Efficacy and safety of the Betamethasone valerate 0.1% plaster in mild-to-moderate chronic plaque psoriasis: a randomized, parallel-group, active-controlled, phase III study

Corticosteroids are a versatile option for the treatment of mild-to-moderate psoriasis due to their availability in a wide range of potencies and formulations. Occlusion of the corticosteroid is a widely accepted procedure to enhance the penetration of the medication, thereby improving its effectiveness. Betamethasone valerate (BMV) is a moderately potent corticosteroid that is available as a cream, ointment, and lotion. A ready-to-use occlusive dressing, which provides a continuous sustained release of BMV, has been developed for the treatment of psoriasis.

A new method to measure higher visual functions in an immersive environment

BACKGROUND: Higher visual functions can be defined as cognitive processes responsible for object recognition, color and shape perception, and motion detection. People with impaired higher visual functions after unilateral brain lesion are often tested with paper pencil tests, but such tests do not assess the degree of interaction between the healthy brain hemisphere and the impaired one. Hence, visual functions are not tested separately in the contralesional and ipsilesional visual hemifields. METHODS: A new measurement setup, that involves real-time comparisons of shape and size of objects, orientation of lines, speed and direction of moving patterns, in the right or left visual hemifield, has been developed. The setup was implemented in an immersive environment like a hemisphere to take into account the effects of peripheral and central vision, and eventual visual field losses. Due to the non-flat screen of the hemisphere, a distortion algorithm was needed to adapt the projected images to the surface. Several approaches were studied and, based on a comparison between projected images and original ones, the best one was used for the implementation of the test. Fifty-seven healthy volunteers were then tested in a pilot study. A Satisfaction Questionnaire was used to assess the usability of the new measurement setup. RESULTS: The results of the distortion algorithm showed a structural similarity between the warped images and the original ones higher than 97%. The results of the pilot study showed an accuracy in comparing images in the two visual hemifields of 0.18 visual degrees and 0.19 visual degrees for size and shape discrimination, respectively, 2.56° for line orientation, 0.33 visual degrees/s for speed perception and 7.41° for recognition of motion direction. The outcome of the Satisfaction Questionnaire showed a high acceptance of the battery by the participants. CONCLUSIONS: A new method to measure higher visual functions in an immersive environment was presented. The study focused on the usability of the developed battery rather than the performance at the visual tasks. A battery of five subtasks to study the perception of size, shape, orientation, speed and motion direction was developed. The test setup is now ready to be tested in neurological patients.

Seals and the Need for more Deference to Vienna by WTO Adjudicators

This paper asks how World Trade Organization (WTO) panels and the Appellate Body (AB) take public international law (PIL) into account when interpreting WTO rules as a part of international economic law (IEL). Splendid isolation of the latter is not new; indeed it is intended by the negotiators of the Understanding on the Settlement of Disputes (DSU). At the same time, the Vienna Convention on the Law of Treaties (VCLT) is quite clear when it provides the general rules and the supplementary means of treaty interpretation. Despite such mandatory guidance, WTO adjudicators (when given a choice and assuming they see the conflict) prefer deference to WTO law over deference to Vienna and take a dogmatic way out of interpretation quandaries. The AB and panels make abundant reference to Vienna, though less so to substantive PIL. Often times, however, they do so simply in order to buttress their findings of violations of WTO rules. Perhaps tellingly, however, none of the reports in EC – Seals contains even a single mention of VCLT, despite numerous references to international standards addressing indigenous rights and animal welfare. In the longer term, and absent a breakthrough on the negotiation front, this pattern of carefully eschewing international treaty law and using PIL just for the sake of convenience could have serious consequences for the credibility and acceptance of the multilateral trading system. Following the adage ‘negotiate or litigate’ recourse to WTO dispute settlement increases when governments are less ready to make treaty commitments commensurate with the challenges of globalisation. This is true even for ‘societal choice’ cases on the margins of classic trade disputes. We will argue here that it is precisely for cases such as these that VCLT and PIL should be used more systematically by panels and the AB. Failing that, instead of building bridges for more coherent international regulation, WTO adjudicators could burn those same bridges which the DSU interpretation margin leaves open for accomplishing their job which is to find a ‘positive solution’. Worse, judicial incoherence could return to WTO dispute settlement like a boomerang and damage the credibility and thus the level of acceptance of the multilateral trading system per se.

