Interval cryotherapy decreases fatigue during repeated weight lifting.
To investigate the effect of icing the arm and shoulder between weight-pulling sets on work, velocity, and power. I used a 1 x 2 factorial, random, counterbalanced design in which each participant pulled 75 per thousand of his 1-repetition maximum on 2 separate days. The individuals pulled the weight 22 times for each set as fast as possible, then either iced (cryotherapy) or placed towels over their arms and shoulders for 3 minutes, and then rested 4.5 minutes at room temperature. The sets continued until the participants could not complete 22 pulls without stopping. Ten male members of a private athletic club, who weight lift on a regular basis, volunteered to participate in the study. Work was determined by the number of arm-pull sets completed before fatigue, velocity was measured by the time to complete each set, and power was determined by dividing work by velocity. Velocity and power were analyzed in 3 ways: first to fourth sets (88 pulls), matched sets (167.2 pulls), and all sets (191.4 cryotherapy and 167.2 towel pulls), using analysis of covariance with the base set as the covariate. Cryotherapy between sets resulted in a significantly greater number of total joules and arm pulls when compared with the towel treatment. Velocity was significantly faster for the first to fourth sets, matched sets, and all sets when subjects received intermittent cryotherapy. Power also was significantly higher for the first to fourth sets and matched sets. The all-sets comparison consisted of 14.5 per thousand more cryotherapy arm pulls. Interval cryotherapy between weight-pulling sets is associated with increased work, velocity, and power.


A DNA microarray-based analysis of the host response to a nonviral gene carrier: a strategy for improving the immune response.
The purpose of this study was to investigate the host response to systemically administered lipid nanoparticles (NPs) encapsulating plasmid DNA (pDNA) in the spleen using a DNA microarray. As a model for NPs, we used a multifunctional envelope-type nano device (MEND). Microarray analysis revealed that 1,581 of the differentially expressed genes could be identified by polyethylene glycol (PEG)-unmodified NP using a threefold change relative to the control. As the result of PEGylation, the NP treatment resulted in the reduction in the expression of most of the genes. However, the expression of type I interferon (IFN) was specifically increased by PEGylation. Based on the microarray and a pathway analysis, we hypothesize that PEGylation inhibited the endosomal escape of NP, and extended the interaction of toll-like receptor-9 (TLR9) with CpG-DNA accompanied by the production of type I IFN. This hypothesis was tested by introducing a pH-sensitive fusogenic peptide, GALA, which enhances the endosomal escape of PEGylated NP. As expected, type I IFN was reduced and interleukin-6 (IL-6) remained at the baseline. These findings indicate that a carrier design based on microarray analysis and the manipulation of intracellular trafficking constitutes a rational strategy for reducing the host immune response to NPs.


Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency.
MTHFR (methylenetetrahydrofolate reductase) catalyses the synthesis of 5-methyltetrahydrofolate, the folate derivative utilized in homocysteine remethylation to methionine. A severe deficiency of MTHFR results in hyperhomocysteinaemia and homocystinuria. Betaine supplementation has proven effective in ameliorating the biochemical abnormalities and the clinical course in patients with this deficiency. Mice with a complete knockout of MTHFR serve as a good animal model for homocystinuria; early postnatal death of these mice is common, as with some neonates with low residual MTHFR activity. We attempted to rescue Mthfr-/- mice from postnatal death by betaine supplementation to their mothers throughout pregnancy and lactation. Betaine decreased the mortality of Mthfr-/- mice from 83% to 26% and significantly improved somatic development from postnatal day 1, compared with Mthfr-/- mice from unsupplemented dams. Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr-/- pups from betaine-supplemented dams. We observed disturbances in proliferation and differentiation in the cerebellum and hippocampus in the knockout mice; these changes were ameliorated by betaine supplementation. The dramatic effects of betaine on survival and growth, and the partial reversibility of the biochemical and developmental anomalies in the brains of MTHFR-deficient mice, emphasize an important role for choline and betaine depletion in the pathogenesis of homocystinuria due to MTHFR deficiency.


Commercial Crop Yields Reveal Strengths and Weaknesses for Organic Agriculture in the United States.
Land area devoted to organic agriculture has increased steadily over the last 20 years in the United States, and elsewhere around the world. A primary criticism of organic agriculture is lower yield compared to non-organic systems. Previous analyses documenting the yield deficiency in organic production have relied mostly on data generated under experimental conditions, but these studies do not necessarily reflect the full range of innovation or practical limitations that are part of commercial agriculture. The analysis we present here offers a new perspective, based on organic yield data collected from over 10,000 organic farmers representing nearly 800,000 hectares of organic farmland. We used publicly available data from the United States Department of Agriculture to estimate yield differences between organic and conventional production methods for the 2014 production year. Similar to previous work, organic crop yields in our analysis were lower than conventional crop yields for most crops. Averaged across all crops, organic yield averaged 67% of conventional yield [corrected]. However, several crops had no significant difference in yields between organic and conventional production, and organic yields surpassed conventional yields for some hay crops. The organic to conventional yield ratio varied widely among crops, and in some cases, among locations within a crop. For soybean (Glycine max) and potato (Solanum tuberosum), organic yield was more similar to conventional yield in states where conventional yield was greatest. The opposite trend was observed for barley (Hordeum vulgare), wheat (Triticum aestevum), and hay crops, however, suggesting the geographical yield potential has an inconsistent effect on the organic yield gap.


Accuracy and reproducibility in phase contrast imaging using SENSE.
The purpose of this study was to evaluate the accuracy and reproducibility of phase contrast imaging using the sensitivity encoding (SENSE) method at different reduction factors. Analytical expressions were derived that state how reproducibility is influenced for velocity and flow measurements. Computer simulations, and in vitro and in vivo studies were performed in order to validate these expressions and to assess how accuracy is affected when different reduction factors are applied. It was shown that reproducibility depends on the reduction and geometry factors. Since the geometry factor varies spatially, so does the reproducibility for phase contrast imaging. In areas with high geometry factors, the standard deviation (SD) may become so large that aliasing occurs. The accuracy of phase contrast imaging is not influenced directly when SENSE is used, but may be indirectly influenced due to high SDs of the measured phase that may subsequently cause aliasing. The current results show that it is possible to achieve accurate flow measurements even at high reduction factors. By taking the geometry factor into account, it may be possible to find areas where phase contrast imaging is accurate even at high reduction factors.


Design of Multiplexers for IoT-Based Applications Using Stub-Loaded Coupled-Line Resonators.
This paper presents the design of microstrip-based multiplexers using stub-loaded coupled-line resonators. The proposed multiplexers consist of a diplexer and a triplexer, meticulously engineered to operate at specific frequency bands relevant to IoT systems: 2.55 GHz, 3.94 GHz, and 5.75 GHz. To enhance isolation and selectivity between the two passband regions, the diplexer incorporates five transmission poles (TPs) within its design. Similarly, the triplexer filter employs seven transmission poles to attain the desired performance across all three passbands. A comprehensive comparison was conducted against previously reported designs, considering crucial parameters such as size, insertion loss, return loss, and isolation between the two frequency bands. The fabrication of the diplexer and triplexer was carried out on a compact Rogers Duroid 5880 substrate. The experimental results demonstrate an exceptional performance, with the diplexer exhibiting a low insertion loss of 0.3 dB at 2.55 GHz and 0.4 dB at 3.94 GHz. The triplexer exhibits an insertion loss of 0.3 dB at 2.55 GHz, 0.37 dB at 3.94 GHz, and 0.2 dB at 5.75 GHz. The measured performance of the fabricated diplexer and triplexer aligns well with the simulated results, validating their effectiveness in meeting the desired specifications.


Porous fluorine-doped tin oxide as a promising substrate for electrochemical biosensors-demonstration in hydrogen peroxide sensing.
Conducting porous substrates of high hydrophilicity are advantageous in applications of electrochemical biosensors as host electrodes, offering not only fast charge transport and large sensing surface areas but also necessary wettability in aqueous analytes. In this study, inexpensive, highly hydrophilic (contact angle < 5°), conducting (sheet resistance of 17 Ω□-1) porous fluorine-doped tin oxide (FTO) glass is fabricated from commercial FTO glass with a novel, simple, one-step Sn4+-based anodic treatment process, and used as a host electrode for electrochemical biosensors. We demonstrate its superior performance with hydrogen peroxide sensing. The hydrogen peroxide sensor is fabricated by simply depositing Pt nanoparticles onto the surface of the porous FTO substrate (PFTO) with a polyol process. Pt-decorated commercial FTO (CFTO) is also investigated as a control. The sensitivity achieved with the Pt-decorated PFTO is almost one order of magnitude higher than that of the Pt-decorated CFTO (25.8 vs. 2.69 mA M-1), and the response time is shortened from 36 s for the Pt-decorated CFTO to 1 s for the Pt-decorated PFTO. The PFTO proves to be a promising electrode substrate for host functional materials in electrochemical biosensors and can be readily applied to sensing of a wide variety of biosubstances.


Crystal structure at 1.63 A resolution of the native form of porcine beta-trypsin: revealing an acetate ion binding site and functional water network.
The active center of a serine protease is the catalytic triad composed of His-57, Ser-195 and Asp-102. The existing crystal structure data on serine proteases have not fully answered a number of fundamental questions relating to the catalytic activity of serine proteases. The new high resolution native porcine beta-trypsin (BPT) structure is aimed at extending the knowledge on the conformation of the active site and the ordered water structure within and around the active site. The crystal structure of BPT has been determined at 1.63 A resolution. An acetate ion bound at the active site of a trypsin molecule by both classical hydrogen bonds and C-HellipsisO hydrogen bonds has been identified for the first time. A large network of water molecules extending from the recognition amino acid Asp-184 to the entry of the active site has been observed in the BPT structure. A detailed comparison with inhibitor complexes and autolysates indicates that the sulfate ion and the acetate ion bind at the same site of the trypsin molecule. The Ser-195 Cbeta-Ogamma-His-57 Nepsilon angle in the catalytic triad of BPT is intermediate between the corresponding values of the complex and native structure due to acetate ion binding. The network of waters from the recognition amino acid to the active site entry is probably the first ever complete picture of functional waters around the active site. Structural comparisons show that the functional waters involved in the binding of small molecule inhibitors and protease inhibitors are distinctly different.


