Quality of life, alcohol detoxification and relapse: is quality of life a predictor of relapse or only a secondary outcome measure?
To estimate variations in Overall Quality Of Life (OQOL) within 12 months following alcohol detoxification and to evaluate the predictive value of OQOL for relapse and alcohol use severity. Alcohol use disorders and four OQOL domains (physical health, psychological health, social relationships and environment) were assessed in 199 patients entering in-patient alcohol detoxification. Follow-up assessments were performed at 6 and 12 months after discharge. Cross-sectional and longitudinal analyses explored the relationship between OQOL and alcohol use severity, examining differences between abstinent and relapsed patients. The predictive value of OQOL was analyzed by logistic and linear regression. Correlation between OQOL and Alcohol Use Disorders Identification Test scores was confirmed at all stages of observation. Abstinent patients showed a significant improvement in all OQOL domains at 6 months after discharge, whereas OQOL domains did not undergo any significant change in relapsed patients. Baseline OQOL did not prove to be predictive of either relapse or alcohol use severity. Overall quality of life changed in parallel with alcohol use severity throughout the duration of the study, confirming it to be a useful and sensitive measure of secondary outcome for alcohol detoxification. Conversely, none of the OQOL baseline scores functioned as predictors of relapse within 12 months following discharge or alcohol use severity in relapsed patients.


Prophylactic vs. Therapeutic Treatment With P2Et Polyphenol-Rich Extract Has Opposite Effects on Tumor Growth.
Polyphenols have tumoricidal effects via anti-proliferative, anti-angiogenic and cytotoxic mechanisms and have recently been demonstrated to modulate the immune response through their anti- or pro- oxidant activity. Nevertheless, it remains controversial whether antioxidant-rich supplements have real beneficial effects on health, especially in complex diseases such as cancer. We previously identified a polyphenol-rich extract obtained from Caesalpinia spinosa (P2Et) with anti-tumor activity in both breast carcinoma and melanoma. The present work evaluated the ability of P2Et extract to modulate the immune system in either the steady state or following tumor challenge. We found that the prophylactic treatment of healthy mice increased the number of CD4+ and CD8+ activated T, NK, regulatory T, dendritic and myeloid-derived suppressor cells in lymphoid organs together with a significant increase in plasma IL-6. Interestingly, this pre-conditioning of the host immune system with P2Et did not involve a protective effect against the control of tumor growth and metastasis in transplantable models of melanoma (B16) and breast cancer (4T1), but in contrast, a detrimental effect was observed in both models. We further demonstrated that this effect was at least partly due to an increase in regulatory T cells, myeloid-derived suppressor cells, and proinflammatory cytokines, with a concomitant decrease in CD4+ and CD8+ T cells. Taken together, these results suggest that the anti-tumor and immunomodulation properties of the P2Et extract critically depend on the presence of the tumor and might be mediated by the complex interactions between the tumor cells and the other components of the tumor microenvironment.


High-efficiency and sustainable sodium humate aerogel evaporator for solar steam generation.
The utilization of solar interface evaporation technology (SIET) for freshwater production from seawater and sewage is a sustainable, green, viable, and promising approach. However, the absorption rate of sunlight, evaporation rates, and high costs still pose large-scale solar steam generation. In this paper, a novel aerogel (named SAS) was prepared by graft copolymerization with sodium alginate (SA), acrylic acid (AA) and sodium humate (SH) in aqueous solution, using N, N'-Methylenebisacrylamide (MBA) as crosslinker and ammonium persulfate (APS) as initiator, which has high light absorption (90 %), high porosity (87.96 %), superhydrophilicity (35 ms), low thermal conductivity (0.23 W m-1 k-1). The evaporation rate of SAS aerogel can reach up to 1.66 kg m-2h-1 under 1 kW m-2 light intensity, and the reusability and reliability of SAS aerogel are verified by 10 cycles of experiments. The utilization of this SAS aerogel holds significant implications for the design and fabrication of cost-effective, high-performance solar steam evaporation systems, thereby offering promising solutions to address global freshwater shortages and enhance wastewater treatment efficiency.