Resistance to Temptation: The Interaction of External and Internal Control on Alcohol Use During Residential Treatment for Alcohol Use Disorder

Background: There is evidence that drinking during residential treatment is related to various factors, such as patients’ general control beliefs and self-efficacy, as well as to external control of alcohol use by program’s staff and situations where there is temptation to drink. As alcohol use during treatment has been shown to be associated with the resumption of alcohol use after discharge from residential treatment, we aimed to investigate how these variables are related to alcohol use during abstinenceoriented residential treatment programs for alcohol use disorders (AUD). Methods: In total, 509 patients who entered 1 of 2 residential abstinence-oriented treatment programs for AUD were included in the study. After detoxification, patients completed a standardized diagnostic procedure including interviews and questionnaires. Drinking was assessed by patients’ selfreport of at least 1 standard drink or by positive breathalyzer testing. The 2 residential programs were categorized as high or low control according to the average number of tests per patient. Results: Regression analysis revealed a significant interaction effect between internal and external control suggesting that patients with high internal locus of control and high frequency of control by staff demonstrated the least alcohol use during treatment (16.7%) while patients with low internal locus of control in programs with low external control were more likely to use alcohol during Treatment (45.9%). No effects were found for self-efficacy and temptation. Conclusions: As alcohol use during treatment is most likely associated with poor treatment outcomes, external control may improve treatment outcomes and particularly support patients with low internal locus of control, who show the highest risk for alcohol use during treatment. High external control may complement high internal control to improve alcohol use prevention while in treatment. Key Words: Alcohol Dependence, Alcohol Use, Locus of Control, Alcohol Testing.

Hypertonic NaCl infusions affect milk composition in goats

The capability of goats to maintain milk production during water deprivation is remarkable and not yet fully understood. The aim of the present study was to investigate whether intravenous infusions of hypertonic NaCl cause release of both vasopressin and oxytocin and whether the peptides, in combination with the hyperosmolality, affect milk flow and milk composition. Six Swedish domestic landrace goats in their first to third lactation were milked every 30 min during experiments. Hypertonic NaCl (HNaCl) or isotonic NaCl (IsoNaCl) were infused for 90 min. Goats were not allowed to drink during infusions. Plasma vasopressin concentration increased during HNaCl infusions, and did not change in response to IsoNaCl infusions. Plasma oxytocin concentration did not change during either infusion. Milk flow was maintained during the infusions. Milk fat concentration decreased in the three samples taken before onset of the infusions, but then increased gradually during HNaCl infusions, while it continued to fall during the IsoNaCl infusions. Milk osmolality followed the rise in plasma osmolality during the HNaCl infusions and did not change in IsoNaCl experiments. Milk lactose concentration increased throughout both series of experiments, the concentration being higher during HNaCl infusions. Milk protein concentration did not change during HNaCl infusions, but fell in the IsoNaCl experiments. It is concluded that the hyperosmolality in combination with elevated plasma vasopressin levels did not disturb the secretory activity of the mammary cells, but rather facilitated emptying of the alveolar milk. Such a mechanism may help to explain the sustained milk production in water deprived goats.

Finite element 3D reconstruction of the pulmonary acinus imaged by synchrotron X-ray tomography

The alveolated structure of the pulmonary acinus plays a vital role in gas exchange function. Three-dimensional (3D) analysis of the parenchymal region is fundamental to understanding this structure-function relationship, but only a limited number of attempts have been conducted in the past because of technical limitations. In this study, we developed a new image processing methodology based on finite element (FE) analysis for accurate 3D structural reconstruction of the gas exchange regions of the lung. Stereologically well characterized rat lung samples (Pediatr Res 53: 72-80, 2003) were imaged using high-resolution synchrotron radiation-based X-ray tomographic microscopy. A stack of 1,024 images (each slice: 1024 x 1024 pixels) with resolution of 1.4 mum(3) per voxel were generated. For the development of FE algorithm, regions of interest (ROI), containing approximately 7.5 million voxels, were further extracted as a working subunit. 3D FEs were created overlaying the voxel map using a grid-based hexahedral algorithm. A proper threshold value for appropriate segmentation was iteratively determined to match the calculated volume density of tissue to the stereologically determined value (Pediatr Res 53: 72-80, 2003). The resulting 3D FEs are ready to be used for 3D structural analysis as well as for subsequent FE computational analyses like fluid dynamics and skeletonization.

