATION OF INTERNET: There were no external sources sources of funding for this study. The authors have no conflicts of interest to declare.

We show experimentally that gaseous CO(2) intercalates into the interlayer space of the synthetic smectite clay Na-fluorohectorite at conditions not too far from ambient. The mean interlayer repetition distance of the clay when CO(2) is intercalated is found to be 12.5 Å for the conditions -20 °C and 15 bar. The magnitude of the expansion of the interlayer upon intercalation is indistinguishable from that observed in the dehydrated-monohydrated transition for H(2)O, but the possibility of water intercalation is ruled out by a careful analysis of the experimental conditions and repeating the measurements exposing the clay to nitrogen gas. The dynamics of the process is observed to be dependent on the pressure, with a higher intercalation rate at increased pressure. The rate of CO(2) intercalation at the studied conditions is found to be several orders of magnitude slower than the intercalation rate of water or humidity at ambient pressure and temperature.

Low priority treatment guidance is used in the National Health Service to manage requests for cosmetic surgery where there is no associated functional impairment. Provision is made in this guidance to provide surgery on exceptional grounds, and this may include significant psychological distress. However, without a good understanding of the common factors that underpin requests for surgery, ideally in the local population, it is very difficult to define an exception in a clear and consistent way. A prospective study of consecutive referrals for cosmetic surgery in an NHS plastic surgery unit was therefore completed over a five-year period. Five hundred and one men and women aged between 16 and 79 (mean 34.5 years) were assessed using standardised questionnaires and clinical interview carried out by two clinical psychologists specialising in the field. Results indicated very marked impact of appearance-related anxiety with significant withdrawal from social activities particularly intimate behaviour. Coping behaviours ranged from use of concealing clothing and complete social avoidance to ominous high risk strategies such as repeated pregnancy with late termination to maintain breast size. Treatment goals were predominantly psychosocial. High levels of psychological morbidity can be characterised as typical of people requesting cosmetic procedures in the NHS rather than exceptional, making the achievement of equitable access to limited resources impossible. Rather than define this population as 'low-priority', a constructive approach is to examine the utility of psychological interventions in a design which evaluates the comparative benefits of surgical and psychological approaches to management of appearance anxiety.

Clays are of paramount importance for soil stability, but also in applications ranging from oil recovery to composites and hydrogels. Generically, clays are divided into two subclasses: macroscopically swelling, 'active' clays that have the capacity for taking up large amounts of water to form stable gels, and 'passive' or non-swelling clays; the former stabilize soils whereas the latter are known to lead to landslides. However, it has been unclear so far what mechanisms underlie clay swelling. Here, we report the first observation of a temperature-induced transition from a passive to an active, swelling clay. We propose a simple description of the swelling transition; while net attractive interactions are dominant at low temperatures so that the clay particles remain attached to each other in stacks, at higher temperatures it is energetically favourable for the clay to swell due to the entropy that is gained by counterions which are liberated during swelling.

Extracellular ATP activates purinergic (P(2)) receptors with an increase in intracellular calcium and phosphorylation of MAPK. In this study we have investigated the effect of progesterone/progestin on ATP-induced calcium mobilization and phosphorylation of the kinase ERK in the T47D-Y breast cancer cell line that exhibits no detectable nuclear progesterone receptor expression. Brief pretreatment with progesterone/progestin results in a dose dependent inhibition of ATP-induced intracellular calcium mobilization, and inhibition of ERK phosphorylation. Response to a cell impermeable ligand and inhibition of the response by an inactivating antibody suggests a mechanism of action at the plasma membrane. These results in T47D-Y cells strongly suggest that progesterone can act in a rapid non-nuclear manner to inhibit extracellular ATP effects on intracellular calcium mobilization and ERK activation. This research provides an example of progesterone action in a breast cancer cell line lacking expression of the classical nuclear progesterone receptors., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