Descriptive and injunctive norms related to concurrent sexual partnerships in Malawi: implications for HIV prevention research and programming.
Concurrent sexual partnerships are hypothesized to be a contributing factor to Malawi's HIV epidemic. As social norms influence health behavior and have been found to influence sexual behavior, the purpose of this study was to explore two types of norms, descriptive and injunctive norms, toward concurrent sexual partnerships in Malawi. Data from 40 focus group discussions and 20 in-depth interviews conducted in five districts in Malawi, which included 318 participants aged 18-55 years, were analyzed. Participants perceived that concurrent sexual partnerships were extremely common, and believed that very few individuals in their communities were not in concurrent sexual partnerships. However, participants perceived that others in their communities heavily disapproved of concurrent sexual partnerships outside of polygamy, as polygamy was viewed as an acceptable type of partnership because it was conducted in the open. Participants asserted that there were no traditional practices that promoted concurrent sexual partnerships, and perceived that those that engaged in the behavior were for the most part stigmatized by community members. Further research is needed to obtain a thorough understanding of the way in which the perceived actions and beliefs of peers influence the beliefs, feelings and actions of individuals to strengthen HIV programming efforts in the region.


Natural History of Cognitive Impairment in Critical Illness Survivors. A Systematic Review.
Long-term cognitive impairment is common among ICU survivors, but its natural history remains unclear. In this systematic review, we report the frequency of cognitive impairment in ICU survivors across various time points after ICU discharge that were extracted from 46 of the 3,350 screened records. Prior studies used a range of cognitive instruments, including subjective assessments (10 studies), single or screening cognitive test such as Mini-Mental State Examination or Trail Making Tests A and B (23 studies), and comprehensive cognitive batteries (26 studies). The mean prevalence of cognitive impairment was higher with objective rather than subjective assessments (54% [95% confidence interval (CI), 51-57%] vs. 35% [95% CI, 29-41%] at 3 months after ICU discharge) and when comprehensive cognitive batteries rather than Mini-Mental State Examination were used (ICU discharge: 61% [95% CI, 38-100%] vs. 36% [95% CI, 15-63%]; 12 months after ICU discharge: 43% [95% CI, 10-78%] vs. 18% [95% CI, 10-20%]). Patients with acute respiratory distress syndrome had higher prevalence of cognitive impairment than mixed ICU patients at ICU discharge (82% [95% CI, 78-86%] vs. 48% [95% CI, 44-52%]). Although some studies repeated tests at more than one time point, the time intervals between tests were arbitrary and dictated by operational limitations of individual studies or chosen cognitive instruments. In summary, the prevalence and temporal trajectory of ICU-related cognitive impairment varies depending on the type of cognitive instrument used and the etiology of critical illness. Future studies should use modern comprehensive batteries to better delineate the natural history of cognitive recovery across ICU patient subgroups and determine which acute illness and treatment factors are associated with better recovery trajectories.


Maximum likelihood estimation of the number of nucleotide substitutions from restriction sites data.
A simple method of the maximum likelihood estimation of the number of nucleotide substitutions is presented for the case where restriction sites data from many different restriction enzymes are available. An iteration method, based on nucleotide counting, is also developed. This method is simpler than the maximum likelihood method but gives the same estimate. A formula for computing the variance of a maximum likelihood estimate is also presented.


Use of the water absorption spectrum to quantify tissue chromophore concentration changes in near-infrared spectroscopy.
We describe a simple method for measuring the 'differential pathlength' of photons in a scattering medium utilizing the spectral absorption features of water. Determination of this differential pathlength is a prerequisite for quantifying chromophore concentration changes measured by near-infrared spectroscopy (NIRS), and the method proposed here achieves this without the need for time- or frequency-resolved measurements. The quantification of tissue chromophore concentration measurements is a major goal in NIRS research, allowing, for example, the non-invasive measurement of blood flow and volume in the brain and other organs. We present the results of validation experiments performed on tissue phantoms comparing the differential path estimates yielded by water absorption and time-resolved measurements, finding that the weak water absorption feature at 820 nm can yield a differential path estimate in addition to the main feature at 975 nm. We also present results from in vivo studies in which we find that whilst the 820 nm feature is measured with lower accuracy for a given light flux than the 975 nm feature, it is intrinsically a more accurate differential path estimator. Studies on the adult forearm showing differences between time-resolved and water absorption differential path estimates suggest that the measurement of both could aid in quantifying NIRS signals in heterogeneous tissues.


Exploitation of the insane in the New World. Benoni Buck, the first reported case of mental retardation in the American colonies.
Documenting the early history of mental illness in North America is complicated by the absence of colonial institutions specializing in the care or management of the insane. However, during the first half of the 17th century, a single authority existed in England, the Court of Wards and Liveries (1540-1660), with responsibility for appointing guardians for the mentally disabled. In 1637, Benoni Buck, a man with severe mental retardation, was referred to this court from Jamestown, Va. The ensuing conflict over Benoni's custody exposed a contradiction between the economic and political exigencies of a new order and the social obligation to protect the mentally ill. Benoni Buck is almost certainly the first case of mental disability reported from the English colonies. The case thereby represents a minor landmark in the history of mental illness in America; May 1987 marks the 350th anniversary of the first petition for guardianship.