Management of infusion reactions in clinical trials and beyond: the US and EU perspectives

Monoclonal antibodies have expanded our cancer-fighting armamentarium in both the United States and Europe. While in general, monoclonal antibodies are well tolerated and do not have significant overlapping side effects with traditional cytotoxic agents, severe infusion reactions (IRs)--sometimes severe enough to be life threatening--have been reported. The pathophysiology of severe infusion reactions associated with monoclonal antibodies is poorly understood, but mechanisms are beginning to be elucidated. Geographic differences in the incidence of IRs have become apparent. Understanding the risk, recognizing the signs and symptoms, and being ready to promptly manage severe IRs are key for the clinician to avoid unnecessarily discontinuing these effective anticancer agents and prevent potentially tragic consequences for their patients. To date, clinical trials have incorporated monoclonal antibodies into combinations with standard cytotoxic regimens; it is expected that in time clinical trials will be testing promising new combinations utilizing multiple targeted agents, resulting in improved toxicity profiles and efficacy for cancer patients.

Practical handling of AIO admixtures - Guidelines on Parenteral Nutrition, Chapter 10

All-in-one admixtures (AIO-admixtures) provide safe, effective and low-risk PN (parenteral nutrition) for practically all indications and applications. Water, energy (carbohydrates and lipids), amino acids, vitamins and trace elements are infused together with PN either as industrially-manufactured AIO admixtures provided as two- or three-chamber bags (shelf life usually more than 12 months) completed with electrolytes and micronutrients where appropriate or as individually compounded ready-to-use AIO admixtures (compounding, usually prepared by a pharmacy on either a daily or weekly basis and stored at 2-8 degrees C). Physico-chemical and microbial stability of an AIO admixture is essential for the safety and effectiveness of patient-specific PN, and its assurance requires specialist pharmaceutical knowledge. The stability should be documented for an application period of 24 (-48) hours. It is advisable to offer a limited selection of different PN regimes in each hospital. For reasons of drug and medication safety, PN admixtures prepared for individual patients must be correctly labelled and specifications for storage conditions must also be followed during transport. Monitoring is required where applicable. Micronutrients are usually administered separately to AIO admixtures. In case compatibility and stability have been well documented trace elements and/or combination preparations including water-soluble or water-soluble/fat soluble vitamin supplements can be added to PN admixtures under strict aseptic conditions. AIO admixtures are usually not used as vehicles for drugs (incompatibilities).

A simple asthma prediction tool for preschool children with wheeze or cough

BACKGROUND Many preschool children have wheeze or cough, but only some have asthma later. Existing prediction tools are difficult to apply in clinical practice or exhibit methodological weaknesses. OBJECTIVE We sought to develop a simple and robust tool for predicting asthma at school age in preschool children with wheeze or cough. METHODS From a population-based cohort in Leicestershire, United Kingdom, we included 1- to 3-year-old subjects seeing a doctor for wheeze or cough and assessed the prevalence of asthma 5 years later. We considered only noninvasive predictors that are easy to assess in primary care: demographic and perinatal data, eczema, upper and lower respiratory tract symptoms, and family history of atopy. We developed a model using logistic regression, avoided overfitting with the least absolute shrinkage and selection operator penalty, and then simplified it to a practical tool. We performed internal validation and assessed its predictive performance using the scaled Brier score and the area under the receiver operating characteristic curve. RESULTS Of 1226 symptomatic children with follow-up information, 345 (28%) had asthma 5 years later. The tool consists of 10 predictors yielding a total score between 0 and 15: sex, age, wheeze without colds, wheeze frequency, activity disturbance, shortness of breath, exercise-related and aeroallergen-related wheeze/cough, eczema, and parental history of asthma/bronchitis. The scaled Brier scores for the internally validated model and tool were 0.20 and 0.16, and the areas under the receiver operating characteristic curves were 0.76 and 0.74, respectively. CONCLUSION This tool represents a simple, low-cost, and noninvasive method to predict the risk of later asthma in symptomatic preschool children, which is ready to be tested in other populations.

