Evaluation of Encequidar as An Intestinal P-gp and BCRP Specific Inhibitor to Assess the Role of Intestinal P-gp and BCRP in Drug-Drug Interactions.
The differences between intestinal and systemic (hepatic and renal) P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) roles in drug disposition are difficult to define. Accordingly, we characterized Encequidar (ECD) as an intestinal P-gp and BCRP specific inhibitor to evaluate their role in drug disposition. We assessed the in vitro and in vivo inhibition potential of ECD towards human and animal P-gp and BCRP. ECD is a potent inhibitor with a high degree of selectivity in inhibiting human P-gp (hP-gp) over human BCRP (hBCRP) (IC50s of 0.0058 ± 0.0006 vs. > 10 µM, respectively). In contrast, ECD is a potent inhibitor of rat and cynomolgus monkey BCRP (IC50 ranged from 0.059 to 0.18 µM). While the AUC of IV paclitaxel (PTX) was significantly increased by elacridar (ELD) (P < 0.05) but not ECD in rats (15 mg/kg; PO) (2.55- vs. 0.93-fold), that of PO PTX was significantly elevated to a similar extent between the inhibitors (39.5- vs. 33.5-fold). Similarly, the AUC of PO sulfasalazine (SFZ) was dramatically increased by ELD and ECD (16.6- vs. 3.04-fold) although that of IV SFZ was not significantly affected by ELD and ECD in rats (1.18- vs. 1.06-fold). Finally, a comparable ECD-induced increase of the AUC of PO talinolol in cynomolgus monkeys was observed compared with ELD (2.14- vs. 2.12-fold). ECD may allow an in-depth appraisal of the role of intestinal efflux transporter(s) in drug disposition in animals and humans through local intestinal drug interactions.


Role of interleukin-7 in T-cell development from hematopoietic stem cells.
All lymphocytes are derived from hematopoietic stem cells (HSC). The interleukin-7 receptor (IL-7R) transduces non-redundant signals for both T and B-cell development from HSC. The upregulation of the IL-7R occurs at the stage of the clonogenic common lymphoid progenitor, a recently identified population that can give rise to all lymphoid lineages (T, B and natural killer cells) at a single cell level. The IL-7R plays a critical role in the rearrangement of immunoglobulin heavy chain genes required for B-cell development. IL-7R expression is critically regulated in developing thymocytes; thymocytes that fail the positive selection process downregulate the IL-7R, but those undergoing positive selection upregulate or maintain IL-7R expression. Recent data indicate that IL-7 signaling enhances the survival of developing thymocytes and mature T cells, presumably by its upregulating Bcl-2. Detailed analysis of the signaling cascades activated by the IL-7R may help to reveal the differential roles of IL-7 signaling in T and B-cell development.


Arrhythmogenic Cardiomyopathy: the Guilty Party in Adipogenesis.
Arrhythmogenic cardiomyopathy (ACM) is a genetic cardiac condition characterized by the replacement of the ventricular myocardium with fibro-fatty tissue, by arrhythmias and sudden death. Adipogenesis in ACM is considered an aberrant remodeling following myocardial loss. Which cell type(s) is (are) responsible for the adipose replacement is still matter of debate. A systematic overview of the different cells that have been, over time, considered as main players in adipose replacement is provided. The comprehension of the cellular component giving rise to arrhythmogenic cardiomyopathy substrate defects may represent both an essential tool for mechanistic studies of disease pathogenesis and a novel possible therapeutic target.


Rett syndrome in Sweden. Neurodevelopment--disability--pathophysiology.
Rett syndrome (RS), a complex and severely disabling neuromotor disorder affecting young girls, was not internationally recognized until in the middle eighties. In Austria and Sweden only, there are clinical experiences since the sixties. The aims of this study were to 1) define the nucleus group of RS in Sweden, 2) develop a frame of defined stages for describing the clinical progress of disease, 3) identify early developmental patterns and their predictivity, 4) give the natural history of neuromotor impairments and disability in adults, 5) analyse the period of clinical regression as to developmental profiles, patterns and progression of symptoms, 6) search informative neurophysiologic correlates to clinical symptoms and signs. By a 6 year (1984-90), nationwide search procedure, comprising an information and tracing program, a travelling consultant program, and a neuropediatric and laboratory examination program, 88 females were added to those 17, observed in Sweden during the sixties and seventies. By March, 1990, 105 females, aged 19 months-44 years (median 17 1/2 years), had entered this series, which was considered representative for the nucleus group of RS in Sweden. 97/105 females (92.3%) fulfilled the criteria for classic RS, according to internationally accepted clinical criteria, and 8 (7.7%), represented so called "formes frustes". The prevalence for classic RS in the south-west region of Sweden was 1:12.000-13.000 girls, the birth years 1965-76 and 1960-84. Based on 29 females with RS, aged 13-28 years, a clinical staging system was constructed and evaluated in 1985, emphasizing the main different phases of the disorder throughout life. This staging system was found a valuable tool for clinical assessment, documentation, and research approach, and has become internationally accepted and widely used. Further experiences have given rise to minor adjustments, which are proposed. By scrutinizing early documentation from 10 girls, at referral aged 20 months-6 1/4 years (median 3 1/4 years) and retrospectively applying the Denver Developmental Screening Test frames, early achievements, signs and symptoms were reconstructed in 1986. Although characteristic neuromotor and neurobehavioural patterns of help for early suspicion, and even subtle signs, possibly reflecting a disorder already during the first months of life, could be identified, predictive clinical manifestations of diagnostic value were not found.(ABSTRACT TRUNCATED AT 400 WORDS)


Degenerative mitral regurgitation.
Degenerative mitral regurgitation is a major threat to public health and affects at least 24 million people worldwide, with an estimated 0.88 million disability-adjusted life years and 34,000 deaths in 2019. Improving access to diagnostic testing and to timely curative therapies such as surgical mitral valve repair will improve the outcomes of many individuals. Imaging such as echocardiography and cardiac magnetic resonance allow accurate diagnosis and have provided new insights for a better definition of the most appropriate timing for intervention. Advances in surgical techniques allow minimally invasive treatment with durable results that last for ≥20 years. Transcatheter therapies can provide good results in select patients who are considered high risk for surgery and have a suitable anatomy; the durability of such repairs is up to 5 years. Translational science has provided new knowledge on the pathophysiology of degenerative mitral regurgitation and may pave the road to the development of medical therapies that could be used to halt the progression of the disease.


[Effect of avoidable and non-avoidable deaths on life expectancy in Mexico, 1998-2000 and 2008-2010].
Estimate the changes in life expectancy related to avoidable and nonavoidable deaths in Mexico between the three-year periods from 1998-2000 and 2008-2010 by sex and age group. A descriptive cross-sectional study was conducted. Data from official sources on deaths recorded from 0-74 years of age and population estimates (Mexican and worldwide) for the three-year periods from 1998-2000 and 2008-2010 was used. The crude and standardized death rates and years of life expectancy lost in the periods studied were calculated. Estimates were made of the effect of avoidable and non-avoidable deaths on life expectancy from 0-74 years of age, using the Arriaga method, and temporary life expectancy by age group. Mortality due to avoidable causes increased by 2.1% whereas mortality related to non-avoidable causes decreased by 2.3%, with differences according to sex. Life expectancy at birth was 74.2 years in the three-year period from 1998-2000 and 75.1 years in the three-year period from 2008-2010. Temporary life expectancy from 0-74 years of age remained nearly the same at about 68.6 years. Years of life expectancy can be gained through actions that promote health and disease prevention, mainly by reducing deaths due to avoidable causes. Cross-sectional population-based interventions and strategies should be developed, focusing on specific subgroups, from a gender and generational perspective, and adjusted for the specific geographical, socioeconomic, and cultural features of the target population.


Monitoring cochlear function intraoperatively using distortion product otoacoustic emissions.
Distortion product otoacoustic emissions (DPOAEs) elicited by a bitonal stimulus complex are low-level sounds that are generated within the cochlea, and are easily measured by a miniature microphone system placed in the external auditory canal. Under conditions of rapid measurement, DPOAEs have been shown in an animal model to be exquisitely sensitive to interruption of the blood supply to the inner ear. Currently, there is no real-time procedure available for monitoring hearing function intraoperatively during neurotologic surgery. The goal of the present study was to determine the utility of DPOAEs in monitoring cochlear status intraoperatively, particularly during procedures commonly used to remove acoustic neuromas. Distortion product otoacoustic emissions were measured pre- and intraoperatively in 11 patients, who were under general anesthesia for a variety of otolaryngologic procedures, including acoustic neuroma resection. High frequency emissions (i.e., > or = 4 kHz) were less affected by the elevated levels of acoustic noise present in the operating-room environment, thus permitting emitted responses to be updated as quickly as every 2 seconds. However, a number of technical problems were encountered and addressed during development of the emission monitoring technique. Despite these difficulties, overall, DPOAEs appear to be a promising adjunct to the intraoperative monitoring of auditory function.


Expression of osteoclast differentiation signals by stromal elements of giant cell tumors.
The mechanisms by which primary tumors of the bone cause bone destruction have not been elucidated. Unlike most other lytic bone tumors, osteoclastomas, otherwise known as giant cell tumors (GCT), contain osteoclast-like cells within the tumor stroma. A new member of the TNF-ligand superfamily member, osteoclast differentiation factor (ODF/OPGL/RANKL/TRANCE), was recently identified. ODF was shown to directly stimulate osteoclastogenesis, in the presence of M-CSF. In this study, the expression of ODF was examined in a number of tumor samples associated with bone lysis in vivo. In addition, we investigated expression of the ODF receptor on osteoclast precursors, RANK, as well as the ODF inhibitor osteoprotegerin (OPG), and another TNF-ligand superfamily member, TRAIL, previously shown to abrogate the inhibitory effects of OPG. We report here the novel finding that GCT stromal cells contain abundant ODF mRNA, whereas the giant cell population exclusively expresses RANK mRNA. These results are consistent with the osteoclast-mediated bone destruction by these tumors. We also report the expression of OPG and TRAIL mRNA in GCT samples. A comparison with other lytic and nonlytic tumors of bone showed that GCT express more ODF and TRAIL mRNA relative to OPG mRNA. In addition, GCT were found to express a number of cytokines previously reported to play central roles in osteoclastogenesis, namely, IL-1, -6, -11, -17, as well as TNF-alpha. Importantly, GCT were also found to express high levels of M-CSF mRNA, a cytokine shown to be an essential cofactor of ODF, and a survival factor for mature and developing osteoclasts. Furthermore, expression of these molecules by stromal cells isolated from GCT continued in vitro. Thus GCT constitutively express all of the signals that are currently understood to be necessary for the differentiation of osteoclasts from precursor cells.