We have studied stable strata of gravity-induced phase separation in suspensions of synthetic Na-fluorohectorite clay in saline solutions. We have observed how the strata depend on clay concentration as well as on salt content. The mass distribution and density variation at the isotropic-nematic interface indicate that existing models and assumptions in existing simulations are able to relatively well account for the observed behavior. We suggest that discrepancies could be due to the high polydispersity and the irregular shape of our Na-fluorohectorite particles, as well as diffusive double-layer effects, which could result in a competition between nematic ordering and gelation. The dependence on ionic strength displays three main regimes irrespective of clay concentration. At low ionic strength (approximately 0.1-5 mM NaCl), the Debye screening length is longer than the van der Waals force range. In this regime, the particles repel each other electrostatically and entropy-driven Onsager-type nematic ordering may occur, although gelation effects could also play a role. For ionic strengths above about 5 mM, we believe that the van der Waals force comes into play and that particles attract each other locally according to the classical Derjaguin, Landau, Verwey, and Overbeek (DLVO) model of colloid interactions, resulting in a small-domain regime of attractive nematiclike ordering. In the third regime, for ionic strengths above approximately 10 mM, the clay particles aggregate into larger assemblies, due to the dominant van der Waals force, and the observed birefringency is reduced. We have studied the nematic phase in detail between crossed polarizers and have found textures showing nematic Schlieren patterns. By rotating the polarizers as well as the samples, we have observed examples of disclinations of strengths -1, -1/2, and +1.

Colloidal suspensions of Na-fluorohectorite synthetic clay platelets in saline water exhibit coexisting isotropic and nematic phases, due to gravitational separation of the polydisperse particles. We study the ordering of the platelets at the interfaces between various coexisting phases. Four different experimental techniques are employed: visual observation of birefringence, synchrotron wide angle and small-angle X-ray scattering, and magnetic resonance imaging. We find that at the narrow isotropic sol-nematic sol interface the platelets are lying horizontally, i.e. with their mean platelet normal along the vertical direction. The experiments indicate that the platelets align homeotropically both at the isotropic sol-nematic sol interface and at the nematic sol-wall interface. We further investigate the complex alignment effect of a horizontally applied magnetic field in the nematic sol, and we compare it with the adjacent nematic gel.

Background: Genotyping of human cytochrome P450s is a pharmacogenetic approach to diagnosing inherited deficiencies in drug metabolizing enzymes that influence therapeutic responses. The P450 CYP2D6 (debrisoquine hydroxylase) metabolizes numerous antidepressants and neuroleptic agents and there is evidence of a relationship between gene polymorphism and variant therapeutic response. Polymorphism in CYP2D6 causes poor, intermediate, efficient or ultrarapid metabolization of substrate drugs affecting pharmacokinetic parameters and requiring dose adjustments. Predictive genotyping for broader clinical application is reliant on fast, technically simple analyses. A new genotyping method was explored. It identifies the single nucleotide polymorphism (SNP) 4469 C>T (NCBI access no. M33388) with one fluorescent hybridization probe (SimpleProbes; SP) using the LightCycler (LC). This SNP is found in 21 alleles, comprising 30% in Caucasian populations and encoding enzymes with poor, intermediate or efficient activity. The remaining 65 known alleles either harbour a C in position 4469 or are deletion mutants., Methods: Comparative detection of C>T polymorphism was done using a well-established polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique and PCR followed by melting-point (T(m)) analysis with an SP covering the SNP position in 144 samples encompassing alleles *2 and *41 with a T, alleles *1,*3, *4, *6, *9, *10, *15 with a C and the deletion mutant allele *5., Results: C>T polymorphism was detected with complete concordance. T(m) of SP/target heteroduplex complexes for C was: T(m) 67, 89 degrees C to 68, 62 degrees C and for T: T(m) 60, 70 degrees C to 61, 51 degrees C., Conclusion: By one-step SP methodology it proved possible within 2 h to identify an SNP in genotypes comprising >90% in Caucasian populations.