Endoscopic retrograde cholangiopancreatography in the infant.
Endoscopic retrograde cholangiopancreatography can safely be performed in the infant, using the standard adult cannulating instrument. Children must be examined under general anesthesia and care must be taken to insure adequate pressure of injection to fill the proximal branches of the intrahepatic radicals.


Comparison of guar gum from different sources for the preparation of prolonged-release or colon-specific dosage forms.
The aim of the present study was to compare some physicochemical properties of guar gum samples from different sources and thus to investigate the suitability of these samples for the formulation of either prolonged-release or colon-specific dosage forms. Twelve different guar gum samples from India, Pakistan and the USA were used. Theophylline was chosen as a model drug. The flow type of the guar gum samples was determined as pseudoplastic. The viscosity and the particle size of the guar gum samples were found to be the main parameters which could affect the drug release from matrix tablets. All of the guar gum samples are suitable for use in the preparation of prolonged-release matrix tablets. But, three of them, obtained from India and the USA, may be potentially the most suitable guar gum samples for the preparation of colon-specific dosage forms.


Hippo gains weight: added insights and complexity to pathway control.
The Hippo pathway is a kinase cascade, formed by Hippo, Salvador, Warts, and Mats, that regulates the subcellular distribution and transcriptional activity of Yorkie. Yorkie is a transcriptional coactivator that promotes the expression of genes that inhibit apoptosis and drive cell proliferation. We review recent studies indicating that activity of the Hippo pathway is controlled by cell-cell junctions, cell adhesion molecules, scaffolding proteins, and cytoskeletal proteins, as well as by regulators of apical-basal polarity and extracellular tension.


Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout.
Gout is a common and disabling cause of arthritis in middle-aged and elderly populations, with its main predisposing factor being hyperuricemia (serum urate > 6.8 mg/dL). Options for treatment of chronic gout until 2008 were allopurinol, a xanthine oxidase inhibitor, and the group of drugs known as uricosurics that stimulate the renal excretion of uric acid. A proportion of patients, including some with chronic kidney disease and solid organ transplantations, could not be treated with the those therapies because of intolerance, drug interactions, or adverse events. Febuxostat is a nonpurine xanthine oxidase inhibitor, recently approved in Europe and the United States for the treatment of chronic gout. To review the clinical evidence (phase II and III studies) of the effectiveness and safety of febuxostat for treatment of hyperuricemia and gout. Febuxostat, at doses ranging from 40 to 240 mg/day, is efficacious in reducing serum urate in patients with hyperuricemia and gout, comparing favorably with fixed doses of allopurinol in that respect. Early safety signals with respect to liver test abnormalities and cardiovascular outcomes have not been confirmed in recent large prospective trials but need to be further monitored. Given its low cost and extensive clinical experience, allopurinol will likely remain the first-line drug for management of hyperuricemia and gout. Febuxostat may provide an important option in patients unable to use allopurinol, those with very high serum urate levels, or in the presence of refractory tophi.


Racialized legal status as a social determinant of health.
This article advances the concept of racialized legal status (RLS) as an overlooked dimension of social stratification with implications for racial/ethnic health disparities. We define RLS as a social position based on an ostensibly race-neutral legal classification that disproportionately impacts racial/ethnic minorities. To illustrate the implications of RLS for health and health disparities in the United States, we spotlight existing research on two cases: criminal status and immigration status. We offer a conceptual framework that outlines how RLS shapes disparities through (1) primary effects on those who hold a legal status and (2) spillover effects on racial/ethnic in-group members, regardless of these individuals' own legal status. Primary effects of RLS operate by marking an individual for material and symbolic exclusion. Spillover effects result from the vicarious experiences of those with social proximity to marked individuals, as well as the discredited meanings that RLS constructs around racial/ethnic group members. We conclude by suggesting multiple avenues for future research that considers RLS as a mechanism of social inequality with fundamental effects on health.


Changes in fatty acid composition in plant tissues expressing a mammalian delta9 desaturase.
Plant tissues expressing a mammalian stearoyl-CoA delta9 desaturase were reported to accumulate delta9 hexadecenoic acid (16:1), normally very minor in most plant tissues. The transgenic plants were thoroughly analyzed for alterations of individual lipids in different subcellular sites. Western blot analysis indicated that the animal desaturase was targeted to the microsomes. The delta9 16:1 was incorporated into both the sn-1 and sn-2 positions of all the major membrane lipids tested, indicating that the endoplasmic reticulum acyltransferases do not exclude unsaturated C16 fatty acids from the sn-2 position. In addition to increases in monounsaturated and decreases in saturated fatty acids, accumulation of 16:1 was accompanied by a reduction in 18:3 in all the lipids tested except phosphatidylglycerol, and increases in 18:2 in phospholipids. Total C16 fatty acid content in the galactolipids of the transgenics was significantly higher than that in the control, but those in the phospholipids were unchanged. In transgenics, delta11 18:1 was detected in the sn-1 position of the lipids tested except phosphatidylinositol and phosphatidylserine. Introduction of the animal desaturase, controlled by a seed-specific phaseolin promoter, into soybean somatic embryo resulted in a significant reduction in saturated fatty acids. Such effects were greater in cotyledons than hypocotyl-radicles. This study demonstrated that the animal desaturase can be used to decrease the levels of saturated fatty acids in a crop plant.


New Molecular Insights into Immune Cell Development.
During development innate lymphoid cells and specialized lymphocyte subsets colonize peripheral tissues, where they contribute to organogenesis and later constitute the first line of protection while maintaining tissue homeostasis. A few of these subsets are produced only during embryonic development and remain in the tissues throughout life. They are generated through a unique developmental program initiated in lympho-myeloid-primed progenitors, which lose myeloid and B cell potential. They either differentiate into innate lymphoid cells or migrate to the thymus to give rise to embryonic T cell receptor-invariant T cells. At later developmental stages, adaptive T lymphocytes are derived from lympho-myeloid progenitors that colonize the thymus, while lymphoid progenitors become specialized in the production of B cells. This sequence of events highlights the requirement for stratification in the establishment of immune functions that determine efficient seeding of peripheral tissues by a limited number of cells.


Enhanced Identification of Group B Streptococcus and Escherichia Coli in Young Infants with Meningitis Using the Biofire Filmarray Meningitis/Encephalitis Panel.
FilmArray Meningitis/Encephalitis (ME) polymerase chain reaction (PCR) panel was tested on 62 cerebrospinal fluid (CSF) samples from young infants (0-3 months) with suspected meningitis and compared with CSF cultures. Twelve CSF samples from 9 infants were positive by ME PCR panel (10 Group B Streptococcus (GBS) and 2 Escherichia coli) of which only 5 were positive by culture. The 7 CSF samples that were positive only by ME PCR panel were obtained from infants who had received prior antibiotic treatment. The ME PCR panel can be a useful tool in the rapid diagnosis of bacterial meningitis in pretreated young infants.


Influence of numerical model decisions on the flow-induced vibration of a computational vocal fold model.
Computational vocal fold models are often used to study the physics of voice production. In this paper the sensitivity of predicted vocal fold flow-induced vibration and resulting airflow patterns to several modeling selections is explored. The location of contact lines used to prevent mesh collapse and assumptions of symmetry were found to influence airflow patterns. However, these variables had relatively little effect on the vibratory response of the vocal fold model itself. Model motion was very sensitive to Poisson's ratio. The importance of these parameter sensitivities in the context of vocal fold modeling is discussed.


Ultra hybrid plasmonics: strong coupling of plexcitons with plasmon polaritons.
We report a ternary-coupled plasmonic system consisting of excitons of J-aggregated dye, localized surface plasmon polaritons of Ag nanoparticles, and propagating surface plasmon polaritons of continuous Ag film. J-aggregate dyes are uniformly self-assembled on colloidally synthesized Ag nanoprisms forming plexcitonic nanoparticles, which are placed at a distance nanometers away from the Ag thin film. The reflection measurements, corroborated by theoretical predictions, reveal that the strong coupling of plasmon polaritons and plexcitons results in a newly formed plasmon-exciton-plasmon hybridized state that we call here, reportedly for the first time, a plexcimon state. The hybrid plasmonic system shows dispersion characteristics similar to a coupled resonator optical waveguide. The group velocity of the plexcimon state approaches zero at the band edges. The ultrahybrid plasmonic system presented here is promising for a variety of light-matter interaction studies, including polariton lasers, plasmonic devices, plasmonic waveguiding, and spectroscopy.


Femtomole isotopic-enzymatic microassay of histamine in microgram amounts of brain tissue.
We present a modification of a previously described radioenzymatic technique (Snyder et al., Journal of Pharmacology and Experimental Therapeutics, 153: 544-549, 1966) for the determination of histamine. This assay is based on the incubation of tissue histamine with a partially purified preparation of histamine-N-methyltransferase (S-adenosyl-L-methionine: histamine N-methyltransferase, E.C. 18.104.22.168; HMT) in the presence of the natural donor of methyl groups, [3H]-methyl-S-adenosyl-L-methionine ([3H]-SAMe). We have found that HMT retains its histamine N-methylating activity at 4 degrees C. Incubation at low temperature results in a considerable increase in the sample to blank ratio. The reduction of the total amount of [3H]-SAMe used and addition of anhydrous sodium sulfate before the last organic extraction step further reduced the blank levels. With these modifications, the sensitivity of the method was increased to the lower femtomole range. The present assay can be used for the determination of as little as 1 to 2 pg of histamine in samples from individual rat brain nuclei containing 2 to 10 micrograms of protein.


Detection and management of epidural haematomas related to anaesthesia in the UK: a national survey of current practice.
Epidural haematoma is a rare, but potentially disastrous complication of epidural analgesia. Favourable neurological outcome depends upon early recognition and surgical decompression; therefore, the management of epidural analgesia should include a systematic approach to recognition of the signs of epidural haematoma. We conducted a national postal survey of the policies and protocols used by acute pain services for investigating clinical signs suggestive of epidural haematoma, and the availability of urgent MRI scans. This was a repeat of a survey that was carried out in 2001, but not published. The response rate was 84%. Of the acute pain services that responded, 99% have a written protocol for running epidural infusions, 91% include regular assessment of sensory and motor function, and 55% have a written protocol for the investigation of abnormal motor block. On-site 24 h access to MRI scanning facilities was available to 57%, 33% have arrangements with another hospital, and 10% do not have 24 h access to MRI. Thirty per cent of respondents knew of an epidural haematoma related to epidural analgesia in their hospital, one-third of which were not diagnosed and treated within 24 h. Improvements in monitoring have occurred over the last 5 yr, but observations of neurological function are not routine in all units, and are not continued after removal of the epidural catheter in the majority. The authors suggest that acute pain services should be responsible for protocols for the investigation and treatment of epidural haematomas.