Four species of land snails from Costa Rica and Panama (Pulmonata: Spiraxidae).
Four species of land snails are described from Costa Rica and Panama. Two are new species and two have remained poorly known since their first discovery. A fifth species from Mexico and Guatemala is illustrated for comparative purposes because it has not been figured since 1877, and previous figures of it are inadequate for comparative purposes. The Spiraxidae subfamilies and the Spiraxinae genera are redefined.


[Preparation of neurotoxin and hemagglutinin from Clostridium botulinum A and characterization of its neurotoxin].
A procedure for preparation of electrophoretically and serologically homogeneous neurotoxin and a highly purified hemagglutinin from the culture fluid of Cl. botulinum A, strain 501 is described. The yield of neurotoxin with specific activity of 80-100 X 10(6) DLM/mg of protein is 5-20%. Neurotoxin has a molecular weight of 150,000, sedimentation coefficient of 7.1S, pI of 6.2-6.3; the maximum of its fluorescence corresponds to 332 nm. The toxin molecule contains 4 SH-groups. Neurotoxin consists of two subunits with molecular weights of 98,000 and 56,000. The storage of neurotoxin at -20 degrees C causes inactivation and electrophoretical heterogeneity of the protein. The inactivation leads to an alteration of the toxin molecule charge, a shift of the lambda max of fluorescence and a loss of the SH-group reactivity without affecting the molecular weight or serological properties of the protein. The data obtained suggest that the conformational state of toxin molecules is essential for its biological activity.


Pyruvate aldolases in chiral carbon-carbon bond formation.
A procedure for the preparation of optically pure alpha-keto-gamma-hydroxy carboxylic acids through stereospecific aldol addition catalyzed by pyruvate aldolases from the Entner-Doudoroff and the DeLey-Doudoroff glycolytic pathways is described. This highly versatile fragment serves as a precursor for a variety of commonly encountered functionalities, including beta-hydroxy aldehydes and carboxylic acids, alpha-amino-gamma-hydroxy carboxylic acids and alpha,gamma-dihydroxy carboxylic acids. The protocol described here uses recombinant His6-tagged KDPG aldolase for the synthesis of (S)-4-hydroxy-2-keto-4-(2'-pyridyl)butyrate. A protocol for evaluating enantiomeric excess through formation of the gamma-lactone of the dithioacetal followed by chiral-phase gas-liquid chromatography is also described. Enzyme expression and enzymatic synthesis can be accomplished in approximately 1 week. The enzymatic aldol addition proceeds in nearly quantitative yields with enantiomeric excesses greater than 99.7%.


Effectiveness of Prescription-Based CNS Stimulants on Hospitalization in Patients With Schizophrenia: A Nation-Wide Register Study.
Negative symptoms and cognitive deficits are main features of schizophrenia but with limited treatment options. Earlier studies have suggested that central nervous system (CNS) stimulants have a small effect on these domains, but with inconclusive results. As the first study to date, we aimed to investigate whether CNS stimulants improve naturalistic outcomes (psychiatric admissions and antipsychotic use) in patients with schizophrenia. By using extensive health registers all patients with schizophrenia and their use of CNS stimulants in Denmark were identified. Two models were used to investigate the effectiveness of CNS stimulants in patients with schizophrenia between 1995 and 2014; a mirror-image model with 605 individuals, using paired t tests and Wilcoxon signed rank tests, and a follow-up study with 789 individuals, using a conditional risk-set model. CNS stimulants use was associated with a reduction in number of psychiatric admissions from 3.43 (95% CI = 2.86 to 4.01) to 2.62 (95% CI = 1.99 to 3.25) (P = .009), with a more pronounced reduction for women (mean difference: -1.37, 95% CI = -2.34 to -0.40, P = .006). Psychiatric bed-days were reduced by 40 (95% CI = 24.5 to 55.6, P < .001) for individuals with at least 1 admission before CNS stimulant use. In addition, the total amount of antipsychotic use (Defined Daily Dose [DDD]) was reduced (P = .001). The Hazard rate ratio in psychiatric admissions between women taking CNS stimulants compared to women not taking CNS stimulants was 0.77 (95% CI = 0.67 to 0.88). CNS stimulants may have clinical potentials for improving functional outcomes in patients with schizophrenia and randomized clinical studies evaluating this topic are warranted.


Comparative Greenhouse Gas Footprinting of Online versus Traditional Shopping for Fast-Moving Consumer Goods: A Stochastic Approach.
Variability in consumer practices and choices is typically not addressed in comparisons of environmental impacts of traditional shopping and e-commerce. Here, we developed a stochastic model to quantify the variability in the greenhouse gas (GHG) footprints of product distribution and purchase of fast-moving consumer goods (FMCGs) via three prevalent retail channels in the United Kingdom (U.K.). We found that shopping via bricks and clicks (click and fulfillment via physical store delivery) most likely decreases the GHG footprints when substituting traditional shopping, while FMCGs purchased through pure players with parcel delivery often have higher GHG footprints compared to those purchased via traditional retail. The number of items purchased and the last-mile travel distance are the dominant contributors to the variability in the GHG footprints of all three retail channels. We further showed that substituting delivery vans with electric cargo bikes can lead to a GHG emission reduction of 26% via parcel delivery. Finally, we showed the differences in the "last mile" GHG footprint of traditional shopping in the U.K. compared to three other countries (China, Netherlands, and the United States), which are primarily caused by the different shares of modes of transport (walking and by car, bus, and bike).


Effects of a transoceanic rowing challenge on cardiorespiratory function and muscle fitness.
Ultra-endurance sports and exercise events are becoming increasingly popular for older age groups. We aimed to evaluate changes in cardiac function and physical fitness in males aged 50-60 years who completed a 50-day transoceanic rowing challenge. This case account of four self-selected males included electro- and echo-cardiography (ECG, echo), cardiorespiratory and muscular fitness measures recorded nine-months prior to and three weeks after a transatlantic team-rowing challenge. No clinically significant changes to myocardial function were found over the course of the study. The training and race created expected functional changes to left ventricular and atrial function; the former associated with training, the latter likely due to dehydration, both resolving towards baseline within three weeks post-event. From race-start to finish all rowers lost 8.4-15.6 kg of body mass. Absolute cardiorespiratory power and muscular strength were lower three weeks post-race compared to pre-race, but cardiorespiratory exercise economy improved in this same period. A structured programme of moderate-vigorous aerobic endurance and muscular training for >6 months, followed by 50-days of transoceanic rowing in older males proved not to cause any observable acute or potential long-term risks to cardiovascular health. Pre-event screening, fitness testing, and appropriate training is recommended, especially in older participants where age itself is an increasingly significant risk factor.


[The future of radiation oncology: technology, ethical considerations and economical aspects].
We are facing a real technical revolution in radiation oncology. The radiation oncologist is pushed by the industry to implement rapidly new and "high-tech" therapeutic modalities. All of the technical improvements are obviously aiming at an increase in the therapeutic index. However, one should be cautious before implementing on a large scale those technical innovations as no one really knows neither what the possible impact is on medical outcome (efficacy, toxicity and risk), nor what the economical consequences will be. It is our duty as radiation oncologists to make a comprehensive estimation of the impacts in order to be able to set up guidelines for use that are both ethical and in respectful of human dignity.


ProtoBug: functional families from the complete proteomes of insects.
ProtoBug (http://www.protobug.cs.huji.ac.il) is a database and resource of protein families in Arthropod genomes. ProtoBug platform presents the relatedness of complete proteomes from 17 insects as well as a proteome of the crustacean, Daphnia pulex. The represented proteomes from insects include louse, bee, beetle, ants, flies and mosquitoes. Based on an unsupervised clustering method, protein sequences were clustered into a hierarchical tree, called ProtoBug. ProtoBug covers about 300,000 sequences that are partitioned to families. At the default setting, all sequences are partitioned to ∼20,000 families (excluding singletons). From the species perspective, each of the 18 analysed proteomes is composed of 5000-8000 families. In the regime of the advanced operational mode, the ProtoBug provides rich navigation capabilities for touring the hierarchy of the families at any selected resolution. A proteome viewer shows the composition of sequences from any of the 18 analysed proteomes. Using functional annotation from an expert system (Pfam) we assigned domains, families and repeats by 4400 keywords that cover 73% of the sequences. A strict inference protocol is applied for expanding the functional knowledge. Consequently, secured annotations were associated with 81% of the proteins, and with 70% of the families (≥10 proteins each). ProtoBug is a database and webtool with rich visualization and navigation tools. The properties of each family in relation to other families in the ProtoBug tree, and in view of the taxonomy composition are reported. Furthermore, the user can paste its own sequences to find relatedness to any of the ProtoBug families. The database and the navigation tools are the basis for functional discoveries that span 350 million years of evolution of Arthropods. ProtoBug is available with no restriction at: www.protobug.cs.huji.ac.il. Database URL: www.protobug.cs.huji.ac.il


Monte Carlo simulation of a planar shoulder model.
Although variability of anthropometric measures within a population is a well established phenomenon, most biomechanical models are based on average parameter values. For example, optimisation models for predicting muscle forces from net joint reaction moments typically use average muscle moment arms. However, understanding the distribution of musculoskeletal morbidity within a population requires information about the variation of tissue loads within the population. This study investigated the use of Monte Carlo simulation techniques to predict the statistical distribution of deltoid and rotator cuff muscle forces during static arm elevation. Muscle moment arms were modelled either as independent random variables or jointly distributed random variables. Moment arm data was collected on 22 cadaver specimens. The results demonstrated the use of Monte Carlo techniques to describe the statistical distribution of muscle forces. Although assuming statistically independent moment arms did affect the statistical distribution shape, that assumption did not affect the median predicted forces. The standard deviations of muscle forces predicted using Monte Carlo techniques were similar to the standard deviation of muscle force predictions using the whole sample of specimens. It is concluded that Monte Carlo simulation techniques are a useful tool to analyse the interindividual variability of rotator cuff muscle forces.