Identification of Potential Barriers to Timely Access to Pediatric Hearing Aids.
Despite various barriers identified to early pediatric access to cochlear implantation, barriers to timely access to pediatric hearing aids are not well characterized. To identify socioeconomic, demographic, and clinical factors that may be associated with pediatric access to hearing aids. This retrospective cohort study included 90 patients aged 1 to 15 years who were referred for auditory brainstem response (ABR) testing and evaluation for hearing aids at a single tertiary care academic medical center from March 2004 to July 2018. Children who did not receive both ABR testing and hearing aids at the same center were excluded from analysis. Associations of insurance type (private vs public), race/ethnicity (white vs other), primary language (English vs other), cause of hearing loss (complex vs not complex), zip code, hearing aid manufacturer, and severity of hearing loss (in decibels) with the duration of intervals from newborn hearing screening to ABR testing, from ABR testing to ordering of hearing aids, and from ABR testing to dispensing of hearing aids. Of the 90 patients, mean (SD) age was 5.6 (3.7) years, 56% were female, and 77 (86%) were non-Hispanic. Results of χ2 tests indicated significant assocations existed between public insurance and race/ethnicity and between public insurance and primary language other than English. Variables associated with the interval from newborn hearing screening to ABR testing included insurance type (mean difference, 7.4 months; 95% CI, 2.6-12.2 months) and race/ethnicity (mean difference, 6.9 months; 95% CI, 2.7-11.1 months). Increased delays between birth and a child's first ABR test were associated with public insurance (mean difference, 6.0 months; 95% CI, 1.8-10.2 months) and race/ethnicity other than white (mean difference, 6.0 months; 95% CI, 2.3-9.7 months). The mean time from birth to initial ABR testing was a mean of 6 months longer for patients from non-English-speaking families than for those from English-speaking families (mean [SD] interval, 14.9 [16.3] months vs 9.0 [8.5] months), although the difference was not statistically significant. Severity of hearing loss was associated with a decrease in the interval from ABR testing to ordering of hearing aids after accounting for other potential barriers (odds ratio, 0.6; 95% CI, 0.4-0.9). Zip code and complexity of the child's medical condition did not appear to be associated with timely access to pediatric hearing aids. This study's findings suggest that insurance type, race/ethnicity, and primary language may be barriers associated with pediatric access to hearing aids, with the greatest difference observed in time to initial ABR testing. Clinical severity of hearing loss appeared to be associated with a significant decrease in time from ABR testing to ordering of hearing aids. Greater efforts to assist parents with ABR testing and coordination of follow-up may help improve access for other at-risk children.


Why it is difficult to model sperm displacement in Drosophila melanogaster: the relation between sperm transfer and copulation duration.
We have investigated the effects of experimental manipulation of copulation duration on sperm displacement in Drosophila melanogaster. Both spermless and normal males were used as second (displacing) males in the experiments. Displacement induced in the absence of sperm, that is, by males that pass accessory gland fluid alone, was a relatively inefficient process and produced much lower levels of displacement than normal males. Therefore, the presence of second-male sperm is necessary (but unlikely sufficient) for the high levels of displacement commonly observed in D. melanogaster. Furthermore, when second matings were interrupted at various times after the initiation of copulation, the distribution of displacement was strongly bimodal. We conclude that sperm transfer is relatively rapid, beginning shortly after the initiation of copulation, and is essentially complete before the midpoint of copulation. Therefore, sperm transfer bears no simple relation to copulation duration. Because it would be difficult to manipulate the numbers of sperm transferred by manipulating copulation duration, methods used to study sperm displacement in other insect species are unlikely to be appropriate for D. melanogaster. We also investigated why males mate for more than twice the duration that appears to be necessary to complete sperm transfer. Experimental interruption of first matings indicated that the extra copulation time serves to delay female remating, rather than to increase that rate at which of offspring are sired before remating.