Construction and updating of event models in auditory event processing.
Humans segment the continuous stream of sensory information into distinct events at points of change. Between 2 events, humans perceive an event boundary. Present theories propose changes in the sensory information to trigger updating processes of the present event model. Increased encoding effort finally leads to a memory benefit at event boundaries. Evidence from reading time studies (increased reading times with increasing amount of change) suggest that updating of event models is incremental. We present results from 5 experiments that studied event processing (including memory formation processes and reading times) using an audio drama as well as a transcript thereof as stimulus material. Experiments 1a and 1b replicated the event boundary advantage effect for memory. In contrast to recent evidence from studies using visual stimulus material, Experiments 2a and 2b found no support for incremental updating with normally sighted and blind participants for recognition memory. In Experiment 3, we replicated Experiment 2a using a written transcript of the audio drama as stimulus material, allowing us to disentangle encoding and retrieval processes. Our results indicate incremental updating processes at encoding (as measured with reading times). At the same time, we again found recognition performance to be unaffected by the amount of change. We discuss these findings in light of current event cognition theories. (PsycINFO Database Record


Bilateral chorea/ballismus: detection and management of a rare complication of non-ketotic hyperglycaemia.
Non-ketotic hyperglycaemia (NKH) is the most common metabolic cause of hemichorea-hemiballismus (HC-HB) and an often-reversible condition. A 68-year-old man presented to the emergency department with a severe hyperglycaemic episode and altered mental status. He was treated appropriately and discharged home after his blood glucose levels were normal with an improvement of mental status. Four weeks after the discharge, he returned with flailing movements of bilateral upper and lower limbs. MRI of the brain revealed hyperintensities of the bilateral putamen on T1-weighted imaging. The patient's symptoms improved with a combination of amantadine, clonazepam and tetrabenazine. Several hypotheses involving gemistocytes, calcification and petechial haemorrhage were proposed in support of imaging abnormalities in the striatum. Dopamine-depleting agents and neuroleptics are used in the treatment of chorea. It is recommended to try a dose of tetrabenazine in patients with NKH-induced HC-HB if no improvement is appreciated with initial treatment of glycaemic control.


Relationship Between Sleep and Behavior in Autism Spectrum Disorder: Exploring the Impact of Sleep Variability.
The relationship between sleep (caregiver-reported and actigraphy-measured) and other caregiver-reported behaviors in children and adults with autism spectrum disorder (ASD) was examined, including the use of machine learning to identify sleep variables important in predicting anxiety in ASD. Caregivers of ASD (n = 144) and typically developing (TD) (n = 41) participants reported on sleep and other behaviors. ASD participants wore an actigraphy device at nighttime during an 8 or 10-week non-interventional study. Mean and variability of actigraphy measures for ASD participants in the week preceding midpoint and endpoint were calculated and compared with caregiver-reported and clinician-reported symptoms using a mixed effects model. An elastic-net model was developed to examine which sleep measures may drive prediction of anxiety. Prevalence of caregiver-reported sleep difficulties in ASD was approximately 70% and correlated significantly (p < 0.05) with sleep efficiency measured by actigraphy. Mean and variability of actigraphy measures like sleep efficiency and number of awakenings were related significantly (p < 0.05) to ASD symptom severity, hyperactivity and anxiety. In the elastic net model, caregiver-reported sleep, and variability of sleep efficiency and awakenings were amongst the important predictors of anxiety. Caregivers report problems with sleep in the majority of children and adults with ASD. Reported problems and actigraphy measures of sleep, particularly variability, are related to parent reported behaviors. Measuring variability in sleep may prove useful in understanding the relationship between sleep problems and behavior in individuals with ASD. These findings may have implications for both intervention and monitoring outcomes in ASD.


Alcoholic liver disease.
Alcohol is a major cause of liver cirrhosis in the Western world and accounts for the majority of cases of liver cirrhosis seen in district general hospitals in the UK. The three most widely recognised forms of alcoholic liver disease are alcoholic fatty liver (steatosis), acute alcoholic hepatitis, and alcoholic cirrhosis. The exact pathogenesis of alcoholic liver injury is still not clear but immune mediated and free radical hepatic injury are thought to be important. There is increasing interest in genetic factors predisposing to hepatic injury in susceptible individuals. Diagnosis is based on accurate history, raised serum markers such as gamma-glutamyltransferase, mean corpuscular volume, and IgA and liver histology when obtainable. Abstinence is the most important aspect of treatment. Newer drugs such as acamprosate and naltrexone are used to reduce alcohol craving. Vitamin supplements and nutrition are vital while corticosteroids have a role in acute alcoholic hepatitis where there is no evidence of gastrointestinal haemorrhage or sepsis. Liver transplantation has excellent results in abstinent patients with end stage liver disease but there are concerns about recidivism after transplant.


Ultrafast Formation of Small Polarons and the Optical Gap in CeO2.
The ultrafast dynamics of excited states in cerium oxide are investigated to access the early moments of polaron formation, which can influence the photocatalytic functionality of the material. UV transient absorbance spectra of photoexcited CeO2 exhibit a bleaching of the band edge absorbance induced by the pump and a photoinduced absorbance feature assigned to Ce 4f → Ce 5d transitions. A blue shift of the spectral response of the photoinduced absorbance signal in the first picosecond after the pump excitation is attributed to the dynamical formation of small polarons with a characteristic time of 330 fs. A further important result of our work is that the combined use of steady-state and ultrafast transient absorption allows us to propose a revised value for the optical gap for ceria (Eog = 4 eV), significantly larger than usually reported.


Effect of dietary carotenoids on vitamin A status and skin pigmentation in false tomato frogs (Dyscophus guineti).
Several species in captivity develop nutritional diseases including vitamin A deficiency; cases of this disease have been documented in amphibians, which may be linked to an insectivorous diet lacking in vitamin A or carotenoids. Adults and young of Dyscophus guineti were fed three diets over 9 weeks to evaluate effects on carotenoids and vitamin A status and skin pigmentation. Feeder crickets were either supplemented with soy oil (control, CON), soy oil enriched with β-carotene (BC) or mixed carotenoids (MIX) by direct injection of known dosages. Vitamin A from feeder crickets (measured as retinol) was higher in insects supplemented with both BC and MIX; (P=0.0001) and plasma retinol concentrations were significantly higher in frogs fed MIX (P<0.02). Results suggest that both false tomato frogs and feeder crickets could receive some provitamin A activity through consumption of diets supplemented with β-carotene, and xanthophylls like lutein and zeaxanthin. Pigmentation was evaluated weekly through the use of visual color charts, as well as quantitatively using a hand-held spectrophotometer. MIX diets had a significant effect on skin color values (P<0.0001), as well as on lightness (P=0.0005) and hue (P=0.0022). Results indicated that frogs fed with BC changed to yellower colors, and frogs fed with MIX changed to oranger colors. Visual color chart observations also scored significantly different between CON and MIX diets (P<0.05); the animals fed MIX also appeared oranger according to the qualitative observations. Dietary supplements with carotenoids resulted in color changes and higher circulating retinol concentrations in false tomato frogs. These pigments may provide provitamin A activity in diets, thus may support improved nutrition and health of captive-fed insectivorous amphibians.


Novel therapeutics for aggressive non-Hodgkin's lymphoma.
Application of advances in genomic and proteomic technologies has provided molecular insights into distinct types of aggressive B- and T-cell non-Hodgkin's lymphomas (NHLs). This has led to the validation of novel biomarkers of classification, risk-stratification, and druggable targets. The promise of novel treatments from genomic research has been slow to materialize because of the lack of a therapeutic signature for the distinct NHL subtypes. Patients with lymphoma with aggressive disease urgently require the development of novel therapies on the basis of investigation of dysregulated intracellular oncogenic processes that arise during lymphomagenesis. Although monoclonal antibodies have made significant contributions to the armamentarium of B-cell NHL therapy (eg, anti-CD20), parallel development of small-molecule inhibitors (SMIs) to intracellular targets has lagged behind. Despite these deficiencies, several promising anti-NHL therapies are in development that target immune kinases of the B-cell receptor signaling pathway, mammalian target of rapamycin complex, proteasome, DNA/histone epigenetic complex, antiapoptosis, neoangiogenesis, and immune modulation. This review focuses on novel SMI therapeutic strategies that target overlapping core oncogenic pathways in the context of the 10 hallmarks of cancer. Furthermore, we have developed the concept of a therapeutic signature using the 10 hallmarks of cancer, which may be incorporated into novel phase I/II drug development programs.


A universal law for cell uptake of one-dimensional nanomaterials.
Understanding cell interaction with one-dimensional nanomaterials, including nanotubes, nanowires, nanofibers, filamentous bacteria, and certain nanoparticle chains, has fundamental importance to many applications such as biomedical diagnostics, therapeutics, and nanotoxicity. Here we show that cell uptake of one-dimensional nanomaterials via receptor-mediated endocytosis is dominated by a single dimensionless parameter that scales with the membrane tension and radius of the nanomaterial and inversely with the membrane bending stiffness. It is shown that as cell membrane internalizes one-dimensional nanomaterials the uptake follows a near-perpendicular entry mode at small membrane tension but it switches to a near-parallel interaction mode at large membrane tension.


Suicide by firearm: One family's lived experience.
In this paper, my nephews and I will share our individual perspectives of their father's completed suicide 30 years ago. Our intention is that the importance of recovery, hope, and support will be illuminated by telling our unique stories to describe the lived experience of a tragedy by gun violence and its longstanding effects.


An enantioselective access to 1-alkyl-1,2,3,4-tetrahydroisoquinolines. Application to a new synthesis of (-)-argemonine.
Potassium ferricyanide oxidation of salt 1 gave isoquinolinone 7 whose treatment with Grignard reagents resulted in a high-yield formation of substituted isoquinolinium salts 5. The selectivity of the reduction of these salts to give derivatives 6 has been studied. Particularly good selectivities (82-84%) were observed when R is a benzylic group. On the basis of these results, a practical and enantioselective synthesis of the natural alkaloid (-)-argemonine is presented.