Prevalence, genetic diversity and antimicrobial susceptibility of Listeria monocytogenes isolated from open-air food markets in Greece

A total of 210 food samples originating from milk products, ready-to-eat salads, raw meat and raw meat products purchased in ten open-air market places in Thessaloniki, Greece, were analyzed for the presence of Listeria monocytogenes. Thirty (14.3%) contained L. monocytogenes with the highest prevalence in raw meat (27.5%), raw meat products (18%) and cheese (8%). The strains were susceptible to 16 antimicrobials as determined by microbroth dilution, except one strain which displayed resistance to tetracycline (MIC > 32 μg/ml). This strain carried the tetracycline resistance gene tet(M). Pulsed-field gel electrophoresis (PFGE) revealed a low genetic diversity among the isolates, irrespective of their origin. This suggests that dominant L. monocytogenes clones are widespread in different food product types in open-air food markets in Greece. The high prevalence of L. monocytogenes in these products indicates that appropriate hygienic measures and periodic bacteriological controls are also necessary in open-air food markets to reduce contamination with food-borne pathogens. Greek specialties made with raw meat and raw milk may contain L. monocytogenes and should not be consumed by persons at risk.

Perioperative use of crystalloids in patients undergoing open radical cystectomy: balanced Ringer's maleate versus a glucose 5%/potassium-based balanced solution: study protocol for a randomized controlled trial

BACKGROUND The optimal crystalloid solution to use perioperatively in patients undergoing open radical cystectomy remains unclear. Many of the fluids used for intravenous hydration contain supraphysiologic concentrations of chloride, which can induce hyperchloremia and metabolic acidosis, resulting in renal vasoconstriction and decreased renal function. In addition, patients receiving less fluid and less sodium show faster recovery of gastrointestinal (GI) function after colonic surgery. METHODS AND DESIGN This is an investigator-initiated, single-center, randomized, controlled, parallel group trial with assessor-blinded outcome assessment, in the Department of Urology, University Hospital Bern, Switzerland. The study will involve 44 patients with bladder cancer scheduled for radical cystectomy and urinary diversion. The primary outcome is the duration between the end of surgery and the return of the GI function (first defecation). Secondary outcomes are fluid balance (body weight difference postoperatively versus preoperatively) and the incidence of kidney function disorders according to the Risk-Injury-Failure-Loss-End Stage Renal Disease (RIFLE classification). An equal number of patients are allocated to receive Ringerfundin® solution or a glucose/potassium-based balanced crystalloid solution as baseline infusion during the entire time that intravenous administration of fluid is necessary during the perioperative period. The randomized crystalloid solution is infused at a rate of 1 ml/kg/h until the bladder has been removed, followed by 3 ml/kg/h until the end of surgery. Postoperative hydration is identical in both groups and consists of 1,500 ml of the randomized crystalloid solution per 24 hours. Postoperative patient care is identical in both groups; patients are allowed to drink clear fluids immediately after surgery, and liquid diet is started on postoperative day 1, as well as active mobilization and the use of chewing gum. Body weight is measured daily in the morning. Time of first flatus and first defecation are recorded. DISCUSSION This trial assesses the benefits and harms of two different balanced crystalloid solutions for perioperative fluid management in patients undergoing open radical cystectomy with urinary diversion, with regard to return of GI function and effects on postoperative renal function. TRIAL REGISTRATION Current Controlled Trials ISRCTN32976792 (registered on November 21 2013).

Mining microsatellite markers from public expressed sequence tags databases for the study of threatened plants

Background Simple Sequence Repeats (SSRs) are widely used in population genetic studies but their classical development is costly and time-consuming. The ever-increasing available DNA datasets generated by high-throughput techniques offer an inexpensive alternative for SSRs discovery. Expressed Sequence Tags (ESTs) have been widely used as SSR source for plants of economic relevance but their application to non-model species is still modest. Methods Here, we explored the use of publicly available ESTs (GenBank at the National Center for Biotechnology Information-NCBI) for SSRs development in non-model plants, focusing on genera listed by the International Union for the Conservation of Nature (IUCN). We also search two model genera with fully annotated genomes for EST-SSRs, Arabidopsis and Oryza, and used them as controls for genome distribution analyses. Overall, we downloaded 16 031 555 sequences for 258 plant genera which were mined for SSRsand their primers with the help of QDD1. Genome distribution analyses in Oryza and Arabidopsis were done by blasting the sequences with SSR against the Oryza sativa and Arabidopsis thaliana reference genomes implemented in the Basal Local Alignment Tool (BLAST) of the NCBI website. Finally, we performed an empirical test to determine the performance of our EST-SSRs in a few individuals from four species of two eudicot genera, Trifolium and Centaurea. Results We explored a total of 14 498 726 EST sequences from the dbEST database (NCBI) in 257 plant genera from the IUCN Red List. We identify a very large number (17 102) of ready-to-test EST-SSRs in most plant genera (193) at no cost. Overall, dinucleotide and trinucleotide repeats were the prevalent types but the abundance of the various types of repeat differed between taxonomic groups. Control genomes revealed that trinucleotide repeats were mostly located in coding regions while dinucleotide repeats were largely associated with untranslated regions. Our results from the empirical test revealed considerable amplification success and transferability between congenerics. Conclusions The present work represents the first large-scale study developing SSRs by utilizing publicly accessible EST databases in threatened plants. Here we provide a very large number of ready-to-test EST-SSR (17 102) for 193 genera. The cross-species transferability suggests that the number of possible target species would be large. Since trinucleotide repeats are abundant and mainly linked to exons they might be useful in evolutionary and conservation studies. Altogether, our study highly supports the use of EST databases as an extremely affordable and fast alternative for SSR developing in threatened plants.