Intraductal papillary-mucinous neoplasia of the pancreas: Histopathology and molecular biology.
Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is a clinically and morphologically distinctive precursor lesion of pancreatic cancer, characterized by gradual progression through a sequence of neoplastic changes. Based on the nature of the constituting neoplastic epithelium, degree of dysplasia and location within the pancreatic duct system, IPMNs are divided in several types which differ in their biological properties and clinical outcome. Molecular analysis and recent animal studies suggest that IPMNs develop in the context of a field-defect and reveal their possible relationship with other neoplastic precursor lesions of pancreatic cancer.


The anatomy and functional morphology of Diplodon rhombeus fontainianus (Orbigny, 1835) (Mollusca Bivalvia, Hyriidae).
Diplodon rhombeus fontainianus (Orbigny, 1835), belongs to the family Hyriidae Swainson 1840, the distribution of which is restricted to South America and Australasia. This species, endemic to Brazil, occurs in the central-southern geographical region, Upper Paraná Basin and Atlantic Microbasins Espirito Santo to Paraná states. The mollusk lives buried in muddy substrata, has similar sized adductor muscles, and is dioecious, lacking sexual dimorphism. The apertures are simple (type AII of Yonge, 1948, 1957) as in Diplodon rotundus gratus, Castalia undosa martensi, Castalia undosa undosa and mantle fusion is present only in the base of the exalant aperture. The inhalant aperture exhibits tentacles originating from the inner fold while the exhalant aperture has no tentacles. The ctenidia are type D (of Atkins, 1937). A well-developed marsupium is present in the inner demibranch. The association between the ctenidia and the labial palps belongs to category I (of Stasek, 1963). The stomach constitutes a type IV structure (of Purchon, 1958). The posterior sorting area (psa) presents two pouches in Diplodon rhombeus fontainianus. Among the Hyriidae, the presence of these pouches has also been described in several species of Hyriidae from South America. The organization of the gut in the visceral mass follows the same pattern seen in the Hyriidae already studied: Castalia undosa martensi, Castalia undosa undosa, Diplodon rotundus gratus,Diplodon charruanus and Diplodon pilsbryi.


[Muir-Torre syndrome and familial colorectal cancer: 2 families with molecular genetic analysis].
The Muir-Torre Syndrome is a rare genodermatosis, defined by the occurrence of cutaneous tumors (such as sebaceous adenomas, epitheliomas, or carcinomas, and/or keratoacanthomas), and internal malignancies. Recently, molecular analysis in hereditary non polyposis colorectal cancer demonstrated a common genetic basis, linking these two disorders, with the observation of germline mutations in the hMSH2 gene (one of the DNA mismatch repair system genes) in both syndromes. Such molecular demonstration of a single nosological entity should be clinically used to improve the indications of molecular testings in oncogenetics, still restricted to highly stringent criteria for hereditary non polyposis colorectal cancer. We identified three patients from two different families, who fulfilled the criteria for both Muir-Torre Syndrome and hereditary non polyposis colorectal cancer. The search of a germline mutation of the hMSH2 gene was performed on an affected member from each family, and their relatives with their informed consent. Within each family, all individuals with colorectal cancer were carriers of the same mutation. In the first family, this mutation was a pathogenic microinsertion, usable for predictive testing. In the second family, a missense mutation was identified, requesting further demonstration of its pathogenicity before its use in a predictive purpose. The diagnosis of cutaneous tumors compatible with Muir-Torre syndrome should lead the dermatologist to suspect an hereditary non polyposis colorectal cancer that should bring to an oncogenetic approach: personnal and familial history of colorectal cancer, molecular analysis, recommendations for colonoscopic screening in at-risk relatives. In the case of a colorectal cancer at a young age, or in the case of familial cases, the gastroenterologist should screen for cutaneous lesions of Muir-Torre syndrome, which could add a criteria for an hereditary syndrome, and lead to molecular oncogenetic analysis.


Metrizamide, iothalamate, and metrizoate: effects of internal carotid arterial injections on the blood-brain barrier of the rabbit.
Experiments were conducted on anesthetized rabbits to determine the effect of internal carotid artery injection of various contrast media on permeability changes in the blood-brain barrier. Changes in respiratory pattern, neuromuscular effects, and trypan blue extravasation were recorded after 3-ml injections of ionic and nonionic contrast media. Metrizamide and iothalamate meglumine were compared at iodine doses of 300, 400, and 500 mg I/ml. Metrizoate at 280 and 440 mg I/ml and diatrizoate meglumine at 385 mg I/ml were also included for comparison. The results demonstrated that metrizamide at all three iodine concentrations used caused minimal disruption of the blood-brain barrier, the effect being no greater, statistically, than saline controls. Iothalamate was benign at the lowest iodine concentration, but caused significant barrier breakdown at the two higher concentrations. These results suggest that alterations in blood-brain barrier permeability following angiography are mediated by both hyperosmolality of the contrast medium and the chemotoxicity of the contrast molecule.


Enantioselective Total Synthesis of (+)-Alterbrassicicene C.
Herein, the first total synthesis of (+)-alterbrassicicene C (2) is described. Key features of the synthesis include an oxiranium mediated ether ring expansion, an oxa-Michael/retro-oxa-Michael cascade, and installation of a vinyl methoxy ether moiety via Stille coupling.


Integrity of White Matter is Compromised in Mice with Hyaluronan Deficiency.
Brain white matter is the means of efficient signal propagation in brain and its dysfunction is associated with many neurological disorders. We studied the effect of hyaluronan deficiency on the integrity of myelin in murine corpus callosum. Conditional knockout mice lacking the hyaluronan synthase 2 were compared with control mice. Ultrastructural analysis by electron microscopy revealed a higher proportion of myelin lamellae intruding into axons of knockout mice, along with significantly slimmer axons (excluding myelin sheath thickness), lower g-ratios, and frequent loosening of the myelin wrappings, even though the myelin thickness was similar across the genotypes. Analysis of extracellular diffusion of a small marker molecule tetramethylammonium (74 MW) in brain slices prepared from corpus callosum showed that the extracellular space volume increased significantly in the knockout animals. Despite this vastly enlarged volume, extracellular diffusion rates were significantly reduced, indicating that the compromised myelin wrappings expose more complex geometric structure than the healthy ones. This finding was confirmed in vivo by diffusion-weighted magnetic resonance imaging. Magnetic resonance spectroscopy suggested that water was released from within the myelin sheaths. Our results indicate that hyaluronan is essential for the correct formation of tight myelin wrappings around the axons in white matter.


Prevalence of antibodies against Toxoplasma gondii in polar bears (Ursus maritimus) from Svalbard and East Greenland.
Serum samples from 419 polar bears (Ursus maritimus) from Svalbard and the Barents Sea (collected 1990-2000) and 108 polar bears from East Greenland (collected 1999-2004) were assayed for antibodies against Toxoplasma gondii using the modified agglutination test. Antibody prevalences were 3.6% among cubs dependent on their mothers and 21.4% among subadults and adults. Among subadults and adults there was an interaction between population and sex, with similar prevalences among females (Svalbard = 19.5%, Greenland = 18.0%), but a high frequency among Svalbard males (28.7%) as compared to Greenland males (5.8%). The pattern was also significant after correcting for differences in age distribution. The sex-population interaction term is believed to be connected to area- and sex-specific feeding ecology. The prevalences of antibodies against T. gondii in Svalbard and Greenland were high compared to previously reported findings in polar bears from Russian and Alaskan areas.


An Ionophore-Based Anion-Selective Optode Printed on Cellulose Paper.
A general anion-sensing platform is reported based on a portable and cost-effective ion-selective optode and a smartphone detector equipped with a color analysis app. In contrast to traditional anion-selective optodes using a hydrophobic polymer and/or plasticizer to dissolve hydrophobic sensing elements, the new optode relies on hydrophilic cellulose paper. The anion ionophore and a lipophilic pH indicator are inkjet-printed and adsorbed on paper and form a "dry" hydrophobic sensing layer. Porous cellulose sheets also allow the sensing site to be modified with dried buffer that prevents any sample pH dependence of the observed color change. A highly selective fluoride optode using an AlIII -porphyrin ionophore is examined as an initial example of this new anion sensing platform for measurements of fluoride levels in drinking water samples. Apart from Lewis acid-base recognition, hydrogen bonding recognition is also compatible with this sensing platform.


Future Advances in Spine Surgery: The AOSpine North America Perspective.
This focus issue highlights state-of-the-art techniques, equipment, and practices in the modern era of spine surgery while providing a glimpse into the next generation of patient care. A broad range of topics are presented to cover the full spectrum of the field. Degenerative diseases are discussed in a series of 3 articles on (1) pathophysiology, management, and surgical approaches to degenerative cervical myelopathy; (2) novel approaches to degenerative thoracolumbar disease (eg, interspinous process spacers, minimally invasive/endoscopic approaches); and (3) animal models and emerging therapeutics in degenerative disk disease. Also included is a unique study aiming to establish the critically important cost-benefit relationship for spine procedures with perspectives on how value is defined and how to address variability.Primary and metastatic spine oncology are reviewed with a focus on upcoming targeted biologics, subspecialized radiotherapy (eg, proton-beam, carbon-ion, stereotactic radiosurgery), genetic profiling to stratify risk, and morbidity-reducing surgical approaches (eg, minimally invasive/endoscopic resections, percutaneous instrumentation). Trauma is discussed in 2 high-quality papers on controversies in spinal trauma and neuroprotective/neuroregenerative interventions for traumatic spinal cord injury. A stimulating article on cervical, thoracolumbar, and pediatric deformity highlights the rapid evolution of deformity surgery with a look at innovative tools (eg, high-fidelity 3-dimensional reconstructions, magnetically controlled growing rods) and their impact on quality of life. Additionally, a must-read article on surgical site infections discusses key risk factors and evidence-based preventative techniques to remain aware of. Finally, cutting-edge technologies, including computer-assisted navigation, shared-control robotics, neuromodulation, novel osteobiologics, and biomaterials, are covered in detail in a series of 3 fascinating papers on the next generation of the field.Each section intends to highlight the salient literature and afford insights from multiple key thought leaders in an effort to minimize bias and provide varied perspectives. Overall, we hope this issue provides high-quality, evidence-based data relevant to trainees and practicing surgeons while also stimulating excitement about the future of spine surgery.