Gamma ventral capsulotomy for obsessive-compulsive disorder: a randomized clinical trial.
Select cases of intractable obsessive-compulsive disorder (OCD) have undergone neurosurgical ablation for more than half a century. However, to our knowledge, there have been no randomized clinical trials of such procedures for the treatment of any psychiatric disorder. To determine the efficacy and safety of a radiosurgery (gamma ventral capsulotomy [GVC]) for intractable OCD. In a double-blind, placebo-controlled, randomized clinical trial, 16 patients with intractable OCD were randomized to active (n = 8) or sham (n = 8) GVC. Blinding was maintained for 12 months. After unblinding, sham-group patients were offered active GVC. Patients randomized to active GVC had 2 distinct isocenters on each side irradiated at the ventral border of the anterior limb of the internal capsule. The patients randomized to sham GVC received simulated radiosurgery using the same equipment. Scores on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Clinical Global Impression-Improvement (CGI-I) Scale. Response was defined as a 35% or greater reduction in Y-BOCS severity and "improved" or "much improved" CGI-I ratings. Three of 8 patients randomized to active treatment responded at 12 months, while none of the 8 sham-GVC patients responded (absolute risk reduction, 0.375; 95% CI, 0.04-0.71). At 12 months, OCD symptom improvement was significantly higher in the active-GVC group than in the sham group (Y-BOCS, P = .046; Dimensional Y-BOCS, P = .01). At 54 months, 2 additional patients in the active group had become responders. Of the 4 sham-GVC patients who later received active GVC, 2 responded by post-GVC month 12. The most serious adverse event was an asymptomatic radiation-induced cyst in 1 patient. Gamma ventral capsulotomy benefitted patients with otherwise intractable OCD and thus appears to be an alternative to deep-brain stimulation in selected cases. Given the risks inherent in any psychiatric neurosurgery, such procedures should be conducted at specialized centers. clinicaltrials.gov Identifier: NCT01004302.


PinX1t, a Novel PinX1 Transcript Variant, Positively Regulates Cardiogenesis of Embryonic Stem Cells.
Background Pin2/TRF1-interacting protein, PinX1, was previously identified as a tumor suppressor. Here, we discovered a novel transcript variant of mPinX1 (mouse PinX1), mPinX1t (mouse PinX1t), in embryonic stem cells (ESCs). The aims of this investigation were (1) to detect the presence of mPinX1 and mPinX1t in ESCs and their differentiation derivatives; (2) to investigate the role of mPinX1 and mPinX1t on regulating the characteristics of undifferentiated ESCs and the cardiac differentiation of ESCs; (3) to elucidate the molecular mechanisms of how mPinX1 and mPinX1t regulate the cardiac differentiation of ESCs. Methods and Results By 5' rapid amplification of cDNA ends, 3' rapid amplification of cDNA ends, and polysome fractionation followed by reverse transcription-polymerase chain reaction, mPinX1t transcript was confirmed to be an intact mRNA that is actively translated. Western blot confirmed the existence of mPinX1t protein. Overexpression or knockdown of mPinX1 (both decreased mPinX1t expression) both decreased while overexpression of mPinX1t increased the cardiac differentiation of ESCs. Although both mPinX1 and mPinX1t proteins were found to bind to cardiac transcription factor mRNAs, only mPinX1t protein but not mPinX1 protein was found to bind to nucleoporin 133 protein, a nuclear pore complex component. In addition, mPinX1t-containing cells were found to have a higher cytosol-to-nucleus ratio of cardiac transcription factor mRNAs when compared with that in the control cells. Our data suggested that mPinX1t may positively regulate cardiac differentiation by enhancing export of cardiac transcription factor mRNAs through interacting with nucleoporin 133. Conclusions We discovered a novel transcript variant of mPinX1, the mPinX1t, which positively regulates the cardiac differentiation of ESCs.


Preparation and application of polyvinyl alcohol-decorated cell membrane chromatography for screening anti-osteoporosis components from Liuwei Dihuang decoction-containing serum.
Cell membrane chromatography is a powerful tool for screening active components from complex matrices. New cell membrane carriers need to be developed to increase the coverage of cell membranes on the surface of stationary phases, thereby improving cell membrane chromatographic retention. In this work, we prepared polyvinyl alcohol-poly dimethyl diallyl ammonium chloride modified silica gel as a cell membrane carrier. Osteoblast cell was used as cell membrane source, which was widely used to evaluate the osteogenic activity of drugs. The new cell membrane chromatographic stationary phase was used to screen anti-osteoporosis components in Liuwei Dihuang decoction-containing serum. The chemical structures of the new modified materials were characterized by scanning electronic microscopy, Fourier transform infrared spectroscopy, and elemental analysis characterization. Compared with the common cell membrane column, the cell membrane coverage of this modified material was increased by 30%, and thus provided a stronger retention effect in positive drugs. Nineteen metabolites in rat serum samples were retained on the cell membrane chromatography and identified by ultra-high-performance liquid chromatography/time-of-flight mass spectrometry. Among those, four components (morroniside, catalpol, loganin, and acteoside) were selected for in vitro pharmacodynamics validation. They significantly increased the osteoblast proliferation. The new modified material was successfully applied to screen anti-osteoporosis components from Liuwei Dihuang Decoction-containing serum.


Flagellar-phase variation: isolation of the rh1 gene.
In Salmonella, expression of flagellar antigen alternates between two serotypes (phases) encoded by two genes, H1 and H2. The mechanism which controls the alternative expression of the H1 and H2 genes was examined by cloning these genes and the genetic elements which control their activity on hybrid vehicles in Escherichia coli. H2 gene activity was shown to be controlled by a recombinational switch located adjacent to the H2 gene. Activity of the H1 gene is thought to be repressed, when the H2 gene is expressed, by the product of another gene, rh1 (repressor of H1), which is controlled coordinately with the H2 gene. In this report, we describe the construction of hybrid lambda vehicles which contain, in addition to the H2 gene, a genetic activity corresponding to rh1. Variation of flagellar antigens analogous to that observed in Salmonella was observed when E. Coli strains were transduced with the hybrid lambda. By using the lambdaH2rh1 hybrid to program protein synthesis in UV-irradiated cells, the synthesis of a polypeptide was correlated with rh1 gene product activity. We conclude that the H2 region consists of two cotranscribed genes, H2 and rh1. The expression of both gene products is regulated by the same recombinational event.


IMMUNOCHEMICAL IDENTIFICATION OF PARATHYROID HORMONE IN NON-PARATHYROID NEOPLASMS ASSOCIATED WITH HYPERCALCEMIA.
1. Immunochemical cross-reactivity, but not identity, has been demonstrated between bovine parathyroid hormone and an antigen in biologically active extracts of human parathyroid tissue by quantitative C' fixation and C' fixation inhibition. 2. An antigen that fixes C' with rabbit antibody to bovine parathyroid hormone has been found in urea extracts of six human non-parathyroid neoplasms associated with a hypercalcemic syndrome mimicking primary hyperparathyroidism. Comparable extracts of control tissues and other tumors were serologically negative. 3. It is concluded that the tumor antigen is parathyroid hormone or a very closely related protein, and that its production by these neoplasms was the cause of the hypercalcemic syndrome in these six patients.


An improved genetically encoded red fluorescent Ca2+ indicator for detecting optically evoked action potentials.
Genetically encoded Ca(2+) indicators (GECIs) are powerful tools to image activities of defined cell populations. Here, we developed an improved red fluorescent GECI, termed R-CaMP1.07, by mutagenizing R-GECO1. In HeLa cell assays, R-CaMP1.07 exhibited a 1.5-2-fold greater fluorescence response compared to R-GECO1. In hippocampal pyramidal neurons, R-CaMP1.07 detected Ca(2+) transients triggered by single action potentials (APs) with a probability of 95% and a signal-to-noise ratio >7 at a frame rate of 50 Hz. The amplitudes of Ca(2+) transients linearly correlated with the number of APs. The expression of R-CaMP1.07 did not significantly alter the electrophysiological properties or synaptic activity patterns. The co-expression of R-CaMP1.07 and channelrhodpsin-2 (ChR2), a photosensitive cation channel, in pyramidal neurons demonstrated that R-CaMP1.07 was applicable for the monitoring of Ca(2+) transients in response to optically evoked APs, because the excitation light for R-CaMP1.07 hardly activated ChR2. These technical advancements provide a novel strategy for monitoring and manipulating neuronal activity with single cell resolution.


Demodex positive discoid lupus erythematosus: Is it a separate entity or an overlap syndrome?
Discoid lupus erythematosus (DLE) is a chronic inflammatory erythematous skin disease that can be triggered by several factors. Rosacea is another skin disease that causes facial redness and tenderness. Demodex mites have been reported in rosacea and DLE patients commonly in the literature. These two diseases can be seen concomitant, mimic each other clinically and share common possible etiologic factors. To assess demodex mite infestation in both clinical and histopathological findings in DLE patients. We retrospectively evaluated the files of 42 patients with DLE who had been diagnosed DLE based on clinical and histopathological findings between August 2018 and August 2019. Demodex positivity was detected 50% of patients (n = 21). Neutrophile percentages in the dermal and perivascular area were higher in the demodex positive patients (4.43%) than in the Demodex negative patients (2.19%). The intensity of demodex mites correlated positively with dermal neutrophile percentages. ANA was negative in 29 patients (69%) and positive in 13 patients (31%). Anti-dsDNA was negative in serology and follicular plugging was positive in histopathology in all 42 patients (100%). This was a retrospective study. DLE and rosacea share common features in etiopathogenesis and clinical presentation. Inflammation and exacerbations caused by the demodex mites may increase the clinical severity of DLE. Although the position of demodex mites in DLE etiopathogenesis is not known exactly, the presence of high demodex in DLE patients has been determined. Standard skin surface biopsy can be a routine procedure for the evaluation of DLE patients in daily clinical practice.


Excessive TV watching in patients with frontotemporal dementia.
The "environmental dependency syndrome" refers to a loss of personal autonomy such that a person's environment almost entirely controls their actions. The goal of this study is to learn if patients with frontotemporal degeneration (FTD) exhibit prolonged TV watching, a behavior which may be a symptom of environmental dependency. We recruited 40 patients with FTD and 48 patients with Alzheimer's disease (AD), and asked these participants' caregivers about TV watching behaviors including total viewing time and channel/show preference, along with other behaviors indicative of environmental dependency. Compared to AD patients, FTD patients watched TV for a longer time. In addition, the patients who watched more TV showed more signs of environmental dependency. Increased TV watching may be a sign of environmental dependency, however further research is needed to explore other hypotheses.