Prevention of ischemic complications during aneurysm surgery

Ischemic complications during aneurysm surgery are a frequent cause of postoperative infarctions and new neurological deficits. In this article, we discuss imaging and neurophysiological tools that may help the surgeon to detect intraoperative ischemia. The strength of intraoperative digital subtraction angiography (DSA) is the full view of the arterial and venous vessel. DSA is the gold standard in complex and giant aneurysms, but due to certain disadvantages, it cannot be considered standard of care. Microvascular Doppler sonography is probably the fastest diagnostic tool and can quickly aid diagnosis of large vessel occlusions. Intraoperative indocyanine green videoangiography is the best tool to assess flow in perforating and larger arteries, as well as occlusion of the aneurysm sac. Intraoperative neurophysiological monitoring with somatosensory and motor evoked potentials indirectly measures blood flow by recording neuronal function. It covers all causes of intraoperative ischemia, provided that ischemia occurs in the brain areas under surveillance. However, every method has advantages and disadvantages. No single method is superior to the others in every aspect. Therefore, it is very important for the neurosurgeon to know the strengths and weaknesses of each tool in order to have them available, to know how to use them for each individual situation, and to be ready to apply them within the time window for reversible cerebral ischemia.

The Art of Enduring Contradictory Goals: Challenges in the Institutional Co‐construction of a ‘Good Death’

This paper focuses on the normative notion of ‘good death’, its practical relevance as a frame of reference for ‘death work’ procedures in institutional elder care in Switzerland and the ways in which it may be challenged within migrant ‘dying trajectories’. In contemporary palliative care, the concept of ‘good death’ focuses on the ideal of an autonomous dying person, cared for under a specialised biomedical authority. Transferred to the nursing home context, characterised by long-term basic care for the very old under conditions of scarce resources, the notion of ‘good death’ is broken down into ready-to-use, pragmatic elements of daily routines. At the same time, nursing homes are increasingly confronted with socially and culturally diversified populations. Based on ethnographic findings, we give insight into current practices of institutional ‘death work’ and tensions arising between contradicting notions of a ‘good death’, by referring to decision-making, life-prolonging measures, notions on food/feeding and the administration of sedative painkillers.

Funduscopy in adult zebrafish and its application to isolate mutant strains with ocular defects

Funduscopy is one of the most commonly used diagnostic tools in the ophthalmic practice, allowing for a ready assessment of pathological changes in the retinal vasculature and the outer retina. This non-invasive technique has so far been rarely used in animal model for ophthalmic diseases, albeit its potential as a screening assay in genetic screens. The zebrafish (Danio rerio) is well suited for such genetic screens for ocular alterations. Therefore we developed funduscopy in adult zebrafish and employed it as a screening tool to find alterations in the anterior segment and the fundus of the eye of genetically modified adult animals.A stereomicroscope with coaxial reflected light illumination was used to obtain fundus color images of the zebrafish. In order to find lens and retinal alterations, a pilot screen of 299 families of the F3 generation of ENU-treated adult zebrafish was carried out.Images of the fundus of the eye and the anterior segment can be rapidly obtained and be used to identify alterations in genetically modified animals. A number of putative mutants with cataracts, defects in the cornea, eye pigmentation, ocular vessels and retina were identified. This easily implemented method can also be used to obtain fundus images from rodent retinas.In summary, we present funduscopy as a valuable tool to analyse ocular abnormalities in adult zebrafish and other small animal models. A proof of principle screen identified a number of putative mutants, making funduscopy based screens in zebrafish feasible.