A Missense Mutation in the Vacuolar Protein Sorting 11 (VPS11) Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs.
Canine neuroaxonal dystrophy (NAD) is a recessive, degenerative neurological disease of young adult Rottweiler dogs (Canis lupus familiaris) characterized pathologically by axonal spheroids primarily targeting sensory axon terminals. A genome-wide association study of seven Rottweilers affected with NAD and 42 controls revealed a significantly associated region on canine chromosome 5 (CFA 5). Homozygosity within the associated region narrowed the critical interval to a 4.46 Mb haplotype (CFA5:11.28 Mb - 15.75 Mb; CanFam3.1) that associated with the phenotype. Whole-genome sequencing of two histopathologically confirmed canine NAD cases and 98 dogs unaffected with NAD revealed a homozygous missense mutation within the Vacuolar Protein Sorting 11 (VPS11) gene (g.14777774T > C; p.H835R) that was associated with the phenotype. These findings present the opportunity for an antemortem test for confirming NAD in Rottweilers where the allele frequency was estimated at 2.3%. VPS11 mutations have been associated with a degenerative leukoencephalopathy in humans, and VSP11 should additionally be included as a candidate gene for unexplained cases of human NAD.


Transit dose of an Ir-192 high dose rate brachytherapy stepping source.
Clinical dosimetry for high dose rate (HDR) brachytherapy with a single stepping source generally neglects the transit dose. This study investigates the effects of the transit dose in the target volume of an HDR brachytherapy stepping source. A video method was used to analyse the entrance, exit and the interdwell transit speed of the source for different path lengths and step sizes ranging from 2.5 mm to 995 mm. The transit speed was found to vary with the step size and path length. For the travelled distances of 2.5, 5.0, 10.0, 230 and 995 mm, the average transit speeds were 54, 72, 233, 385 and 467 mm s(-1) respectively. The results also show that the manufacturer has attempted to compensate for the effects of interdwell transit dose by reducing the actual dwell time of the source. A well-type chamber was used to determine the dose differences between two sets of measurements, one being the stationary dose only and the other being the sum of stationary and transit doses. Single catheters of active lengths of 20 and 40 mm, different dwell times of 0.5, 1, 2 and 5 s and different step sizes of 2.5, 5 and 10 mm were used in the measurements with the well-type chamber. Most of the measured dose differences between stationary and stationary plus interdwell source movement were within 2%. The additional dose due to the source transit can be as high as 24.9% for the case of 0.5 s dwell time, 10 mm step size and 20 mm active length. The dose difference is mainly due to the entrance and exit source movement but not the interdwell movement.


Panoptes: web-based exploration of large scale genome variation data.
The size and complexity of modern large-scale genome variation studies demand novel approaches for exploring and sharing the data. In order to unlock the potential of these data for a broad audience of scientists with various areas of expertise, a unified exploration framework is required that is accessible, coherent and user-friendly. Panoptes is an open-source software framework for collaborative visual exploration of large-scale genome variation data and associated metadata in a web browser. It relies on technology choices that allow it to operate in near real-time on very large datasets. It can be used to browse rich, hybrid content in a coherent way, and offers interactive visual analytics approaches to assist the exploration. We illustrate its application using genome variation data of Anopheles gambiae, Plasmodium falciparum and Plasmodium vivax. Freely available at https://github.com/cggh/panoptes, under the GNU Affero General Public License. firstname.lastname@example.com.


Analysis of bronchovascular downstream blood pressure changes in exercising sheep.
The relative roles of neural and pressure gradient factors, causing a fall or maintenance of bronchial blood flow in exercising sheep, are unknown. These were examined in sheep prepared under thiopentone/isoflurane general anaesthesia with a pulsed Doppler probe mounted on the bronchial artery, and aortic pressure (Pa) catheter in superficial cervical artery. After recovery, Swan-Ganz catheters were inserted under local anaesthesia into the pulmonary artery. Bronchial flow and conductance (Qbr, Cbr), and pressure gradients (Pg; i.e. aortic minus right atrial, Pg_RAP; pulmonary artery, Pg_Ppa; and, left atrial (wedge) Pg_LAP) were derived from continuous records, after switching between downstream sites during and after moderately severe treadmill exercise (3.8 km.h(-1), for 1.7 min, 6 min recovery). The protocol was repeated after combined alpha1,alpha2-adrenoceptor/cholinoceptor blockade using phentolamine methanesulfonate and methscopolamine bromide. Bronchial flow fell in both receptor intact (INT) and (BL) blocked state. Pa rose in INT, but downstream pressures rose only 3.7 (RAP), 2.8 (Ppa) and 2.0 (LAP) mmHg (P for each < 0.05) in both INT and BL. Pg_RAP and Pg_Ppa did not rise, but Pg_LAP rose 4.0 mmHg (P < 0.05). In BL, Pa fell, as did Pg_RAP (7.0 mmHg, P < 0.05), Pg_Ppa (8.9 mmHg, P < 0.001), but Pg_LAP did not change. Thus, downstream pressures change by small amounts, and pressure gradients to RAP and Ppa sites do not change during moderately severe exercise in normal sheep. The fall in Qbr in INT is due to neural factors, but in BL is due to a fall in Pg. The relative rise in Pg_LAP in both INT and BL favours redistribution within total Qbr to the pulmonary capillary/vein/left atrium site.


The Poggendorff illusion in Ruben's Descent from the Cross in Antwerp: Does the illusion even matter?
Two experiments are described, the purpose of which was to investigate the presence of a misalignment illusion caused by Poggendorff-like conditions in two paintings by Peter Paul Rubens, both depicting the Descent from the Cross, one located in Antwerp (Belgium), the other in Lille (France). The first shows a geometrical misalignment made by Rubens in a minor detail, which is considered proof that the artist observed the Poggendorff illusion. The second painting, instead, shows a perfect geometrical alignment in a similar detail. In experiment 1, participants were asked to align a top segment to a lower one in two types of stimuli: a full-size digitally manipulated reproduction of the painting and a Poggendorff-like configuration that recalled the painting's lines displacement and tilt. Adjustments were performed from two distances, one up close (painting distance) and one from below and far (observation distance). Results confirmed the presence of the Poggendorff illusion, but mean adjustments significantly differed from the misalignment perpetrated by Rubens. Experiment 2 was set up in a similar fashion with the Lille painting. Results confirmed the presence of the Poggendorff illusion also in this painting; however, the alignment by Rubens coincides with the geometrical one. Results from both experiments do not support the claim that Rubens observed the Poggendorff illusion and therefore corrected for it in the Antwerp painting. An alternative account is discussed, which relates to the structural layout of the painting.


Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia.
Amplitude-integrated electroencephalogram (aEEG) at <6 hours is the best single outcome predictor in term infants with perinatal asphyxia at normothermia. Hypothermia has been used to treat those infants and proved to improve their outcome. The objectives of this study were to compare the predictive value of aEEG at <6 hours on outcomes in normothermia- and hypothermia-treated infants and to investigate the best outcome predictor (time to normal trace or sleep-wake cycling [SWC]) in normothermia- and hypothermia-treated infants. Seventy-four infants were recruited by using the CoolCap entry criteria, and their outcomes were assessed by using the Bayley Scales of Infant Development II at 18 months. The aEEG was recorded for 72 hours. Patterns and voltages of aEEG backgrounds were assessed. The positive predictive value of an abnormal aEEG pattern at the age of 3 to 6 hours was 84% for normothermia and 59% for hypothermia. Moderate abnormal voltage background at 3 to 6 hours of age did not predict outcome. The recovery time to normal background pattern was the best predictor of poor outcome (96.2% in hypothermia, 90.9% in normothermia). Never developing SWC always predicted poor outcome. Time to SWC was a better outcome predictor for infants who were treated with hypothermia (88.5%) than with normothermia (63.6%). Early aEEG patterns can be used to predict outcome for infants treated with normothermia but not hypothermia. Infants with good outcome had normalized background pattern by 24 hours when treated with normothermia and by 48 hours when treated with hypothermia.


Mooren''s ulcer following extracapsular cataract extraction.
Prior cataract surgery is a recognized risk factor for the development of Mooren''s ulcer, but the demographic and clinical features of a large cohort of such patients have not been described. The authors performed a retrospective review of demographic and clinical data from 14 eyes in 13 patients who developed Mooren's ulcer following extracapsular cataract extraction at Aravind Eye Hospital in Madurai, South India. Eight (62%) of the 13 patients were men and 5 (39%) were women. The median age in our population was 65 years, with a range of 45 to 85 years. The median number of months from surgery to the onset of Mooren's ulcer was 19, with a range of 4 to 156 months. Of the 14 eyes with prior cataract surgery, the location of the ulcer was at or contiguous with the wound in 10 eyes (71%), which was 2.5 times more likely than other circumlimbal locations, and only one patient (8%) had bilateral disease. Mooren''s ulcer may occur following extracapsular cataract extraction and when it does it is most likely to be unilateral and contiguous with the wound. These findings support the notion that exposure of normally concealed corneal antigens may contribute to the pathogenesis of Mooren''s ulcer in some patients.


Structure of isolated tryptophyl-glycine dipeptide and tryptophyl-glycyl-glycine tripeptide: ab initio SCC-DFTB-D molecular dynamics simulations and high-level correlated ab initio quantum chemical calculations.
The tryptophyl-glycine (Trp-Gly) and tryptophyl-glycyl-glycine (Trp-Gly-Gly) peptides have been studied by means of molecular dynamic simulations combined with high-level correlated ab initio quantum chemical and statistical thermodynamic calculations. The lowest energy conformers were localized in the free energy surface. The structures of the different Trp-Gly and Trp-Gly-Gly conformers coexisting in the gas phase have been for the first time reported and their scaled theoretical IR spectra unambiguously assigned and compared with previous gas-phase experimental results. Common geometrical features have been systematically observed for the sequence Trp, Trp-Gly, and Trp-Gly-Gly. In addition, the peptide backbone of Trp-Gly-Gly has been compared with that of the previously studied Phe-Gly-Gly (Reha, D. et. al. Chem. Eur. J. 2005, 11, 6803). From the observed systematic structural behavior between these peptide analogues, it is expected that the gas-phase conformers of other similar aromatic small peptides would present equivalent geometries. The DFT methodology failed to describe the potential energy surface of the studied peptides since the London dispersion energy (not covered in DFT) plays a significant role in the stabilization of most stable conformers.