Inositol phospholipid metabolism and myoblast fusion.
The fusion of chick embryonic myoblasts has been studied in tissue culture. Myoblasts are maintained at 0.1 microM-Ca2+ for 50 h. During this time they achieve fusion competence. Fusion is initiated by raising the medium Ca2+ concentration to 1.4 mM. A rapid breakdown of the polyphosphoinositides was detected within 3 min of Ca2+ addition. Rapid synthesis of phosphatidic acid was also detected at this time. Breakdown of phosphatidylinositol and synthesis of 1,2-diacylglycerol were also detected. Other phospholipids were unaffected. Sr2+ could replace Ca2+ in this process but Mg2+ could not and also inhibited the Ca2+ effect. The Ca2+-ionophore A23187 stimulated further apparent polyphosphoinositide breakdown in the presence of Ca2+. 6. The results are discussed with respect to myoblast fusion.


Eligibility for Statin Treatment in Korean Subjects with Reduced Renal Function: An Observational Study.
The purpose of this study was to investigate the relationship between statin eligibility and the degree of renal dysfunction using the Adult Treatment Panel (ATP) III and the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines in Korean adults. Renal function was assessed in 18,746 participants of the Kangbuk Samsung Health Study from January 2011 to December 2012. Subjects were divided into three groups according to estimated glomerular filtration rate (eGFR): stage 1, eGFR ≥90 mL/min/1.73 m²; stage 2, eGFR 60 to 89 mL/min/1.73 m²; and stages 3 to 5, eGFR <60 mL/min/1.73 m². Statin eligibility in these groups was determined using the ATP III and ACC/AHA guidelines, and the risk for 10-year atherosclerotic cardiovascular disease (ASCVD) was calculated using the Framingham Risk Score (FRS) and Pooled Cohort Equation (PCE). There were 3,546 (18.9%) and 4,048 (21.5%) statin-eligible subjects according to ATP III and ACC/AHA guidelines, respectively. The proportion of statin-eligible subjects increased as renal function deteriorated. Statin eligibility by the ACC/AHA guidelines showed better agreement with the Kidney Disease Improving Global Outcomes (KDIGO) recommendations compared to the ATP III guidelines in subjects with stage 3 to 5 chronic kidney disease (CKD) (κ value, 0.689 vs. 0.531). When the 10-year ASCVD risk was assessed using the FRS and PCE, the mean risk calculated by both equations significantly increased as renal function declined. The proportion of statin-eligible subjects significantly increased according to worsening renal function in this Korean cohort. ACC/AHA guideline showed better agreement for statin eligibility with that recommended by KDIGO guideline compared to ATP III in subjects with CKD.


Trans-4-aminocrotonic acid (TACA), a potent agonist of GABA(A) and GABA(C) receptors, shows a proconvulsant action in the electroconvulsive threshold test in mice.
In the present study, we evaluated TACA (a potent agonist of GABA(A) and GABA(C) receptors) in the electroconvulsive threshold test in mice. Surprisingly, TACA (at 15 and 25 mg/kg) significantly decreased the threshold. The highest ineffective dose of TACA was estimated as 10 mg/kg. The obtained results indicate that the drug enhancing GABAergic transmission may possess proconvulsant properties in the electroconvulsive test. Such effect was completely opposite to our primary assumption and expectance.


Children's annoyance reactions to aircraft and road traffic noise.
Since annoyance reactions of children to environmental noise have rarely been investigated, no source specific exposure-response relations are available. The aim of this paper is to investigate children's reactions to aircraft and road traffic noise and to derive exposure-response relations. To this end, children's annoyance reactions to aircraft and road traffic noise in both the home and the school setting were investigated using the data gathered in a cross-sectional multicenter study, carried out among 2844 children (age 9-11 years) attending 89 primary schools around three European airports. An exposure-response relation was demonstrated between exposure to aircraft noise at school (L(Aeq,7-23 h)) and severe annoyance in children: after adjustment for confounders, the percentage severely annoyed children was predicted to increase from about 5.1% at 50 dB to about 12.1% at 60 dB. The findings were consistent across the three samples. Aircraft noise at home (L(Aeq,7-23 h)) demonstrated a similar relation with severe annoyance. Children attending schools with higher road traffic noise (L(Aeq,7-23 h)) were more annoyed. Although children were less annoyed at levels above 55 dB, the shapes of the exposure-response relations found among children were comparable to those found in their parents.


Rule-Based Learning for More Accurate ECG Analysis.
Long-term electrocardiograms exhibit a small number of QRS morphologies (waveform shapes) whose analysis can reveal cardiac abnormalities. We considered the problem of accurately identifying instances of each in 24-h ECG recordings. A new learning algorithm was developed. Each QRS morphology is represented as a tree of rule activations, which associate attribute measurements with a rule. Each rule has a syntactic pattern together with a semantic procedure which manages and applies the knowledge stored in the activation. A single rule may be activated several times to learn different waveform segments. Delineation refinement improves each hypothesized signal interpretation. A simple conflict resolution mechanism resolves conflicting interpretations into a single unambiguous one. Comparison of the system with an existing program confirmed the promise of the new approach.


Removal of trace organic contaminants by a membrane bioreactor-granular activated carbon (MBR-GAC) system.
The removal of trace organics by a membrane bioreactor-granular activated carbon (MBR-GAC) integrated system were investigated. The results confirmed that MBR treatment can be effective for the removal of hydrophobic (log D>3.2) and readily biodegradable trace organics. The data also highlighted the limitation of MBR in removing hydrophilic and persistent compounds (e.g. carbamazepine, diclofenac, and fenoprop) and that GAC could complement MBR very well as a post-treatment process. The MBR-GAC system showed high removal of all selected trace organics including those that are hydrophilic and persistent to biological degradation at up to 406 bed volumes (BV). However, over an extended period, breakthrough of diclofenac was observed after 7320 BV. This suggests that strict monitoring should be applied over the lifetime of the GAC column to detect the breakthrough of hydrophilic and persistent compounds which have low removal by MBR treatment.


Arthroscopic management of septic arthritis of the shoulder joint.
Nineteen patients with septic arthritis of the glenohumeral joint were treated with a combination of arthroscopic irrigation and débridement and systemic antibiotics according to bacterial sensitivity. We retrospectively reviewed the series to determine the efficacy and safety of this treatment. There were seventeen men and two women, with a mean age of fifty-nine years. Underlying medical disease was present in thirteen patients, with six of them having diabetes. The average duration of symptoms prior to the arthroscopic lavage was three weeks. Fifteen patients had had local injections into the shoulder joint. The arthroscopic staging of the infection was based on the modified criteria of Gächter. The functional outcome was evaluated with use of the UCLA scoring system. As determined at arthroscopy, one infection was classified as stage I; seven, as stage II; nine, as stage III; and two, as stage IV. Staphylococcus was the most common organism identified. The infection was eradicated completely with a single arthroscopic procedure in fourteen patients. The mean UCLA score at the time of the last follow-up was 26 points, with a mean score of 23.7 points for the eleven patients with a rotator cuff tear and 29 points for the eight with an intact rotator cuff. Patients who had had symptoms for no more than two weeks prior to the arthroscopic lavage had better results than those who had had symptoms for longer than two weeks. Arthroscopic débridement for the treatment of septic arthritis of the shoulder is safe and efficient, particularly in the early stages of the disease. Underlying medical diseases such as diabetes, prior injections, or a preexisting rotator cuff tear were seen in a high proportion of these patients.


Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells.
Antiandrogens given to antagonize androgen receptor (AR) activity gradually lose their efficacy as antagonists and eventually function as agonists to promote (instead of block) AR-mediated growth of prostate cancer cells. The mechanisms of how antiandrogens acquire this agonist activity during hormonal therapy are largely unknown. Here, we report that expression of a dominant-negative AR-associated protein 55 (dARA55) coregulator, inhibits AR transcriptional activity and reduces the agonist activity of antiandrogens. Inducibly expressed dARA55 inhibits prostate-specific antigen and cell growth in prostate cancer cells. Further dissection of the molecular mechanism shows dARA55 can selectively suppress endogenous AR-associated protein 55 (ARA55) enhanced AR transactivation by means of interruption of dimerization between ARA55 and ARA55. These results were confirmed by using RNA interference-mediated silencing of the ARA55 gene. These results therefore provide evidence that AR function could be suppressed without mutation or change in AR itself. Taken together, these findings not only demonstrate the important roles of the ARA55 coregulator in the AR-mediated growth of prostate cancer, they also may provide a critical target for developing therapeutic agents for the antiandrogen therapy that almost always fails in the treatment of hormone-refractory prostate cancer.


Curriculum Mapping of the Master's Program in Pharmacy in Slovenia with the PHAR-QA Competency Framework.
This article presents the results of mapping the Slovenian pharmacy curriculum to evaluate the adequacy of the recently developed and validated European Pharmacy Competences Framework (EPCF). The mapping was carried out and evaluated progressively by seven members of the teaching staff at the University of Ljubljana's Faculty of Pharmacy. Consensus was achieved by using a two-round modified Delphi technique to evaluate the coverage of competences in the current curriculum. The preliminary results of the curriculum mapping showed that all of the competences as defined by the EPCF are covered in Ljubljana's academic program. However, because most EPCF competences cover healthcare-oriented pharmacy practice, a lack of competences was observed for the drug development and production perspectives. Both of these perspectives are important because a pharmacist is (or should be) responsible for the entire process, from the development and production of medicines to pharmaceutical care in contact with patients. Nevertheless, Ljubljana's graduates are employed in both of these pharmaceutical professions in comparable proportions. The Delphi study revealed that the majority of differences in scoring arise from different perspectives on the pharmacy profession (e.g., community, hospital, industrial, etc.). Nevertheless, it can be concluded that curriculum mapping using the EPCF is very useful for evaluating and recognizing weak and strong points of the curriculum. However, the competences of the framework should address various fields of the pharmacist's profession in a more balanced way.