Relative gene expression analysis of human pterygium tissues and UV radiation-evoked gene expression patterns in corneal and conjunctival cells.
A sight threatening, pterygium is a common ocular surface disorders identified by fibrovascular growth of the cornea and induced by variety of stress factors, like ultraviolet (UV) exposure. However, the genes involved in the etiopathogenesis of this disease is not well studied. Herein, we identified the gene expression pattern of pterygium and examined the expression of pterygium-related genes in UV-B-induced human primary cultured corneal epithelial cells (HCEpCs), telomerase immortalized human corneal epithelial (hTCEpi), primary conjunctival fibroblast (HConFs) and primary pterygium fibroblast cells (HPFCs). A careful analysis revealed that the expression of 10 genes was significantly modulated (by > 10-fold). Keratin 24 (KRT24) and matrix metalloproteinase 9 (MMP-9) were dramatically upregulated by 49.446- and 24.214-fold, respectively. Intriguingly, UV-B exposure (50 J/m2) induced the upregulation of the expressions of MMP-9 in corneal epithelial cells such as HCEpCs and hTCEpi. Furthermore, UV-B exposure (100 and/or 200 J/m2) induced the upregulation of the expressions of MMP-9 in fibroblast such as HConFs and HPFCs. The exposure of HCEpCs to 100 and 200 J/m2 UV-B induced significant expressions of KRT24 mRNA. Nevertheless, no expression of KRT24 mRNA was detected in HConFs and HPFCs. The findings provide evidence that the progression of pterygium may involve the modulation of extracellular matrix-related genes and vasculature development and the up-regulation of KRT24 and MMP-9 by UV stress. UV radiation may promote the modulation of these pterygium-related genes and induce the initiation and progression of human pterygium.


Optical properties of oakwood in the near-infrared range of semi-transparency.
The spectral absorption and scattering properties of oakwood are retrieved from the measurements of both the normal-hemispherical reflectance and transmittance in the visible and near-infrared ranges of semi-transparency. We employ two alternative methods for the radiative transfer in wood samples: the modified two-flux approximation and the high-order discrete ordinate method. The modifications of both methods take into account the effect of total internal reflection at both surfaces of the wood samples. The analytical approximate solution of the first method gives very accurate results for the absorption coefficient, but the transport scattering coefficient of wood appeared to be systematically underestimated. Fortunately, this error is between 7% and 12%, and that is acceptable for the estimates. The oakwood samples of four different thicknesses were used in the experiments. The effect of the wood cell orientation appears to be insignificant and can be observed in the reflectance from optically thin samples only. There is a considerable decrease in the transport scattering coefficient of oakwood with the wavelength. This effect is explained by a predominant contribution of micron-sized longitudinal pores in oakwood. The latter is used to develop an approximate theoretical model of scattering based on the rigorous solution for arbitrary-oriented cylindrical pores. The model suggested is in good agreement with the experimental data.


Pathologic anatomy and CT correlations in the glioblastoma multiforme.
6 cases of glioblastoma multiforme, 1 anaplastic astrocytoma, and 1 astrocytoma were studied pathologically post mortem. The specimens were compared to antemortem CT scans, when available. By use of whole brain sections, each glioblastoma was divided into a central area of necrosis, a surrounding rim of hypercellular neoplasm, and a peripheral zone of infiltration. The dimensions and areas of these three zones were quantified. The striking findings of the study were the often small diameter of the hypercellular region and the frequently narrow peripheral zone of detectable infiltrating cells. Comparison of the autopsy specimens with CT scans confirmed previous studies of the glioblastoma. The radiographic central area of low density is necrosis; the enhancing rim is a markedly hypercellular region, and the perilesional low density encompasses a population of infiltrating tumor cells.


Manipulation and Localized Deposition of Particle Groups with Modulated Electric Fields.
This paper presents a new micro additive manufacturing process and initial characterization of its capabilities. The process uses modulated electric fields to manipulate and deposit particles from colloidal solution in a contactless way and is named electrophoretically-guided micro additive manufacturing (EPμAM). The inherent flexibility and reconfigurability of the EPμAM process stems from electrode array as an actuator use, which avoids common issues of controlling particle deposition with templates or masks (e.g., fixed template geometry, post-process removal of masks, and unstable particle trapping). The EPμAM hardware testbed is presented alongside with implemented control methodology and developed process characterization workflow. Additionally, a streamlined two-dimensional (2D) finite element model (FEM) of the EPμAM process is used to compute electric field distribution generated by the electrode array and to predict the final deposition location of particles. Simple particle manipulation experiments indicate proof-of-principle capabilities of the process. Experiments where particle concentration and electric current strength were varied demonstrate the stability of the process. Advanced manipulation experiments demonstrate interelectrode deposition and particle group shaping capabilities where high, length-to-width, aspect ratio deposits were obtained. The experimental and FEM results were compared and analyzed; observed process limitations are discussed and followed by a comprehensive list of possible future steps.