Activation of afferent renal nerves modulates RVLM-projecting PVN neurons.
Renal denervation for the treatment of hypertension has proven to be successful; however, the underlying mechanism/s are not entirely clear. To determine if preautonomic neurons in the paraventricular nucleus (PVN) respond to afferent renal nerve (ARN) stimulation, extracellular single-unit recording was used to investigate the contribution of the rostral ventrolateral medulla (RVLM)-projecting PVN (PVN-RVLM) neurons to the response elicited during stimulation of ARN. In 109 spontaneously active neurons recorded in the PVN of anesthetized rats, 25 units were antidromically activated from the RVLM. Among these PVN-RVLM neurons, 84% (21/25) were activated by ARN stimulation. The baseline discharge rate was significantly higher in these neurons than those PVN-RVLM neurons not activated by ARN stimulation (16%, 4/25). The responsiveness of these neurons to baroreflex activation induced by phenylephrine and activation of cardiac sympathetic afferent reflex (CSAR) was also examined. Almost all of the PVN neurons that responded to ARN stimulation were sensitive to baroreflex (95%) and CSAR (100%). The discharge characteristics for nonevoked neurons (not activated by RVLM antidromic stimulation) showed that 23% of these PVN neurons responded to ARN stimulation. All the PVN neurons that responded to ARN stimulation were activated by N-methyl-D-aspartate, and these responses were attenuated by the glutamate receptor blocker AP5. These experiments demonstrated that sensory information originating in the kidney is integrated at the level of preautonomic neurons within the PVN, providing a novel mechanistic insight for use of renal denervation in the modulation of sympathetic outflow in disease states such as hypertension and heart failure.


False-negative triple-phase bone scans in spinal cord injury to detect clinically suspect heterotopic ossification: a case series.
Heterotopic ossification (HO) is a complication seen in patients after spinal cord injury (SCI). Triple-phase nuclear bone scanning is the most sensitive test for the detection of HO. This retrospective study assesses whether patients with clinically suspected HO but negative triple-phase nuclear bone scans develop delayed positive nuclear bone scans. A cohort of patients with SCI and clinically suspected HO who underwent triple phase nuclear bone scans over a period of 2 years was identified from retrospective chart review of an acute inpatient SCI rehabilitation service. A subgroup of 7 patients with initially negative but subsequently positive triple-phase nuclear bone scans was identified, and the following data were collected: date, mechanism, admission level, and admission completeness of injury as well as date, number, and results of bone scans. Laboratory studies were also collected during the time of imaging. Over a 2-year period, 343 patients were admitted to the SCI rehabilitation service; 60 patients were suspected of having HO and underwent a total of 85 triple-phase nuclear bone scans. Seven patients were identified with initially negative but subsequently positive bone scans. In patients with clinically suspicious HO but negative bone scans, follow-up scans are indicated to identify initial false-negative studies.


ESMO International Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in countries outside of Europe.
The availability and affordability of safe, effective, high-quality, affordable anticancer therapies are a core requirement for effective national cancer control plans. Online survey based on a previously validated approach. The aims of the study were to evaluate (i) the availability on national formulary of licensed antineoplastic medicines across the globe, (ii) patient out-of-pocket costs for the medications, (iii) the actual availability of the medication for a patient with a valid prescription, (iv) information relating to possible factors adversely impacting the availability of antineoplastic agents and (v) the impact of the country's level of economic development on these parameters. A total of 304 field reporters from 97 countries were invited to participate. The preliminary set of data was posted on the ESMO website for open peer review and amendments have been incorporated into the final report. Surveys were submitted by 135 reporters from 63 countries and additional peer-review data were submitted by 54 reporters from 19 countries. There are substantial differences in the formulary availability, out-of-pocket costs and actual availability for many anticancer medicines. The most substantial issues are in lower-middle- and low-income countries. Even among medications on the WHO Model List of Essential Medicines (EML) the discrepancies are profound and these relate to high out-of-pocket costs (in low-middle-income countries 32.0% of EML medicines are available only at full cost and 5.2% are not available at all, and for low-income countries, the corresponding figures are even worse at 57.7% and 8.3%, respectively). There is wide global variation in formulary availability, out-of-pocket expenditures and actual availability for most licensed anticancer medicines. Low- and low-middle-income countries have significant lack of availability and high out-of-pocket expenditures for cancer medicines on the WHO EML, with much less availability of new, more expensive targeted agents compared with high-income countries.


Paranodal axoglial junction is required for the maintenance of the Nav1.6-type sodium channel in the node of Ranvier in the optic nerves but not in peripheral nerve fibers in the sulfatide-deficient mice.
In myelinated axons, voltage-gated sodium channels specifically cluster at the nodes of Ranvier, while voltage-gated potassium channels are located at the juxtaparanodes. These characteristic localizations are influenced by myelination. During development, Nav1.2 first appears in the predicted nodes during myelination, and Nav1.6 replaces it in the mature nodes. Such replacements may be important physiologically. We examined the influence of the paranodal junction on switching of sodium channel subunits using the sulfatide-deficient mouse. This mutant displayed disruption of paranodal axoglial junctions and altered nodal lengths and channel distributions. The initial switching of Nav1.2 to Nav1.6 occurred in the mutant optic nerves; however, the number of Nav1.2-positive clusters was significantly higher than in wild-type mice. Although no signs of demyelination were observed at least up to 36 weeks of age, sodium channel clusters decreased markedly with age. Interestingly, Nav1.2 stayed in some of the nodal regions, especially where the nodal lengths were elongated, while Nav1.6 tended to remain in the normal-length nodes. The results in the mutant optic nerves suggested that paranodal junction formation may be necessary for complete replacement of nodal Nav1.2 to Nav1.6 during development as well as maintenance of Nav1.6 clusters at the nodes. Such subtype abnormality was not observed in the sciatic nerve, where paranodal disruption was observed. Thus, the paranodal junction significantly influences the retention of Nav1.6 in the node, which is followed by disorganization of nodal structures. However, its importance may differ between the central and peripheral nervous system.


Metal(loid)s content in Concholepas concholepas (Mollusca) and human health assessment in a coastal environmental sacrifice zone, central Chile (∼32°S).
In seafood, the study of metal(loid)s is essential to assess their toxicity and to establish risks of human exposure. This study investigates the content of As, Cd, Cu, Ni and Pb in Concholepas concholepas in a coastal environmental sacrifice zone (Chile) to assess potential human-health risks by consumption of C. concholepas. The Cu and Cd content was found to be above the safety level established in chilean and international regulations. The Estimated Daily Intake (EDI) and Target Hazard Quotient (THQ) for As were comparatively high with respect to the other metals analysed. The THQ-As and Hazard Index (HI) suggest a moderate carcinogenic risk due to the consumption of C. concholepas in six of the nine sectors analysed. THQ and HI are reasonable indicators to assess risks to human-health from the consumption of shellfish with HMs. C. concholepas can be considered as a biomonitor to study metal(loid)s on the Chilean coast.


Biopsychosocial approach to tendinopathy.
Tendinopathy describes a spectrum of changes that occur in damaged tendons, leading to pain and reduced function that remains extremely challenging for all clinicians. There is an increasing awareness of the influence that psychological and psychosocial components, such as self-efficacy and fear-avoidance, have on rehabilitation outcomes in musculoskeletal medicine. Although it is widely accepted that psychological/psychosocial factors exist in tendinopathy, there is currently a distinct lack of trials measuring how these factors affect clinical outcomes. Biopsychosocial treatments acknowledge and address the biological, psychological and social contributions to pain and disability are currently seen as the most efficacious approach to chronic pain. Addressing and modulating these factors are crucial in the pathway of personalised treatments in tendinopathy and offer a real opportunity to drive positive outcomes in patients. In this education review, we also provide the current evidence-based guidance on psychological and psychosocial developments in musculoskeletal medicine and how these may be translated to treating tendinopathy using a biopsychosocial model.


Effects of vitamin D supplementation on upper and lower body muscle strength levels in healthy individuals. A systematic review with meta-analysis.
To investigate the effects of vitamin D supplementation on muscle strength in healthy individuals. A systematic review with meta-analysis. In October 2013 a computerised literature search of three databases (PubMed, Web of Knowledge and Scopus) was performed. Included in the review were controlled and randomised controlled trials, published in English, which measured muscle strength and serum vitamin D concentration in participants 18-40 years old. References of identified articles were then cross-checked and citations scanned for additional articles. Quality was assessed using the PEDro scale. Muscle strength and vitamin D levels were extracted for a meta-analysis on upper and lower limb strength with standardised mean differences calculated to analyse effect. Six randomised controlled trials and one controlled trial were identified and quality assessment showed all seven trials were of 'good quality'. Data was extracted from 310 adults, 67% female, with mean ages ranging from 21.5 to 31.5 years. Trials lasted from 4 weeks to 6 months and dosages differed from 4000 IU per day to 60,000 IU per week. Upper and lower limb muscle strength had a standardised mean difference of 0.32 (95% CI=0.10, 0.54) and 0.32 (95% CI=0.01, 0.63) respectively, suggesting vitamin D supplementation significantly increased muscle strength in the experimental group for upper (P=0.005) and lower limbs (P=0.04). Vitamin D supplementation increases upper and lower limb strength. Further research should focus on its effect on muscle power, endurance and maximal strength.


Life events and survival in dementia: a 5-year follow-up study.
To examine the relationship between life events and survival for people with dementia. To investigate whether this relationship differs from that for people without dementia. To identify which psychiatric and social factors are associated with survival in people with dementia. A prospective cohort study with external controls. One hundred and sixteen people with dementia and 50 fit, elderly controls were assessed for life events over a 6-month period. They were followed-up at 5 years and data collected on length of survival. There was an association between two or more severe life events and reduced survival. This association appeared stronger for controls than people with dementia although the interaction was not significant (p = 0.052). The only psychiatric or social factor associated with poor survival in dementia was depression. Other factors associated with reduced survival in the dementia group were male sex, older age, poor physical health, later age of onset and a poorer level of functioning. This study provides some evidence that having two or more stressful and negative life events may reduce survival in older people with and without dementia. If replicated, this finding will have implications for our understanding of the clinical course of dementia.