Radioimmunoassay for colchicine in plasma and urine.
A radioimmunoassay for the measurement of colchicine (in quantities as small as 0.05 nanogram) in plasma and urine was developed with the use of an antibody from immunized rabbits. After the intravenous injection of 2 milligrams of colchicine in seven subjects, the calculated zero-time concentration in the plasma was 2.9 +/- 1.5 micrograms per deciliter, and the mean half-time in the plasma was 58 +/- 20 minutes. Declining, but measurable, amounts of colchicine could be detected in urine up to day 9 after the drug was administered.


MRI-based screening for structural definition of eligibility in clinical DMOAD trials: Rapid OsteoArthritis MRI Eligibility Score (ROAMES).
Our aim was to introduce a simplified MRI instrument, Rapid OsteoArthritis MRI Eligibility Score (ROAMES), for defining structural eligibility of patients for inclusion in disease-modifying osteoarthritis drug trials using a tri-compartmental anatomic approach that enables stratification of knees into different structural phenotypes and includes diagnoses of exclusion. We also aimed to define overlap between phenotypes and determine reliability. 50 knees from the Foundation for National Institutes of Health Osteoarthritis Biomarkers study, a nested case-control study within the Osteoarthritis Initiative, were selected within pre-defined definitions of phenotypes as either inflammatory, subchondral bone, meniscus/cartilage, atrophic or hypertrophic. A focused scoring instrument was developed covering cartilage, meniscal damage, inflammation and osteophytes. Diagnoses of exclusion were meniscal root tears, osteonecrosis, subchondral insufficiency fracture, tumors, malignant marrow infiltration and acute traumatic changes. Reliability was determined using weighted kappa statistics. Descriptive statistics were used for determining concordance between the a priori phenotypic definition and ROAMES and overlap between phenotypes. ROAMES identified 43 of 50 (86%) pre-defined phenotypes correctly. Of the 50 participants, 27 (54%) had no additional phenotypes other than the pre-defined phenotype. 18 (36%) had one and 5 (10%) had two additional phenotypes. None had three or four additional phenotypes. All features of ROAMES showed almost perfect agreement. One case with osteonecrosis and one with a tumor were detected. ROAMES is able to screen and stratify potentially eligible knees into different structural phenotypes and record relevant diagnoses of exclusion. Reliability of the instrument showed almost perfect agreement.


Comfortably Numb: The Role of Momentary Dissociation in the Experience of Negative Affect Around Binge Eating.
Evidence suggests that both dissociation and negative affect (NA) may precipitate binge eating. The extent to which dissociation may impact the experience of NA around binge eating is unclear. Women with bulimia nervosa completed a 2-week ecological momentary assessment protocol of dissociation, NA, and binge eating. Multilevel modeling was used to examine dissociation as a moderator of NA before and after binge eating. NA was greater at the time of binge eating for participants higher in average dissociation (between subjects) and when momentary dissociation was greater than one's average (within subjects). The trajectory of NA was characterized by a sharper increase before binge eating for participants higher in average dissociation; the NA trajectories were characterized by sharper increases before and decreases after binge eating when momentary dissociation was greater than one's average. Results support the salience of both dissociation and NA in relation to the occurrence of binge eating.


Induction of inducible nitric oxide synthase, argininosuccinate synthase, and GTP cyclohydrolase I in arthritic joints of human tumor necrosis factor-alpha transgenic mice.
Transgenic mice that express human tumor necrosis factor-alpha (Tg197 h-TNF-alpha) develop polyarthritis at 3 to 4 weeks of age leading to severe joint destruction at 8 to 10 weeks of age. Studies have suggested that inducible nitric oxide synthase (iNOS) activity can modulate the progression of arthritis. We investigated the induction of iNOS together with argininosuccinate synthase (AS) and GTP cyclohydrolase I (GTPCH), 2 of the rate-limiting enzymes for high output NO generation, in the Tg197 h-TNF-alpha transgenic model of arthritis. We used 4 and 8-week-old Tg197 h-TNF-alpha transgenic mice and wild-type CBA C57B1/6 control mice to investigate the expression of iNOS with respect to that of AS, GTPCH, and 3-nitrotyrosine by quantitative RT-PCR and immunocytochemistry. Urinary NO metabolites were analyzed using a chemiluminescence assay. Inducible NOS, AS, and GTPCH mRNA was found in all study groups; however, only iNOS mRNA showed a clear increase in 4-week-old Tg197 h-TNF-alpha transgenics in comparison to age matched wild-type controls. Abundant iNOS protein expression was found in macrophages and vascular smooth muscle cells in hyperplastic synovium and pannus. AS expression was found in vascular endothelium and fibroblasts of the inflammatory synovium and pannus. GTPCH immunoreactivity was mostly restricted to macrophages in inflammatory synovium. Localization of 3-nitrotyrosine overlapped with that of iNOS, indicating formation of reactive nitrogen species. Consistent with the high output NO generation, there was a 5-fold increase in urinary NO metabolites in 8-week-old Tg197 h-TNF-alpha transgenic mice. We characterized the Tg197 h-TNF-alpha transgenic model of inflammatory arthritis in terms of high output NO-generating pathway, and showed that both AS and GTPCH are intimately associated with inflammatory arthritis. The concomitant induction of AS and GTPCH with that of iNOS suggests that they may be important modulators of arthritis, and that they may represent novel targets for modulation of disease activity.


Auditory Mismatch Negativity Response in Institutionalized Children.
The attunement of speech perception/discrimination to the properties of one's native language is a crucial step in speech and language development at early ages. Studying these processes in young children with a history of institutionalization is of great interest, as being raised in institutional care (IC) may lead to lags in language development. The sample consisted of 82 children, split into two age groups. The younger age group (<12 months) included 17 children from the IC and 17 children from the biological-family-care (BFC) group. The older group (>12 months) consisted of 23 children from the IC group, and 25 children from the BFC group. A double-oddball paradigm with three consonant-vowel syllables was used, utilizing native (Russian) and foreign (Hindi) languages. A Mismatch Negativity (MMN) component was elicited within a 125-225 ms time window in the frontal-central electrode. Findings demonstrate the absence of MMN effect in the younger age group, regardless of the living environment. Children in the older group are sensitive to native deviants and do not differentiate foreign language contrasts. No significant differences were observed between the IC and BFC groups for children older than 12 months, indicating that children in the IC have typical phonological processing. The results show that the MMN effect is not registered in Russian speaking children before the age of 12 months, regardless of their living environment. At 20 months of age, institutionally reared children show no evidence of delays in phonetic development despite a limited experience of language.


Dating rare mutations from small samples with dense marker data.
We present a method for estimating the age of a mutation based on the genetic length of ancestral haplotypes shared between individuals carrying the mutation. The method can be reliably applied to small samples, typical of situations involving rare mutations, and makes effective use of modern high-density SNP data, thus overcoming two of the limitations with existing methods. The method provides age estimates and confidence intervals without the use of asymptotic theory and is applicable to genealogies in which the data are independent or correlated. In the correlated case we estimate the correlation directly from the data, rather than relying on a model for the genealogy. To demonstrate the method's efficacy, we provide simulation results and compare it to other methods. The length data are obtained with a simple procedure, and an R script is available for performing the calculations.


Monolithic enantiomer-selective stationary phases for capillary electrochromatography.
Monolithic materials have become a well-established format for stationary phases in the field of capillary electrochromatography. Four types of monoliths, namely particle-fixed, silica-based, polymer-based, and molecularly imprinted monoliths, have been utilized as enantiomer-selective stationary phases in CEC. This review summarizes recent developments in the area of monolithic enantiomer-selective stationary phases for CEC. The preparative procedure and the characterization of these columns are highlighted. In addition, the disadvantages and limitations of different monolithic enantiomer-selective stationary phases in CEC are briefly discussed.


Recombinant human serum albumin fusion proteins and novel applications in drug delivery and therapy.
Fusion proteins have been well-studied and widely applied in biopharmaceutics. Albumin fusion proteins are simple to construct, easy to purify, and stable to formulate. One main application of fusion protein is to extend the plasma half-life of therapeutic proteins and peptides. Albiglutide for diabetes treatment is the first albumin fusion protein drug approved by FDA. Balugrastim and other albumin fusion proteins have been evaluated in clinical trials. Taking advantage of the physiological functions of albumin, albumin fusion proteins can also been applied to act on an essential intracellular target and carry fatty acid-modified drugs. This novel approach makes it possible to co-deliver two different types of drug to one tumor cell for synergistic cytotoxicity.


The molecular basis of inter-alpha-inhibitor heavy chain transfer on to hyaluronan.
The inflammation-associated protein TSG-6 (the product of tumour necrosis factor-stimulated gene-6) can form covalent complexes with the heavy chains (HC1 and HC2) of IalphaI (inter-alpha-inhibitor); namely, TSG-6.HC1 and TSG-6.HC2, which act as intermediates in the covalent transfer of HCs on to the GAG (glycosaminoglycan) HA (hyaluronan). HC.HA, which is formed for example in the synovial fluids of arthritis patients, is more aggregated than unmodified HA and has altered mechanical and cell-binding properties. The expansion of the HA-rich cumulus ECM (extracellular matrix) during ovulation is critically dependent on the catalysis of HC.HA generation by TSG-6, with TSG-6(-/-) mice being female infertile because of failure of HA cross-linking. It has been shown recently that TSG-6-mediated HC.HA formation is essential for the formation of HA-rich pericellular matrix and for cell migration in a model of wound healing. In contrast, in this model, the formation of cell-associated HA cable-like structures, although requiring the transfer of HCs on to HA, might not involve TSG-6. TSG-6-mediated HC transfer involves two sequential transesterification processes, where HCs are transferred from the CS (chondroitin sulfate) of IalphaI first on to TSG-6 and then on to HA. TSG-6 is an essential co-factor and catalyst in this chain of events, with both TSG-6.HC formation and HC transfer being dependent on the presence of Mg(2+) or Mn(2+) ions.