A Hebbian feedback covariance learning paradigm for self-tuning optimal control.
We propose a novel adaptive optimal control paradigm inspired by Hebbian covariance synaptic adaptation, a preeminent model of learning and memory as well as other malleable functions in the brain. The adaptation is driven by the spontaneous fluctuations in the system input and output, the covariance of which provides useful information about the changes in the system behavior. The control structure represents a novel form of associative reinforcement learning in which the reinforcement signal is implicitly given by the covariance of the input-output (I/O) signals. Theoretical foundations for the paradigm are derived using Lyapunov theory and are verified by means of computer simulations. The learning algorithm is applicable to a general class of nonlinear adaptive control problems. This on-line direct adaptive control method benefits from a computationally straightforward design, proof of convergence, no need for complete system identification, robustness to noise and uncertainties, and the ability to optimize a general performance criterion in terms of system states and control signals. These attractive properties of Hebbian feedback covariance learning control lend themselves to future investigations into the computational functions of synaptic plasticity in biological neurons.


A Deterministic Analysis of an Online Convex Mixture of Experts Algorithm.
We analyze an online learning algorithm that adaptively combines outputs of two constituent algorithms (or the experts) running in parallel to estimate an unknown desired signal. This online learning algorithm is shown to achieve and in some cases outperform the mean-square error (MSE) performance of the best constituent algorithm in the steady state. However, the MSE analysis of this algorithm in the literature uses approximations and relies on statistical models on the underlying signals. Hence, such an analysis may not be useful or valid for signals generated by various real-life systems that show high degrees of nonstationarity, limit cycles and that are even chaotic in many cases. In this brief, we produce results in an individual sequence manner. In particular, we relate the time-accumulated squared estimation error of this online algorithm at any time over any interval to the one of the optimal convex mixture of the constituent algorithms directly tuned to the underlying signal in a deterministic sense without any statistical assumptions. In this sense, our analysis provides the transient, steady-state, and tracking behavior of this algorithm in a strong sense without any approximations in the derivations or statistical assumptions on the underlying signals such that our results are guaranteed to hold. We illustrate the introduced results through examples.


Possible effects of different doses of 2.1 GHz electromagnetic radiation on learning, and hippocampal levels of cholinergic biomarkers in Wistar rats.
The present study evaluated whether short-term exposure to different doses of 2.1 GHz radiofrequency electromagnetic radiation (RF-EMR) has different effects on rats' behaviour and hippocampal levels of central cholinergic biomarkers. Animals were divided into three equal groups namely; group 1 was sham-exposed group, group 2-3 were exposed to 45 V/m and 65 V/m doses of 2.1 GHz frequency for 1 week respectively. Numerical dosimetry simulations were carried out. Object location and Y-maze were used as behavioural tasks. The protein and mRNA expression levels of AChE, ChAT, and VAChT, in the hippocampus were tested using Western Blotting and Real-Time PCR. The impairment performance of rats subjected to 65 V/m dose of 2.1 GHz RF-EMR in both object location and Y-maze tasks was observed. The hippocampal levels of AChE, ChAT, and VAChT, were significantly lower in rats exposed to 65 V/m dose of 2.1 GHz RF-EMR than others. The stronger effect of "65 V/m" dose on both rat's hippocampal-dependent behavioural performances and hippocampal levels of cholinergic biomarkers may be due to the stronger effect of "65 V/m" dose where rats' snouts were located at the nearest distance from the monopole antenna. Furthermore, the simulated SAR values were high for 65 V/m electric-field strengths. For the first time, we report the potential dose-dependent effects of short-term exposure to 2.1 GHz radiation on rat's behavioural performances as well as hippocampal levels of cholinergic biomarkers. Further studies are needed to understand the mechanisms by which RF-EMR influences the function of the central cholinergic system in the brain.


[The sensitivity of catalytic subunit isoforms of Na+,K+-ATPase of rat brain to peroxide membrane modification].
The comparative study of the sensitivity of Na+, K(+)-ATPase isozymes from cerebral cortex to ascorbate-dependent membrane peroxidation was conducted. With highly inactivated Na+, K(+)-ATPase the degree of inactivation of the SH-dependent ouabain-sensitive forms alpha+ (alpha 2 and alpha 3) is higher than glycoside-resistant isoform alpha 1. The process is accompanied by simultaneous lipid peroxidation and decrease of SH-groups amount in enzyme preparations. The combined nature of the oxidative Na+, K(+)-ATPase inactivation, accompanied by the direct oxidation of enzyme SH-groups and modification of lipid environment is supposed.