Background: Antipsychotic drug therapy meets difficulties in predicting response in psychiatric patients. The medical treatment of these patients may be improved significantly by systematic phamacogenetic diagnosis identifying the drug metabolic capacities of each patient. Genetic polymorphisms in the coding sequence for the drug metabolizing cytochrome P450 enzyme CYP2D6 represent a pharmacogenetic target., Methods: A cohort (n = 225) representing psychiatric patients seen during an 18-month trial period was included in the project after the subjects accepted a blood sample being taken to analyse their CYP2D6 allelic composition. To investigate any putative difference in allele frequencies among the psychiatric patients compared to earlier publications on allele frequencies in Caucasian populations, another cohort (n = 122) of local healthy volunteers was likewise included., Results: Allelic frequencies in the psychiatric patients and healthy volunteers were indistinguishable. Alleles *1 and *2 encoding for normal enzyme activity and alleles *3, *4, *5, *6, *13/*16 representing non-active forms were found as well as alleles *9, *10, *41 encoding for enzymes with decreased activity. Furthermore, examples of the previously described duplications of *1 and *2, which result in enhanced enzyme activity, were also identified., Conclusion: A systematic CYP2D6 gene test of hospitalized psychiatric patients revealed the identification of pharmacogenetically relevant alleles affecting capacity to metabolize antipsychotics. The frequencies of phenotypes in affected patients were 8.4 % intermediate metabolizers (IMs), 8.4 % poor metabolizers (PMs) and 3.1 % ultrafast metabolizers (UMs), whereas 52.4 % were extensive metabolizers (EMs) and 27.6 % heterozygous EMs.

Objective: To identify a novel nongenomic progesterone receptor (PR), PR-M, in T47D-Y breast cancer cells lacking genomic PR expression., Methods: Immunofluorescent staining of T47D and T47D-Y breast cancer cells with selective anti-PR antibodies and ligand binding. Transient transfection of breast cancer cells with a cDNA expressing PR-M with a carboxy terminal green fluorescent protein., Results: In the T47D-Y cell line, lacking expression of genomic PR, plasma membrane-bound and intracellular PR(s) are identified with anti-PR antibodies directed to the hormone-binding domain but not with an antibody directed to the amino terminus. A plasma membrane PR is also evident by immunofluorescent ligand binding. Expression of a novel truncated PR (PR-M) tagged with green fluorescent protein showed intracellular localization., Conclusions: These studies support the expression of a novel, truncated PR (PR-M) in a breast cancer cell line known to lack expression of genomic PR. This observation raises the possibility of progesterone action in breast cancer cells classically considered nonresponsive due to lack of genomic PR expression.

Observational studies demonstrate that estradiol and progesterone affect vasoreactivity. In animal studies, progesterone treatment causes immediate relaxation of precontracted arteries with inhibition of calcium influx in vascular endothelial and smooth muscle cells, suggesting a non-genomic mechanism of action. In this study we investigated the presence of novel membrane-bound progesterone receptors in human aortic endothelial cells and correlated the expression with cell-cycle stage. Western blotting analysis with an antibody directed to the hormone-binding domain of the classic progesterone receptors shows predominant bands at 100 and 60 kD, whereas analysis with an antibody to the DNA-binding region shows only the 100-kD band. In contrast, classic nuclear progesterone receptors B and A are identified at 116 and 94 kD in similarly processed T47D cells. Both novel bands localize to the membrane fraction after differential centrifugation. Plasma membrane-bound progesterone receptor was further shown with immunofluorescent antibody and ligand-binding studies in a small percentage of human aortic endothelial cells. Fluorescent activated cell sorting demonstrated that approximately 8% of the human aortic endothelial cells expressed a plasma membrane progesterone receptor and that a greater percentage of the expressing cells were in the G2/M-phase of the cell cycle. Treatment with progesterone conjugated to BSA did not show any significant cell-cycle changes. Plasma membrane-bound progesterone receptor in vascular endothelial cells may regulate the non-genomic actions of progesterone, and expression of the receptor appears to vary with cell cycle stage.

Although it is known that the use of oral contraceptives (OC's) can induce glucuronide conjugating enzymes, currently no data exists as to the potential that the elimination of the glucuronidated drug lamotrigine (LTG) is increased by OC's. We present seven cases in whom the plasma levels of LTG were significantly decreased by OC's (mean 49%, range 41-64%). The interaction was of clinical relevance in most of the patients who either experienced increased seizure frequency/recurrence of seizures after OC's had been added, or adverse effects following withdrawal of OC's.

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.