Using self-report to identify the broad phenotype in parents of children with autistic spectrum disorders: a study using the Autism-Spectrum Quotient.
The concept of the 'broad phenotype' of autism refers to the finding that relatives of people with autism often have mild forms of autistic-like characteristics, such as social and communicative difficulties. This study used the Autism Spectrum Quotient (AQ), a questionnaire devised to assess features of the broad phenotype in adults, with parents of people with autism, to see whether they would be more likely to obtain extreme scores than a control group. The AQ was administered to parents of 69 people with an autism spectrum disorder and parents of 52 controls. On two of the five subscales of the AQ, social skills and communication, parents of people with autism obtained higher scores than control parents. The other three scales, attention to detail, attention switching, and imagination, did not differentiate groups. The correlation between social skills and communication scales was .663. The scales can be combined to give an index of broad phenotype. The AQ appears to be sensitive to the broad phenotype, provided attention is restricted to the social skills and communication scales.


[The characteristics of the action of GABA-ergic agents on the brain microcirculation during motor activity and hypodynamia].
Changes in the microcirculatory bed of the rat brain cortex during motor activity and hypodynamia under the action of piracetam, GABA and bicuculline were studied. The possibility of the development of compensatory processes due to the cerebral blood flow increase under the influence of GABA agonists at a disturbance of the cerebral hemodynamics in combination with increased locomotor activity and also due to the improvement of the microcirculation at early stages of hypodynamia induced by administration of GABA agonists opens up new perspectives in the use of GABA-positive drugs.


Blue light regulated two-component systems: enzymatic and functional analyses of light-oxygen-voltage (LOV)-histidine kinases and downstream response regulators.
Light is an essential environmental cue for diverse organisms. Many prokaryotic blue light photoreceptors use light, oxygen, voltage (LOV) sensory domains to control the activities of diverse output domains, including histidine kinases (HK). Upon activation, these proteins autophosphorylate a histidine residue before subsequently transferring the phosphate to an aspartate residue in the receiver domain of a cognate response regulator (RR). Such phosphorylation activates the output domain of the RR, leading to changes in gene expression, protein-protein interactions, or enzymatic activities. Here, we focus on one such light sensing LOV-HK from the marine bacterium Erythrobacter litoralis HTCC2594 (EL368), seeking to understand how kinase activity and subsequent downstream effects are regulated by light. We found that photoactivation of EL368 led to a significant enhancement in the incorporation of phosphate within the HK domain. Further enzymatic studies showed that the LOV domain affected both the LOV-HK turnover rate (kcat) and Km in a light-dependent manner. Using in vitro phosphotransfer profiling, we identified two target RRs for EL368 and two additional LOV-HKs (EL346 and EL362) encoded within the host genome. The two RRs include a PhyR-type transcriptional regulator (EL_PhyR) and a receiver-only protein (EL_LovR), reminiscent of stress-triggered systems in other bacteria. Taken together, our data provide a biochemical foundation for this light-regulated signaling module of sensors, effectors, and regulators that control bacterial responses to environmental conditions.


[Genetic structure of geographically different populations of candida albicans].
Codominant single-locus markers were developed by amplifying genomic DNA of C. albicans with pairs of random primers. Monomorphic PCR products were screened for polymorphisms by the SSCP technique. Sequencing confirmed that SSCP's were mostly due to single nucleotide substitutions in the polymorphic fragments. A total of 85 polymorphic loci were observed within 13 PCR fragments. Populations from Africa displayed less genotype variation than the populations from Europe and USA. Two genetically similar African C. albicans populations exhibiting an atypical biotype were strictly clonal and perhaps represent a geographically distributed clone. Analyses of "typical" C. albicans populations of different geographical origin provided however evidence for both clonality and recombination. Evidence for clonality was supported by the absence of segregation genotypes, and by deviation of genotypic frequencies from Hardy-Weinberg expectations. Tests for nonrandom association of alleles across loci revealed less evidence for linkage disequilibrium than expected for strictly clonal populations. Although all C. albicans populations tested were primarily clonal, evidence for recombination suggests that sexual reproduction or some other form of genetic exchange occurs in this species.


RNA sequence determinants of a coupled termination-reinitiation strategy for downstream open reading frame translation in Helminthosporium victoriae virus 190S and other victoriviruses (Family Totiviridae).
The genome-length, dicistronic mRNA of the double-stranded RNA fungal virus Helminthosporium victoriae virus 190S (genus Victorivirus, family Totiviridae) contains two long open reading frames (ORFs) that overlap in the tetranucleotide AUGA. Translation of the downstream ORF, which encodes the RNA-dependent RNA polymerase (RdRp), has been proposed to depend on ribosomal reinitiation following termination of the upstream ORF, which encodes the capsid protein. In the current study, we examined the RNA sequence determinants for RdRp translation in this virus and demonstrated that a coupled termination-reinitiation (stop-restart) strategy is indeed used. Signals for termination-reinitiation are found within a 32-nucleotide stretch of RNA immediately upstream of the AUGA motif, including a predicted pseudoknot structure. The close proximity in which this predicted structure is followed by the upstream ORF's stop codon appears to be especially important for promoting translation of the downstream ORF. The normal strong preferences for an AUG start codon and the canonical sequence context to favor translation initiation appear somewhat relaxed for the downstream ORF. Similar sequence motifs and predicted RNA structures in other victoriviruses suggest that they all share a related stop-restart strategy for RdRp translation. Members of the genus Victorivirus thus provide new and unique opportunities for exploring the molecular mechanisms of translational coupling, which remain only partly understood in this and other systems.


[Levitra in the treatment of patients with chronic prostatitis associated with sexual dysfunction].
Sixty patients with chronic prostatitis and sexual dysfunction were divided into two groups. All the patients received one-month standard course of physiotherapy. In addition, group I (n = 30) was given levitra (vardenafil; 5 mg per os each other day), the control group was not given this drug. Follow-up covered 6 months to 1.5 years. General urological examination, questionnaire survey, ultrasound investigation of male genital organs were made before, 1 and 6 months after treatment. The results were processed statistically. Levitra improves circulation in male sexual organs promoting increased arterial inflow to the prostate and penis. Aftertreatment effect persisted for half a year. Regular levitra intake (2-3 times a week) is recommended to correct circulation in the sexual system, including prostatic gland, but not only for correction of erectile dysfunction as a result of psychogenic and vascular disorders in the penis accompanying chronic prostatitis.


Endovascular graft repair of penetrating subclavian artery injuries.
Penetrating subclavian arterial injuries are often difficult to treat. Standard surgical techniques require wide exposure and dissection in traumatized areas, which is often challenging. This report summarizes the early results of endovascularly placed stented grafts for the treatment of penetrating subclavian arterial trauma. Six patients with penetrating injuries of the subclavian artery had stented grafts inserted to repair five pseudoaneurysms and one arteriovenous fistula. The stented grafts consisted of a polytetrafluoroethylene graft sutured over a balloon-expandable Palmaz stent. The devices were inserted from an ipsilateral brachial arteriotomy and deployed using fluoroscopic guidance in the operating room. Immediate success was obtained in all procedures (100%). All patients continue to have patent grafts with a follow-up ranging from 7 to 30 months (mean 19 months). The only procedure-related complication was the need for a brachial artery patch angioplasty at the site of device insertion in the first patient. There was one other patient who developed a stent fracture at 8 months; a second stent was inserted. Duplex studies up to 24 months later show no recurrence in this patient. Endovascular stented grafts offer an effective, less invasive alternative to standard techniques in treating traumatic arterial lesions. Early results are encouraging, but long-term follow-up will be necessary to fully delineate the effectiveness of this technique.


Differences in neurochemical profiles of two gadid species under ocean warming and acidification.
Exposure to future ocean acidification scenarios may alter the behaviour of marine teleosts through interference with neuroreceptor functioning. So far, most studies investigated effects of ocean acidification on the behaviour of fish, either isolated or in combination with environmental temperature. However, only few physiological studies on this issue were conducted despite the putative neurophysiological origin of the CO2-induced behavioural changes. Here, we present the metabolic consequences of long-term exposure to projected ocean acidification (396-548 μatm PCO2 under control and 915-1272 μatm under treatment conditions) and parallel warming in the brain of two related fish species, polar cod (Boreogadus saida, exposed to 0 °C, 3 °C, 6 °C and 8 °C) and Atlantic cod (Gadus morhua, exposed to 3 °C, 8 °C, 12 °C and 16 °C). It has been shown that B. saida is behaviourally vulnerable to future ocean acidification scenarios, while G. morhua demonstrates behavioural resilience. We found that temperature alters brain osmolyte, amino acid, choline and neurotransmitter concentrations in both species indicating thermal responses particularly in osmoregulation and membrane structure. In B. saida, changes in amino acid and osmolyte metabolism at the highest temperature tested were also affected by CO2, possibly emphasizing energetic limitations. We did not observe changes in neurotransmitters, energy metabolites, membrane components or osmolytes that might serve as a compensatory mechanism against CO2 induced behavioural impairments. In contrast to B. saida, such temperature limitation was not detected in G. morhua; however, at 8 °C, CO2 induced an increase in the levels of metabolites of the glutamate/GABA-glutamine cycle potentially indicating greater GABAergic activity in G.morhua. Further, increased availability of energy-rich substrates was detected under these conditions. Our results indicate a change of GABAergic metabolism in the nervous system of Gadus morhua close to the optimum of the temperature range. Since a former study showed that juvenile G. morhua might be slightly more behaviourally resilient to CO2 at this respective temperature, we conclude that the observed change of GABAergic metabolism could be involved in counteracting OA induced behavioural changes. This may serve as a fitness advantage of this respective species compared to B. saida in a future warmer, more acidified polar ocean.