In Vitro Dialysis of Cytokine-Rich Plasma With High and Medium Cut-Off Membranes Reduces Its Procalcific Activity.
Recently developed high-flux (HF) dialysis membranes with extended permeability provide better clearance of middle-sized molecules such as interleukins (ILs). Whether this modulation of inflammation influences the procalcific effects of septic plasma on vascular smooth muscle cells (VSMCs) is not known. To assess the effects of high cut-off (HCO) and medium cut-off (MCO) membranes on microinflammation and in vitro vascular calcification we developed a miniature dialysis model. Plasma samples from lipopolysaccharide-spiked blood were dialyzed with HF, HCO, and MCO membranes in an in vitro miniature dialysis model. Afterwards, IL-6 concentrations were determined in dialysate and plasma. Calcifying VSMCs were incubated with dialyzed plasma samples and vascular calcification was assessed. Osteopontin (OPN) and matrix Gla protein (MGP) were measured in VSMC supernatants. IL-6 plasma concentrations were markedly lower with HCO and MCO dialysis. VSMC calcification was significantly lower after incubation with MCO- and HCO-serum compared to HF plasma. MGP and OPN levels in supernatants were significantly lower in the MCO but not in the HCO group compared to HF. In vitro dialysis of cytokine-enriched plasma samples with MCO and HCO membranes reduces IL-6 levels. The induction of vascular calcification by cytokine-enriched plasma is reduced after HCO and MCO dialysis.


Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, placebo-controlled, crossover trial.
To examine the efficacy and toxicity of oral 3,4 diaminopyridine (DAP) in dosages up to 100 mg/day, 36 patients with multiple sclerosis (MS) enrolled in a randomized, double-blind, placebo-controlled, crossover trial. The primary outcome measure was improvement of a prospectively defined neurologic deficit, which was leg weakness in 34 patients. Secondary outcome measures included the patient's subjective response, scored manual motor testing (MMT) of leg strength, scored leg strength from videotaped motor testing (VMT), quadriceps and hamstrings strength (QMT) measured by isometric dynamometry, neuropsychological testing (NPT), ambulation index (AI), and Expanded Disability Status Scale (EDSS) score. Paresthesias and abdominal pain were common and were dose limiting in eight patients. Three patients had episodes of confusion, and one patient had a seizure while on DAP. Eight patients withdrew from the study, leaving 28 evaluable patients for the efficacy analysis. The prospectively defined neurologic deficit improved in 24 patients-22 on DAP and 2 on placebo (p = 0.0005). All improvements were in leg weakness. Subjective response and measures of leg strength and function (MMT, VMT, QMT, and AI) improved on DAP compared with placebo. Neither NPT nor EDSS scores improved. DAP treatment can induce improvements in leg strength in MS patients, but toxicity is limiting in many patients.


The Dockstore: enhancing a community platform for sharing reproducible and accessible computational protocols.
Dockstore (https://dockstore.org/) is an open source platform for publishing, sharing, and finding bioinformatics tools and workflows. The platform has facilitated large-scale biomedical research collaborations by using cloud technologies to increase the Findability, Accessibility, Interoperability and Reusability (FAIR) of computational resources, thereby promoting the reproducibility of complex bioinformatics analyses. Dockstore supports a variety of source repositories, analysis frameworks, and language technologies to provide a seamless publishing platform for authors to create a centralized catalogue of scientific software. The ready-to-use packaging of hundreds of tools and workflows, combined with the implementation of interoperability standards, enables users to launch analyses across multiple environments. Dockstore is widely used, more than twenty-five high-profile organizations share analysis collections through the platform in a variety of workflow languages, including the Broad Institute's GATK best practice and COVID-19 workflows (WDL), nf-core workflows (Nextflow), the Intergalactic Workflow Commission tools (Galaxy), and workflows from Seven Bridges (CWL) to highlight just a few. Here we describe the improvements made over the last four years, including the expansion of system integrations supporting authors, the addition of collaboration features and analysis platform integrations supporting users, and other enhancements that improve the overall scientific reproducibility of Dockstore content.