Objective: To investigate whether red cell folate (RCF) levels relate to side effects, withdrawals, or disease activity during treatment with the folic acid antagonist methotrexate (MTX) for rheumatoid arthritis (RA)., Methods: Side effects were recorded monthly, RCF levels were measured by lactoglobulin binding radioassays, and 8 variables for disease activity were measured in a placebo controlled double blind trial of 28 weeks' duration comparing efficacy of MTX (n = 23) and D-penicillamine (n = 23)., Results: From Week 20 RCF levels decreased only in the MTX group (p < 0.02), and 5 MTX treated patients withdrew due to side effects. Withdrawals had lower RCF values at Weeks 0 and 9 compared to the remaining patients (p < 0.05). Folate deficiency evolved in 5 patients; 2 of these developed cytopenia. Aberrations in the scheduled dosage increase were related to lower pretreatment values of RCF (p = 0.007). Side effect scores were inversely correlated to RCF values at Weeks 0, 9, and 28 (p < 0.05). RCF levels measured concomitantly with liver enzyme elevation were lower than the remaining values (p < 0.001). When side effects were reported, 96% of concomitantly measured RCF values were below 800 nmol/l. RCF values at entry did not correlate to improvement in any variable for disease activity, or a graded overall improvement., Conclusion: RCF levels decrease during MTX treatment and relate to side effects, withdrawals, liver enzyme elevations and aberrant MTX dosage increase, but not to the therapeutic effect. RCF above 800 nmol/l protects against side effects.

This study deals with the nutritional status of Danish RA patients and address the question of whether or not RA can be directly influenced by dietary manipulation. In a prospective, single-blinded study of 6 months duration, 109 patients with active RA were randomly assigned to either treatment with or without a specialized diet. The energy consumption was adjusted to normal standards of body weights and the intake of fish meals and antioxidants were increased. A daily food diary was completed by the patients, and the total intake of 47 different food-elements was calculated. Nutritional status together with disease activity parameters were recorded. At baseline, the Danish RA-patients had neglected food habits with a significant reduction in intake of total energy, of D-vitamin and of E-vitamin. A very low intake of n-3 fatty acids was also found. During the study, 28 of the 109 patients dropped out, introducing a confounding effect on the overall result. In the remaining 81, those following the diet demonstrated a significant improvement in the duration of morning stiffness, number of swollen joints, pain status, and reduced cost of medicine, while doctors global assessment, laboratory data, X-ray, and daily activities were unaltered. In conclusion, dietary analysis and appropriate, corrective advice should be offered to Danish RA patients.

A simple reversed-phase HPLC method with ultraviolet detection for the simultaneous measurement of lofepramine and desipramine is described. Only a single alkaline extraction was used, with clomipramine as internal standard. The column used was a Supelco PCN column, and the mobile phase was acetonitrile-methanol-0.015 M phosphate buffer (120:35:100, v/v). The average recoveries were 78.8% for desipramine and 103.8% for lofepramine, and limits of quantitation were 25 and 5 nmol/l, respectively. The inter-assay C.V.s for lofepramine and desipramine were 6.0 and 7.6%, respectively. The method is specific and has excellent accuracy, and has been used for therapeutic drug monitoring of patients with depressions treated with lofepramine. Mean steady-state plasma concentrations found for lofepramine and desipramine were 8.5 +/- 6.1 and 123.6 +/- 120.6 nmol/l, respectively. It is concluded that lofepramine in itself has an antidepressive effect.

Three patients with paralytic poliomyelitis have been ventilated via tracheostomy with uncuffed silver cannula for 21 years, with high tidal volumes of atmospheric air (8.3, 7.2, and 5.4 ml/kg b.wt.), at a frequency of 20, passive expiration, and without periodic hyperinflation. No pulmonary complications were seen during the whole of this period. The total compliance was significantly decreased. The pulmonary physiological shunt relative to the total pulmonary blood flow (Qs/Qt) was slightly increased. PaO2 was nevertheless normal, probably due to a high alveolar PO2 caused by the hyperventilation. The physiological dead space realtive to the tidal volume (VD/VT) was within the noraml range, but VD was high in one case. Two of the patients disclosed an extremely low CO2 production and a PaCO2 averaging 12 mmHg, with small fluctuations during a 24-hour study. This profound respiratory alkalosis was only partly compensated in the arterial blood (pH: 7.54 and 7.50), suggesting a new state of acid-base equilibrium. The cerebrospinal fluid lactate was significantly increased to about 4 mmol/l, but the patients revealed no signs of impaired cerebral function. A reduction of the degree of hypocapnia by the use of a mechanical dead space is recommended.