Identification of androgen, estrogen and progesterone receptor mRNAs in the eye.
Previous research has demonstrated that sex steroids exert a significant influence on the structure and function of numerous ocular tissues. To begin to explore the underlying basis of this hormone action, we examined whether various anterior and posterior tissues of the eye contain androgen, estrogen and progesterone receptor mRNAs. Tissue samples were obtained from adult male and female rats, rabbits and humans, processed for the isolation of total RNA and analyzed by RT-PCR, agarose gel electrophoresis and Southern blot hybridization. All PCR amplifications included positive and negative controls. Our findings showed that androgen, estrogen and/or progesterone receptor mRNAs are present in the lacrimal gland, lacrimal gland acinar epithelial cells, meibomian gland, lid, palpebral and bulbar conjunctivae, cornea, iris/ciliary body, lens, retina/uvea, retina/choroid and retinal pigment epithelial cells of rats, rabbits or humans. Our findings demonstrate that sex steroid receptor mRNAs exist in a variety of ocular tissues and suggest that these sites may represent target organs for androgens, estrogens and/or progestins.


Visualizing Alzheimer's Disease Mouse Brain with Multispectral Optoacoustic Tomography using a Fluorescent probe, CDnir7.
Alzheimer's disease (AD) is now clinically considered as a chronic inflammation-based neurodegenerative disease. The CDnir7 probe was previously developed as an optical imaging probe to target macrophages in order to image mouse inflammation using in vivo optical imaging modalities such as In Vivo imaging system (IVIS) and fluorescent molecular tomography (FMT). Here, we demonstrate the application of CDnir7 in AD mouse brain imaging via multispectral optoacoustic tomography (MSOT). Longitudinal MSOT imaging of CDnir7 showed higher CDnir7 localization in AD mouse cerebral cortex compared to that of normal mice. MSOT signals of CDnir7 localization in mouse brain were verified by ex vivo near-infrared (NIR) imaging and immunohistochemistry. Histological evaluation showed strong CDnir7 staining in AD cerebral cortex, hippocampus, basal ganglia and thalamus area. Based on the supporting evidence, CDnir7 has great potential as a molecular imaging probe for AD brain imaging.


Upper gastrointestinal bleeding: audit of a single center experience in Western India.
Upper gastrointestinal (GI) bleeding is defined as bleeding proximal to the ligament of Treitz. The most important aspect of management of GI bleeding is to locate the site and cause of bleeding. The aim of the study is to find out the common etiology, presentation and management, including the role of upper GI endoscopy. Recent advances have meant that endoscopic hemostatic methods are now associated with a reduced rate of re-bleeding, cost, blood transfusion, length of hospital stay and mortality. A prospective study of 50 cases was carried out between August 2001 and July 2003. Patients with signs and symptoms suggestive of upper GI bleeding (UGIB) such as hematemesis, melena, aspirated blood from nasogastric tubes, profuse hematochezia, etc., were included in the study. The patients were selected randomly. The most common cause of UGIB in the present study was acute erosive gastritis (34%) followed by portal hypertension (24%) and peptic ulcer (22%). All 50 patients underwent upper GI endoscopy, of whom 39 patients were treated conservatively and 11 patients underwent endotherapy to control bleeding. Out of 39 patients treated non-endoscopically, 6 cases required laparotomy to control UGIB. 8 of 50 cases had past history of UGIB, 5 of whom had a previous history of endotherapy. One case was treated with de-vascularization as routine hemostatic methods failed. So, initial method of choice to control the bleeding was endotherapy and surgery was undertaken if an endoscopic method failed. The most common cause of hematemesis in our setting was acute erosive gastritis followed by portal hypertension. Endoscopy is a valuable minimal invasive method to diagnose and treat upper GI bleeding.


[Principle of obtaining specific sera for the serotyping of Pseudomonas aeruginosa].
The authors elaborated a method of obtaining sorbed specific sera for serotyping of Ps. aeruginosa on slide. A set of specific sera consisting of 20 sera was prepared; 93% of 500 cultures isolated from pathological material were typed with the aid of this set.


Percutaneous release of trigger digits.
We describe a safe and easy percutaneous technique for release of trigger finger using a specially designed knife. The A1 pulley is sectioned by a blade which has a hooked end. We released, percutaneously, 185 trigger fingers, including 62 which were locked using this technique. Satisfactory results were achieved in 173 (93.5%). There were no significant complications. We recommend this as a safe and effective outpatient procedure for those patients who have not responded successfully to conservative treatment, have longstanding symptoms or severe triggering.


Protective properties of 6-gingerol-rich fraction from Zingiber officinale (Ginger) on chlorpyrifos-induced oxidative damage and inflammation in the brain, ovary and uterus of rats.
Chlorpyrifos (CPF) is an organophosphorus pesticide widely used in agricultural applications and household environments. 6-Gingerol-rich fraction from Zingiber officinale (Ginger, 6-GRF) has been reported to possess potent anti-oxidative, anti-inflammatory and anti-apoptotic properties. Here, we investigated the protective properties of 6-GRF on CPF-induced oxidative damage and inflammation in the brain, ovary and uterus of rats. Five groups of rats containing 14 rats/group received corn oil (control), CPF (5 mg/kg), 6-GRF (100 mg/kg), CPF (5 mg/kg) + 6-GRF (50 mg/kg) and CPF (5 mg/kg) + 6-GRF (100 mg/kg) through gavage once per day for 35 days respectively. The results showed that 6-GRF protected against CPF-induced increases in oxidative stress ((hydrogen peroxide (H2O2) and malondialdehyde (MDA)), inflammatory (myeloperoxidase (MPO), nitric oxide (NO) and tumour necrosis factor-α (TNF- α)), and apoptotic (caspase-3) markers. Also, 6-GRF improved the activities of antioxidant enzymes catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST) as well as glutathione (GSH) level in the brain, ovary and uterus of rats exposed to CPF (p < 0.05). Overall, the protective effects of 6-GRF on CPF-induced toxicity in the brain and reproductive organs of rats may be due to its potent antioxidative, anti-inflammatory and antiapoptotic properties.


Pancharatnam-Berry phase shaping for control of the transverse enhancement of focusing.
We show that elongating a tightly focused field in the direction perpendicular to the optical axis is possible. We demonstrate our approach by specially shaping the Pancharatnam-Berry (PB) phase. Moreover, the analytical formulae required to calculate the strength vectors and energy flux of the three-dimensional electromagnetic fields near the focus of an aplanatic optical system are derived using the Richards and Wolf vectorial diffraction methods. Calculations reveal that the transverse enhancement is controllable and depend on the phase index in the PB phase, thereby giving rise to a focus with tunable length and subwavelength width in the focal plane.


TP53 mutations in endometrial cancers: relation to PTEN gene defects.
The PTEN and TP53 genes participate in the carcinogenesis of many malignancies, but the role of both genes in endometrial carcinogenesis is not fully elucidated. The aim of the study was to determine the quality and the frequency of incidence of TP53 and PTEN gene mutations and to assess their coexistence in endometrial cancers. Besides that, the correlation was studied between the detected defects and clinicohistopathological characteristics of the studied endometrial cancers. The study material included DNA isolated from 81 endometrial cancers. The incidence of TP53 and PTEN gene mutations was assessed using polymerase chain reaction-single-strand conformation polymorphism and sequencing techniques. The statistical analysis of the results was performed using [chi]2 test. In 64.2% of the 81 endometrial cancers, mutations occurred in TP53 and/or PTEN genes: in 16.1%, mutations occurred only in TP53; in 33.3%, only in PTEN gene; and in 14.8%, in both TP53 and PTEN genes. In 35.8% of cases, no mutations were found in these genes. No statistically significant relationship was found between the incidence of mutations in TP53 gene and that in PTEN gene (P = 0.986). The incidence of mutations in PTEN gene was higher in medium and poorly differentiated endometrial cancers than in well-differentiated ones and was statistically significant (G2 + G3 vs G1; P = 0.049). Besides that, mutations in PTEN gene occurred significantly more frequently in patients younger than 55 years than in older women (> or =55 years; P = 0.027). No similar differences were found in TP53 gene. The results of the study demonstrate that TP53 gene mutations occur in some of endometrioid endometrial cancers in the presence of PTEN gene mutations, suggesting that both these genes participate in the development of these tumors.


Na channel distribution in vertebrate skeletal muscle.
The loose patch voltage clamp has been used to map Na current density along the length of snake and rat skeletal muscle fibers. Na currents have been recorded from (a) endplate membrane exposed by removal of the nerve terminal, (b) membrane near the endplate, (c) extrajunctional membrane far from both the endplate and the tendon, and (d) membrane near the tendon. Na current densities recorded directly on the endplate were extremely high, exceeding 400 mA/cm2 in some patches. The membrane adjacent to the endplate has a current density about fivefold lower than that of the endplate, but about fivefold higher than the membrane 100-200 micron from the endplate. Small local variations in Na current density are recorded in extrajunctional membrane. A sharp decrease in Na current density occurs over the last few hundred micrometers from the tendon. We tested the ability of tetrodotoxin to block Na current in regions close to and far from the endplate and found no evidence for toxin-resistant channels in either region. There was also no obvious difference in the kinetics of Na current in the two regions. On the basis of the Na current densities measured with the loose patch clamp, we conclude that Na channels are abundant in the endplate and near-endplate membrane and are sparse close to the tendon. The current density at the endplate is two to three orders of magnitude higher than at the tendon.


Lateral diffusion coefficients of separate lipid species in a ternary raft-forming bilayer: a Pfg-NMR multinuclear study.
By isotopical labeling lipid lateral diffusion coefficients for each of the membrane constituents, including cholesterol, have been measured by 1H, 2H, and 19F pulsed field gradient NMR spectroscopy in macroscopically oriented lipid bilayers. This provides a means of obtaining detailed dynamic and compositional information in raft-forming lipid bilayers without introducing foreign molecules into the systems. The raft systems studied contained dioleoylphosphatidylcholine/dipalmitoylphosphatidylcholine (DPPC)/cholesterol at the molar ratios of 42.5:42.5:15 and 35:35:30 in excess water. At temperatures below 30 degrees C the raft system forms large (>1 microm) domains of a liquid ordered (l(o)) phase, in which the lipid lateral diffusion was approximately 5 times slower than for the lipids in the surrounding liquid disordered (l(d)) phase. Within each domain all lipid species showed the same diffusion coefficient, despite the very different structures of cholesterol and phospholipids. DPPC partitions exclusively into the l(o) domains, whereas cholesterol and dioleoylphosphatidylcholine were distributed in both l(o) and l(d) phases. The cholesterol concentration was found to be 10-20 mol % in the l(d) domain and 30-40 mol % in the l(o) domain. Comparison of these results with data from sphingomyelin-containing systems suggests that DPPC interacts more weakly with cholesterol than does sphingomyelin.