US forensic Y-chromosome short tandem repeats database.
A forensic Y-STR database generated in the US was compiled with profiles containing a portion or complete typing of 16 STR markers DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS456, DYS458, DYS635, DYS448, and Y GATA H4. There were 17,447 samples in the version of database in which 77% and 20% were collected in North America and Asia, respectively. The database was separated into six general populations, African American, Asian, Caucasian, Hispanic, Indian, and Native American. Each population was further classified into subgroups according to geographic regions. Some subgroups were tested, found to be homogenous and merged together. Allele and haplotype frequencies, as well as sample sizes were summarized. Of the full haplotypes (i.e., 16 STRs without missing data), 93.7% in total population were distinct, 92.9% were population specific, and 89.3% were only observed once. The majority of shared haplotypes were found among North American populations as a result of admixture lasting the past few hundred years. The power of discrimination (PD), coancestry coefficient (F(st)), and coefficient of gene differentiation (G(st)) at locus and haplotype levels were also calculated. The most polymorphic marker was DYS385; this marker contains a tandem duplication and actually is composed of two loci. Both G(st) and F(st) estimates were very small with haplotypes composed of a high number of STRs haplotypes (e.g., 10-16 markers), although G(st) is slightly more conservative for these extended haplotypes. With Native American removed from the total population data set, the G(st) and F(st) estimates reduce further. PD was 0.9998 for the total population dataset for all 16 Y-STR markers. Three measures of Y-STR profile frequency were calculated: (1) unconditional haplotype frequency, (2) population substructure adjusted frequency, and (3) binomial upper bound of the haplotype frequency. The binomial upper bound is the most conservative estimate for most forensic applications. Estimates of the weight of a Y-STR haplotype can be estimated using population specific or total population databases.


Acute ketamine challenge increases resting state prefrontal-hippocampal connectivity in both humans and rats.
Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders. We aimed to establish whether acute ketamine challenge has consistent effects in rats and humans by investigating resting-state fMRI PFC-HC connectivity and thus to corroborate its potential utility as a translational probe. Twenty-four healthy human subjects (12 females, mean age 25 years) received intravenous doses of either saline (placebo) or ketamine (0.5 mg/kg body weight). Eighteen Sprague-Dawley male rats received either saline or ketamine (25 mg/kg). Resting-state fMRI measurements took place after injections, and the data were analyzed for PFC-HC functional connectivity. In both species, ketamine induced a robust increase in PFC-HC coupling, in contrast to findings in chronic schizophrenia. This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.


Frozen section evaluation of sentinel lymph nodes in breast carcinoma: a retrospective analysis.
To determine the false-negative rate, sensitivity, and diagnostic accuracy of the frozen section analysis of the sentinel lymph node (SLN) biopsy in early-stage breast cancer compared to the definitive section and to identify the factors that could be associated with the appearance of false-negative cases. Secondarily, to evaluate the pathological results of cases submitted to completion axillary lymph node dissection (ALND) for positive SLN. We performed a five-year review of cases (2011-2015), including patients with early-stage breast cancer undergoing SLN biopsy, with frozen section evaluation and subsequent definitive pathological analysis. These results were compared to calculate the false-negative rate and the factors associated with it. The histopathological findings were also evaluated in patients submitted to completion ALND. A total of 281 patients were evaluated, identifying 18 cases with frozen section results as false negative (false-negative rate: 23.7%), and 55.5% of these cases were micrometastases. The false-negative rate in SLN with macrometastasis was 13.1% and for micrometastasis cases was 66.7% (p < 0.001). True-positive patients that were submitted to completion ALND had additional axillary lymph nodes with metastases in 28% of cases, whereas the group of false negatives had additional positive axillary lymph nodes in 40% of patients (p = 0.62). Frozen section analysis had a false-negative rate acceptable in SLN biopsy in our institution, and the micrometastasis in the SLN was the most important factor associated with the appearance of this phenomenon.


External cavity diode laser based photoacoustic detection of CO2 at 1.43 microm: the effect of molecular relaxation.
Photoacoustic spectroscopy, based on an external cavity diode laser operating at 1431 nm, was used for measuring CO2 concentration as a minority component in a gas mixture. By using N2 as a buffer gas, a molecular relaxation effect was observed, which influenced both the amplitude and the phase of the measured photoacoustic signal and consequently reduced the sensitivity of the PA system. This molecular relaxation effect could be suppressed by adding water vapor of a constant and relatively high (approximately 4%) concentration to the gas sample. In parallel with this, the arising spectral interference between H2O and CO2 necessitated the development of a simple yet efficient signal analysis method, which increased the sensitivity of the system by more than one order of magnitude and accordingly reduced the minimum detectable CO2 concentration down to approximately 1000 ppm.