Requirement of Na+ and K+ for the action of antidiuretic hormone on water permeability.
Previous reports have shown that in the toad bladder the absence of serosal Na+ or K+ inhibits the action of antidiuretic hormone (ADH) on the osmotic permeability (Pf) but not on diffusional permeability (PDW) to water. This dissociation could be due to unstirred layers with low PDW, precluding detection of changes in the PDW of the cells. When serosal Na+ was replaced by choline, Pf (micrometer/s) was inhibited from 201 to 65. In the same conditions, if appropriate corrections were made to allow for the PDW of unstirred layers in the bulk phase and stroma, the PDW (micrometers/s) of the cellular pathway decreased from 19.8 to 15.9. The Pf/PDW ration then became 10 in the presence of serosal Na+ and 11 in its absence. When serosal K+ was deleted Pf decreased from 197 to 127 and PDW (corrected for unstirred layers) from 19.8 to 13.1 The Pf/PDW ratio was 10, both in the presence and absence of serosal K+. In conclusion, it is impossible to estimate the effect of any given experimental manipulation on the ADH-induced increase in PDW and compare it with the effect of Pf unless attention is paid to the restrictions upon measurements of diffusion imposed by unstirred layers. The deletion of Na+ or K+ from the serosa inhibits the effect of ADH on Pf and PDW to the same extent. Therefore, their presence in the serosa is essential for a full effect of ADH on the permeability to water of the apical membrane.


When sleep-related hypermotor epilepsy (SHE) met Charles Darwin and Francis Galton.
Sleep-related hypermotor epilepsy (SHE) is characterized by short-lasting seizures patterned by repetitive and stereotyped motor events in the same person. In autosomal dominant SHE, genetic factors play a well-known key role. In The Expression of Emotions in Man and Animals, Charles Darwin quotes a plausible example of SHE illustrated by his cousin Sir Francis Galton: "the gentleman…lay fast asleep on his back in bed, raising his right arm slowly in front of his face, up to his forehead, and then dropping it with a jerk, so that the wrist fell heavily on the bridge of his nose. The trick did not occur every night, but occasionally, and was independent of any ascertained cause. Sometimes it was repeated incessantly for an hour or more." Similar manifestations during sleep occurred also in the patient's son and granddaughter, suggesting an autosomal inheritance without sex relationship. Differential diagnosis with REM behavior disorder and other parasomnias is discussed. To our knowledge, this could be the first description of a stereotyped SHE pattern with genetic transmission.


Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer disease.
Cell bodies of neurons at risk of death in Alzheimer disease (AD) have increased lipid peroxidation, nitration, free carbonyls, and nucleic acid oxidation. These oxidative changes are uniform among neurons and are seen whether or not the neurons display neurofibrillary tangles and, in fact, are actually reduced in the latter case. In consideration of this localization of damage, in this review, we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote neuronal oxidative damage. First, mitochondrial abnormalities might be the source of reactive oxygen species yielding perikaryal oxidative damage. The common 5-kb deletion mitochondrial (mt)DNA subtype was greatly increased in the AD cases, but only in neurons at risk. The importance of such mitochondrial abnormalities to oxidative stress was indicated by a high correlation coefficient between the extent of the mtDNA increase and RNA oxidative damage (r2 = 0.87). Nonetheless, because mitochondria in AD do not show striking oxidative damage, as one would expect if they were the direct producer of free radical species, we suspected that abnormal mitochondria supply a key reactant that, once in the cytoplasm, releases radicals. One such reactant, hydrogen peroxide, (H2O2), abundant in mitochondria, can react with iron via the Fenton reaction to produce.OH. To demonstrate this directly using a modified cytochemical technique that relies on the formation of mixed valence iron complexes, we found that redox-active iron is associated with vulnerable neurons. Interestingly, removal of iron was completely affected by using deferroxamine, after which iron could be rebound to re-establish lesion-dependent catalytic redox reactivity. Characterization of the iron-binding site suggests that binding is dependent on available histidine residues and on protein conformation. Taken together with our previous studies showing abnormalities in the iron homeostatic system including heme oxygenase, iron regulatory proteins 1 and 2, ceruloplasmin, and dimethylargininase, our results indicate that iron misregulation could play an important role in the pathogenesis of AD and therefore chelation therapy may be a useful therapeutic approach. Finally, we wanted to determine the proximal cause of mitochondrial abnormalities. One interesting mechanisms involves re-entry into the cell cycle, at which point organellokinesis and proliferation results in increased mitochondria. Supporting this, we have considerable in vivo and in vitro evidence for mitotic disturbances in AD and its relationship with the pathogenesis of AD.


Depletion of linoleate induced by weight cycling is independent of extent of calorie restriction.
Recent epidemiological studies have suggested that weight cycling induced by repeated dieting over time may increase the risk of cardiovascular disease. It is speculated that the increased mortality from coronary heart disease for people with a history of excessive weight cycling could be attributed to change in lipid metabolism. Previous studies have demonstrated that repeated cycling of 100% food restriction followed by ad libitum refeeding caused a depletion of linoleate and alpha-linolenate in rats. The objective of the present study was to test the hypothesis that the weight cycling-induced reduction in linoleate and alpha-linolenate is independent of extent of calorie restriction. Two consecutive weight cycles in three experiments were induced by 100% calorie restriction, 60% calorie restriction, and 36% calorie restriction, respectively, followed by ad libitum refeeding. As the consequence of the two weight cycles, linoleate and linolenate were decreased, whereas myristate, palmitate, and palmitoleate were proportionally increased in carcass and adipose tissue lipids. The results of all three experiments showed a preferential depletion of linoleate and alpha-linolenate without changes in final body weight, total body fat, and adipose tissue pads in the weight-cycled rats. In addition, the triacylglycerol species profile in the adipose tissue of weight-cycled rats was significantly remodeled, with a proportional depletion of linoleate-enriched triacylglycerol species (LLL, LLO, and LLP, where L, O, and P are linoleic, oleic, and palmitic acid, respectively) and a proportional accumulation of palmitate-enriched triacylglycerol species (OPPo, PPPo, and PPP, where Po is palmitoleic acid). We conclude that weight cycling changes the ratio of polyunsaturated fatty acids to saturated fatty acids and remodels the adipose tissue triacylglycerol species profile in rats.


Fast excited-state intramolecular proton transfer and subnanosecond dynamic stokes shift of time-resolved fluorescence spectra of the 5-methoxysalicylic acid/diethyl ether complex.
Excited-state intramolecular proton transfer (ESIPT) occurring in the salicylic acid (SA) derivative 5-methoxysalicylic acid (5-MeOSA) in an apolar solvent (cyclohexane) and in the presence of the hydrogen bond accepting agent diethyl ether (DEE) is investigated. Analysis of the directly measured subnanosecond time-resolved emission spectra (TRES) together with conventional steady-state fluorescence and time-correlated single-photon-counting (TCSPC) decays indicates that ESIPT in this system occurs much faster than fluorescence, and that the equilibrium between normal and tautomeric excited states is established before the emission from both states takes place. However, changes in time- and frequency-resolved fluorescence of the 5-MeOSA/DEE complex are observed due to structural relaxation within the complex, which is reflected in the dynamic Stokes shift of the tautomeric fluorescence band. The normal fluorescence band of 5-MeOSA/DEE does not exhibit marked changes within the investigated time range. A single-exponential relaxation time of 460 ps was determined for the dynamic Stokes shift of the tautomeric band, and it is attributed to a geometric change within the 5-MeOSA/DEE complex upon excitation. Since both tautomeric and normal emission bands are well resolved and exhibit different time-dependent behaviors, a double-well potential appears to be adequate to describe the excited state of the system studied.


A MEQ-deleted Marek's disease virus cloned as a bacterial artificial chromosome is a highly efficacious vaccine.
The Marek's disease virus (MDV) induces T-cell tumors in susceptible chickens. Of the 80 to 100 known MDV genes, only the MDV MEQ gene was shown to have transforming properties. Further evidence that MEQ is probably the principal oncogene in MDV came when researchers used overlapping cosmid clones of MDV and demonstrated that deleting MEQ resulted in a highly protective Marek's disease (MD) vaccine. We deleted both copies of MEQ from a bacterial artificial chromosome clone (BAC) of MDV. The virus, BACdelMEQ, was completely attenuated and did not appear to have any adverse effect on chicken body weight in MDV maternal-antibody-positive chickens, as measured at 8 wk of age. In two protection studies, BACdelMEQ efficiently protected susceptible chickens from a challenge by MDV strain 686, one of the most virulent MDV strains. In both protection studies, the BACdelMEQ protected chickens significantly better than the commercial MD vaccine, CVI988/Rispens. Only the protein-coding sequences of MEQ were deleted and all upstream and downstream regulatory sequences were left intact. Thus, BACdelMEQ has the potential to be a superior MD vaccine as well as a vector to deliver various foreign genes to poultry.


Incidence, risk, and outcome of reintervention after aortocoronary bypass surgery.
Reintervention was required in 123 (12%) individuals during a follow up (mean 7.5 years, range 5-14.5) of 1041 patients with consecutive, isolated, first aortocoronary bypass operations. In 89 patients the intervention was a repeat bypass operation, in 24 it was angioplasty, and 10 had both. Procedure related mortality was significantly higher at reintervention (5.6%) than at the primary operation (1.2%). Survival probability after a single bypass procedure was 90% at six years and 82(3)% at nine years. Corresponding figures six and nine years after reintervention were 89(6)% and 87(7)% respectively. Stepwise multivariate analysis showed that survival was significantly correlated with left ventricular function (rate ratio 1.82) and with extent of vascular disease (rate ratio 1.80) but not with reintervention (rate ratio 1.45). Symptomatic improvement occurred in 89% of the survivors with or without reintervention. Repeat procedures are often necessary after coronary artery bypass grafting but they appear to provide appreciable relief of symptoms without reducing any long term improvement in survival brought about by the original operation.


Effective penile block for circumcision in adults.
The dorsal nerve block of the penis during circumcision has not been standardized and the effectiveness of the block can be changeable. The aim of this study was to determine which technique is more suitable for blocking sensory innervations of penis. This prospective study was done on adults who voluntarily applied to be circumcised. Patients were randomized into three distinctive groups; first, just circular infiltration; second, circular plus dorsal penile infiltration; and third, circular plus ventral upward infiltration. Sensation was tested using pinprick sensory testing before and after infiltration. The total duration of the procedure was recorded. In total, 89 adult uncircumcised men were included into the study. The average age of men was 21.4 (min: 20; max: 25). The average operation time in the third group was significantly shorter. The sensation distribution, especially around the frenulum sensitivity results were in the first minute 100, 81.3, 72.4 %; in the third minute 85.7, 37.5, 20.7 %; and in the fifth minute 57.1, 18.8, and 0 % for the first, second, and third group, respectively. In the fifth minute, there was no sensitivity for any patients in the third group and it was significant. Circular plus ventral upward anesthesia is an easy and feasible technique for local anesthesia in circumcision.