The relationship between bone mineral density and periodontitis in postmenopausal women.
Systemic bone loss has been proposed as a risk factor for periodontal disease; however, the relationship between these two diseases is still not clear. The objective of this study was to assess the relationship between systemic bone mineral density and periodontal disease, controlling for known confounders. The study population included 70 postmenopausal Caucasian women aged 51 to 78 (mean +/- SD: 62.10 +/- 7.1 years). Skeletal bone mineral density (BMD) was assessed by dual energy x-ray absorptiometry (DXA) at the neck, trochanter, intertrochanter, Ward's triangle, and total regions of the femur, and from the anterior-posterior view of the lumbar spine. Periodontal disease severity was represented by clinical attachment loss (CAL) and interproximal alveolar bone loss (ABL). Other measures of periodontal status included probing depth (PD), supragingival plaque, gingival bleeding on probing, and calculus. DXA and oral examinations were performed by calibrated examiners. Partial correlation coefficients (r) were obtained from multiple linear regression analysis adjusting for age, age at menopause, estrogen supplementation, cigarette smoking, body mass index, and supragingival plaque. Mean ABL was significantly correlated with BMD of the trochanter (r =- 0.27), Ward's triangle (r = -0.26), and total regions of the femur (r = -0.25). Mean CAL appeared to be related to BMD consistently at all regions of the skeleton, although the association did not reach statistical significance. We can conclude that skeletal BMD is related to interproximal alveolar bone loss and, to a lesser extent, to clinical attachment loss, implicating postmenopausal osteopenia as a risk indicator for periodontal disease in postmenopausal Caucasian women.


Susceptibility to urethane carcinogenesis of transgenic mice carrying a human prototype c-Ha-ras gene (rasH2 mice) and its modification by butylhydroxytoluene.
The susceptibility of rasH2 mice to urethane lung carcinogenesis and the modifying effects of butylhydroxytoluene (BHT) on development of pulmonary lesions were examined. Single i.p. injections of urethane at 250 mg/kg in males or 500 mg/kg in females induced alveolar/bronchiolar adenomas within 6 weeks. At 4 weeks after the injection with a dose of 1000 mg/kg, adenomas occurred in both sexes. BHT administration increased the multiplicity of hyperplasias observed 3 weeks after the urethane injection and additionally caused adenomas which did not occur in the urethane alone-treated animals. The overall data suggest the possibility of rapid assays for lung carcinogens using rasH2 mice.


The laboratory test justified. An effective means to reduce routine laboratory testing.
In an attempt to reduce clinical laboratory testing, a strategy was designed for a clinician-oriented restriction policy imposed on the laboratory test-ordering mechanism. The program examined the requirement of a written justification to accompany test requests. Directed justification, where specified conditions were required for test performance, was applied to the prothrombin and partial thromboplastin times and resulted in a mean reduction of 44% (P less than 0.001) in these tests; a nonspecific justification directive for leukocyte differentials, where any clinical condition listed generated the test, reduced differentials 35% (P less than 0.001). The justification policy then was extended more broadly and applied on a trial basis to general medical wards. Although no review was made on validity of listed test rationalizations, the justification process alone significantly reduced four common laboratory tests from 28% (BUN/creatinine) to 45% (electrolytes); significant reductions were not seen in less frequently ordered tests. The authors concluded that the most common clinical laboratory tests may be reduced by demanding that the clinician perform a clerical justification when requesting these tests. This mild restrictive policy in the ordering process allows the clinician to maintain responsibility over laboratory testing, while effectively reducing laboratory volume.


Control and measurement of permeability for design of microcapsule cell delivery system.
Transplantation of immunoisolated islets of Langerhans has been proposed as a promising approach to treating insulin-dependent diabetes mellitus. Recently, a cell delivery system based on a multicomponent microcapsule has been designed for the immunoisolation of insulin-secreting pancreatic islets. The capsule, formed by polyelectrolyte complexation of sodium alginate and cellulose sulfate with poly(methylene-co-guanidine), markedly has improved mechanical strength compared with the widely used alginate/poly(L-lysine) capsules. It also provides a flexibility for readily adjusting membrane thickness and capsule size, and, more important, the membrane permeability can be altered over a wide range of molecular sizes. To rigorously test the capsule diffusion properties, we have improved capsule permeability measurement by using two complementary methods: (1) size exclusion chromatography with dextran standards; and (2) newly developed methodology for assessing permeability to a series of biologically relevant proteins. Viability and function of rat pancreatic islets enclosed in the capsules with different permeability were tested in vitro. The insulin secretion of encapsulated islets was well preserved even though slightly delayed in comparison with a control group of free islets. We believe that the unique features of this encapsulation system together with the precise characterization of its physical parameters will enable us to find the optimal range of capsule permeability for in vitro and in vivo survival and function of encapsulated pancreatic islets.


A note on estimating the Cox-Snell R2 from a reported C statistic (AUROC) to inform sample size calculations for developing a prediction model with a binary outcome.
In 2019 we published a pair of articles in Statistics in Medicine that describe how to calculate the minimum sample size for developing a multivariable prediction model with a continuous outcome, or with a binary or time-to-event outcome. As for any sample size calculation, the approach requires the user to specify anticipated values for key parameters. In particular, for a prediction model with a binary outcome, the outcome proportion and a conservative estimate for the overall fit of the developed model as measured by the Cox-Snell R2 (proportion of variance explained) must be specified. This proposal raises the question of how to identify a plausible value for R2 in advance of model development. Our articles suggest researchers should identify R2 from closely related models already published in their field. In this letter, we present details on how to derive R2 using the reported C statistic (AUROC) for such existing prediction models with a binary outcome. The C statistic is commonly reported, and so our approach allows researchers to obtain R2 for subsequent sample size calculations for new models. Stata and R code is provided, and a small simulation study.


The Osteoporosis Self-Assessment Tool versus alternative tests for selecting postmenopausal women for bone mineral density assessment: a comparative systematic review of accuracy.
We performed a systematic review of studies comparing the Osteoporosis Self-Assessment Tool (OST) and other tests used to select women for bone mineral density (BMD) assessment. In comparative meta-analyses, we found that the accuracy of OST was similar to other tests that are based on information from the medical history. By contrast, assessment by quantitative ultrasonography at the heel was more accurate than OST in discriminating between women with high and low BMD. The methodological quality of the included studies was generally low. Numerous tests are suggested for triaging postmenopausal women for bone mineral density (BMD) assessment by dual-energy X-ray absorptiometry. Previous studies suggest that OST, based on age and weight only, may be as accurate as more complex triage tests. We systematically compare the accuracy of OST and alternative triage tests in postmenopausal women. We searched PubMed, Embase, Web of Science, citation lists, and conference proceedings. Our main measure of accuracy was the diagnostic odds ratio (DOR). We compared summary estimates of DOR (sDOR) for OST and alternative tests in pairwise meta-analyses by using the Moses-Littenberg approach. Summary estimates of DOR for OST and the clinical decision rules Simple Calculated Osteoporosis Risk Estimation (SCORE) and Osteoporosis Risk Assessment Instrument (ORAI) did not differ significantly in white women (relative sDOR: 0.57-1.17, all p >or= 0.11). By contrast, sDOR was higher for Stiffness Index assessed by calcaneal quantitative ultrasonography than for OST (relative sDOR: 1.9, p = 0.005). Studies were few in Asian and black women. Methodological quality, assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist, was generally low. In white women, the accuracy of OST and alternative clinical decision rules was similar, whereas Stiffness Index was more accurate than OST. Low study quality renders transferability to clinical settings uncertain.


Substrate range of acetohydroxy acid synthase I from Escherichia coli in the stereoselective synthesis of alpha-hydroxy ketones.
Acetohydroxy acid synthase I appears to be the most effective of the AHAS isozymes found in Escherichia coli in the chiral synthesis of phenylacetyl carbinol from pyruvate and benzaldehyde. We report here the exploration of a range of aldehydes as substrates for AHAS I and demonstrate that the enzyme can accept a wide variety of substituted benzaldehydes, as well as heterocyclic and heteroatomic aromatic aldehydes, to produce chiral carbinols. The active site of AHAS I does not appear to impose serious steric constraints on the acceptor substrate. The influence of electronic effects on the reaction has been probed using substituted benzaldehydes as substrates. The electrophilicity of the aldehyde acceptor substrates is most important to their reactivity, but the lipophilicity of substituents also affects their reactivity. AHAS I is an effective biosynthetic platform for production of a variety of alpha-hydroxy ketones, compounds with considerable potential as pharmacological precursors.


LIFU Alleviates Neuropathic Pain by Improving the KCC2 Expression and Inhibiting the CaMKIV-KCC2 Pathway in the L4-L5 Section of the Spinal Cord.
Effective treatment remains lacking for neuropathic pain (NP), a type of intractable pain. Low-intensity focused ultrasound (LIFU), a noninvasive, cutting-edge neuromodulation technique, can effectively enhance inhibition of the central nervous system (CNS) and reduce neuronal excitability. We investigated the effect of LIFU on NP and on the expression of potassium chloride cotransporter 2 (KCC2) in the spinal cords of rats with peripheral nerve injury (PNI) in the lumbar 4-lumbar 5 (L4-L5) section. In this study, rats received PNI surgery on their right lower legs followed by LIFU stimulation of the L4-L5 section of the spinal cord for 4 weeks, starting 3 days after surgery. We used the 50% paw withdraw threshold (PWT50) to evaluate mechanical allodynia. Western blotting (WB) and immunofluorescence (IF) were used to calculate the expression of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), calcium/calmodulin-dependent protein kinase type IV (CaMKIV), phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB), and KCC2 in the L4-L5 portion of the spinal cord after the last behavioral tests. We found that PWT50 decreased (P < 0.05) 3 days post-PNI surgery in the LIFU- and LIFU+ groups and increased (P < 0.05) after 4 weeks of LIFU stimulation. The expression of p-CREB and CaMKIV decreased (P < 0.05) and that of KCC2 increased (P < 0.05) after 4 weeks of LIFU stimulation, but that of p-ERK1/2 (P > 0.05) was unaffected. Our study showed that LIFU could effectively alleviate NP behavior in rats with PNI by increasing the expression of KCC2 on spinal dorsal corner neurons. A possible explanation is that LIFU could inhibit the activation of the CaMKIV-KCC2 pathway.