Prorenin-renin conversion by the contact activation system in human plasma: role of plasma protease inhibitors.
Acid-pretreated normal human plasma generates renin activity at 0 degree C and neutral pH by the activation of prorenin. The activation is caused by kallikrein generated from prekallikrein by activated factor XII. Nonacidified plasma also generates renin at 0 degree C, but at a lower rate (cold-promoted activation). In normal plasma, 14% +/- 1% of prorenin (mean +/- SEM, n = 30) was activated during incubation at 0 degree C for 7 days (range 6% to 26%). Cold-promoted activation of prorenin was within the normal range in plasma deficient in factor XI, X, IX, VIIIC, VII, V, prothrombin, or high mol wt kininogen. Cold-promoted activation of prorenin was less than or equal to 1% in plasma deficient in factor XII or prekallikrein. Reconstitution of these plasmas with highly purified factor XII or prekallikrein restored normal prorenin activation. Correction of high mol wt kininogen deficiency had no effect. Thus cold-promoted activation of prorenin depends on the presence of factor XII and prekallikrein, whereas the other clotting factors are not essential. The influence of the inhibitors C1 esterase-inhibitor, alpha 2-macroglobulin, antithrombin III, and alpha 1-antitrypsin on the activation of prorenin was studied in factor XII-deficient plasma from which one or more of these inhibitors had been selectively removed by immunoadsorption. Factor XII was subsequently added, and the generation of renin at 37 degrees C was observed after complete factor XII-high mol wt kininogen-mediated activation of prekallikrein induced by dextran sulfate. No activation of prorenin was observed at 37 degrees C after depletion of C1 esterase inhibitor, alpha 2-macroglobulin, antithrombin III, or alpha 1-antitrypsin. When prekallikrein was activated in plasma depleted of both C1 esterase-inhibitor and alpha 2-macroglobulin, 6% of prorenin was activated in 2 hours at 37 degrees C. After additional depletion of antithrombin III, the activation increased to 47%. These results indicate that the contact activation system is capable of activating prorenin in plasma at physiologic pH and temperature when the three most important kallikrein inhibitors, C1 esterase-inhibitor, alpha 2-macroglobulin, and antithrombin III, are absent.


Wave propagation in 0-3/3-3 connectivity composites with complex microstructure.
This work presents a study of the properties of particulate composites. The whole range of particle volume fraction (0-1) and ideal 0-3, 3-3 and intermediate 0-3/3-3 connectivities are analysed. Two different approaches to produce a realistic model of the complex microstructure of the composites are considered. The first one is based on a random location of mono-dispersed particles in the matrix; while the second incorporates a size distribution of the particles based on experimental measurements. Different particle shapes are also considered. A commercial finite element package was used to study the propagation of acoustic plane waves through the composite materials. Due to the complexity of the problem, and as a first step, a two-dimensional model was adopted. The results obtained for the velocity of sound propagation from the finite element technique are compared with those from other theoretical approaches and with experimental data. The study validates the use of this technique to model acoustic wave propagation in 0-3/3-3 connectivity composites. In addition, the finite element calculations, along with the detailed description of the microstructure of the composite, provide valuable information about the micromechanics of the sample and the influence of the microstructure on macroscopic properties.


Real-time tissue elastography as a tool for the noninvasive assessment of liver stiffness in patients with chronic hepatitis C.
Although histopathological examination by "invasive" liver biopsy remains the gold standard for evaluating disease progression in chronic liver disease, noninvasive tools have appeared and have led to great progress in diagnosing the stage of hepatic fibrosis. The aim of this study was to assess the value of real-time tissue elastography, using an instrument made in Japan, for the visible measurement of liver elasticity; in particular, comparing the results with those of transient elastography (Fibroscan). Real-time tissue elastography (RTE), transient elastography (Fibroscan), liver biopsy, and routine laboratory analyses were performed in 101 patients with chronic hepatitis C. The values for tissue elasticity obtained using novel software (Elasto_ver 1.5.1) connected to RTE were transferred to four image features, Mean, Standard Deviation (SD), Area, and Complexity. Their association with the stage of fibrosis at biopsy and with liver stiffness (kPa) obtained by Fibroscan was analyzed. Colored images obtained by RTE were classified into diffuse soft, intermediate, and patchy hard patterns and the calculated elasticity differed significantly between patients according to and correlated with the stages of fibrosis (p < 0.0001). Mean, SD, Area, and Complexity showed significant differences between the stages of fibrosis (Tukey-Kramer test, p < 0.05). In discriminating patients with cirrhosis, the areas under the receiver operating characteristic curves (AUC) were 0.91 for Mean, 0.84 for SD, 0.91 for Area, 0.93 for Complexity, and 0.95 for Fibroscan. RTE is a noninvasive instrument for the colored visualization of liver elasticity in patients with chronic liver disease.


Non-invasive advanced respiratory support in end-of-life care and symptom management: systematic review.
To narrate the canon of knowledge around symptom control at end of life for patients using, or having recently used, non-invasive advanced respiratory support (NARS) at end of life for respiratory failure. A systematic review forming a narrative synthesis from a wide range of sample papers from Medline, Embase, CINAHL, Emcare, Cochrane and OpenGrey databases. A secondary search of grey literature was also performed with hand searching reference lists and author citations. The review was undertaken using the ENTREQ checklist for quality. In total, 22 studies were included in the synthesis and four themes were generated: NARS as a buoy (NARS can represent hope and relief from the symptoms of respiratory failure), NARS as an anchor (NARS brings significant treatment burden), Impact on Staff (uncertainty over the balance of benefit and burden as well as complex patient care drives distress among staff providing care) and the Process of Withdrawal (withdrawal of therapy felt to be futile exists as discrete event in patient care but is otherwise poorly defined). NARS represents a complex interplay of hope, symptom control, unnaturally prolonged death and treatment burden. The literature captures the breadth of these issues, but further, detailed, research is required in almost every aspect of practice around end-of-life care and NARS-especially how to manage symptoms at the end of life.


Emergency physicians' views of direct notification of laboratory and radiology results to patients using the Internet: a multisite survey.
Patients are increasingly using the Internet to communicate with health care providers and access general and personal health information. Missed test results have been identified as a critical safety issue with studies showing up to 75% of tests for emergency department (ED) patients not being followed-up. One strategy that could reduce the likelihood of important results being missed is for ED patients to have direct access to their test results. This could be achieved electronically using a patient portal tied to the hospital's electronic medical record or accessed from the relevant laboratory information system. Patients have expressed interest in accessing test results directly, but there have been no reported studies on emergency physicians' opinions. The aim was to explore emergency physicians' current practices of test result notification and attitudes to direct patient notification of clinically significant abnormal and normal test results. A cross-sectional survey was self-administered by senior emergency physicians (site A: n=50; site B: n=39) at 2 large public metropolitan teaching hospitals in Australia. Outcome measures included current practices for notification of results (timing, methods, and responsibilities) and concerns with direct notification. The response rate was 69% (61/89). More than half of the emergency physicians (54%, 33/61) were uncomfortable with patients receiving direct notification of abnormal test results. A similar proportion (57%, 35/61) was comfortable with direct notification of normal test results. Physicians were more likely to agree with direct notification of normal test results if they believed it would reduce their workload (OR 5.72, 95% CI 1.14-39.76). Main concerns were that patients could be anxious (85%, 52/61), confused (92%, 56/61), and lacking in the necessary expertise to interpret their results (90%, 55/61). Although patients' direct access to test results could serve as a safety net reducing the likelihood of abnormal results being missed, emergency physicians' concerns need further exploration: which results are suitable and the timing and method of direct release to patients. Methods of access, including secure Web-based patient portals with drill-down facilities providing test descriptions and result interpretations, or laboratories sending results directly to patients, need evaluation to ensure patient safety is not compromised and the processes fit with ED clinician and laboratory work practices and patient needs.


Computerized navigation for the internal fixation of femoral neck fractures.
Accurate placement of cannulated screws is essential to ensure secure fixation of femoral neck fractures. We compared computerized navigation and conventional fluoroscopy with regard to the accuracy of screw placement for the fixation of femoral neck fractures. We retrospectively compared two groups of twenty consecutive patients with a femoral neck fracture who underwent internal fixation with three cannulated screws. Computer-based navigation was used to guide screw placement in one group, and conventional fluoroscopy was used in the other group. Radiographic evaluation included the measurement of screw parallelism and spread, the calibrated distance from the lesser trochanter, and joint penetration. The follow-up period was two years. The rates of complications in both groups were evaluated. The navigation-assisted group had better screw parallelism and greater spread of the screws. There was a tendency for fewer reoperations and significantly fewer overall complications in the patients in whom computerized navigation was used (p < 0.018). Computerized navigation improves the accuracy of cannulated screw placement in the internal fixation of femoral neck fractures. It may provide better mechanical stability and improved fracture outcome.


Corticosterone facilitates saccharin intake in adrenalectomized rats: does corticosterone increase stimulus salience?
Unlike normal rats, adrenalectomized rats do not voluntarily drink sweet saccharin solutions. To test whether this is a function of corticosterone in the circulation, and if corticosterone also increases the impetus for drinking saccharin after a period of withdrawal, we performed the following experiments. Young male rats were sham adrenalectomized (sham) or adrenalectomized (ADX); the ADX rats were provided with subcutaneous pellets containing (percent replacement of corticosterone, %B) 0%B, 15%B, 30%B or 100%B. Sham and ADX rats were immediately provided with saline (0.5%) and saccharin (2 mM) bottles in their home cages. Saccharin was allowed for 4 days on, 3 days off, 4 days on, 3 days off and a final day on, over the 15 days experiment. The dose of corticosterone determined both how much saccharin was voluntarily drunk by the ADX rats and the degree of overshoot after days off. Corticosterone also determined energy balance of the groups of ADX rats. The 30%B pellets restored food intake, body weight gain, insulin and caloric efficiency to the normal levels observed in sham rats. White fat depot weights and uncoupling protein concentration in brown adipose tissue were restored to sham levels by 100%B, suggesting that these variables which depend on activity in the sympathetic nervous system require considerable glucocorticoid receptor occupancy. We conclude that corticosterone increases the willingness to ingest sweetened water in a unimodal, dose-related manner, while moderate doses of corticosterone restore energy balance.