A genome-wide association study identifies variants underlying the Arabidopsis thaliana shade avoidance response.
Shade avoidance is an ecologically and molecularly well-understood set of plant developmental responses that occur when the ratio of red to far-red light (R:FR) is reduced as a result of foliar shade. Here, a genome-wide association study (GWAS) in Arabidopsis thaliana was used to identify variants underlying one of these responses: increased hypocotyl elongation. Four hypocotyl phenotypes were included in the study, including height in high R:FR conditions (simulated sun), height in low R:FR conditions (simulated shade), and two different indices of the response of height to low R:FR. GWAS results showed that variation in these traits is controlled by many loci of small to moderate effect. A known PHYC variant contributing to hypocotyl height variation was identified and lists of significantly associated genes were enriched in a priori candidates, suggesting that this GWAS was capable of generating meaningful results. Using metadata such as expression data, GO terms, and other annotation, we were also able to identify variants in candidate de novo genes. Patterns of significance among our four phenotypes allowed us to categorize associations into three groups: those that affected hypocotyl height without influencing shade avoidance, those that affected shade avoidance in a height-dependent fashion, and those that exerted specific control over shade avoidance. This grouping allowed for the development of explicit hypotheses about the genetics underlying shade avoidance variation. Additionally, the response to shade did not exhibit any marked geographic distribution, suggesting that variation in low R:FR-induced hypocotyl elongation may represent a response to local conditions.


Mitral valve repair for functional mitral regurgitation: is annuloplasty alone enough?
To outline indications and contraindications to mitral valve surgery in the clinical context of dilated cardiomyopathy and the surgical principles to follow in performing an undersized annuloplasty. Moreover, we will describe the characteristics of the patients for whom an annuloplasty alone is unlikely to provide an effective result and for whom,therefore, some other procedures or mitral valve replacement should be preferred. In functional mitral regurgitation, competence of the mitral valve can be restored by using a restrictive annuloplasty. This procedure leads to symptomatic improvement and reverse left ventricular remodeling in a substantial proportion of patients. However, the failure rate of undersized annuloplasty is still high and is mainly due to inappropriate patient selection and to technical issues that have been progressively identified. In the treatment of functional mitral regurgitation, annuloplasty alone should only be carried out in the early phase of the disease before the occurrence of advanced left ventricular remodeling and echocardiographic predictors of unfavorable outcome should be taken into account. Under certain circumstances, surgery should include additional procedures apart from annuloplasty to enhance the durability of the repair. Mitral valve replacement should be considered when unsatisfactory results are expected with mitral valve repair due to advanced left ventricular remodeling and long-lasting heart failure.


Increased circulating endothelial progenitor cells in patients with bacterial pneumonia: evidence that bone marrow derived cells contribute to lung repair.
Tissue repair often occurs in organs damaged by various inflammatory diseases including pneumonia. Inflammatory stimuli induce a rapid and massive release of inflammatory cells from the bone marrow. Recent studies have suggested that bone marrow cells have the potential to differentiate into a variety of cell types. It has been shown that administration of lipopolysaccharide (LPS) to murine lungs induces a rapid release of endothelial progenitor cells (EPCs) into the circulation, and that bone marrow derived progenitor cells including EPCs contribute to lung repair after lung injury in mice. This study was undertaken to investigate the mobilisation of EPCs in humans following acute pneumonia. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood taken from 23 patients with pneumonia during both the acute and convalescent phase. 1x10(6) PBMCs were plated on fibronectin coated culture slides and cultured in culture medium for endothelium. The numbers of EPCs were counted 8 days after plating. The number of circulating EPCs significantly increased in patients with pneumonia (p<0.0001). Patients with low EPC counts tended to have persistent fibrotic changes in their lungs even after their recovery from pneumonia. Inflammatory stimuli induce a rapid release of EPCs into the circulation in humans. A sufficient number of EPCs is necessary for proper lung repair following bacterial pneumonia.


Tau splicing and the intricacies of dementia.
Tau is a microtubule-associated protein that fulfills several functions critical for neuronal formation and health. Tau discharges its functions by producing multiple isoforms via regulated alternative splicing. These isoforms modulate tau function in normal brain by altering the domains of the protein, thereby influencing its localization, conformation, and post-translational modifications and hence its availability and affinity for microtubules and other ligands. Disturbances in tau expression result in disruption of the neuronal cytoskeleton and formation of tau structures (neurofibrillary tangles) found in brains of dementia sufferers. More specifically, aberrations in tau splicing regulation directly cause several neurodegenerative diseases, which lead to dementia. In this review, I present our cumulative knowledge of tau splicing regulation in connection with neurodegeneration and also briefly go over the still-extensive list of questions that are connected to tau (dys)function.


Anticoagulant Preferences and Concerns among Venous Thromboembolism Patients.
Warfarin and direct oral anticoagulants (DOACs) are used for the initial treatment and secondary prevention of venous thromboembolism (VTE), and have similar efficacy. Patient concerns and preferences are important considerations when selecting an anticoagulant, yet these are not well studied. VTE patients (n = 519) were surveyed from online sources (clotconnect.org, stoptheclot.org and National Blood Clot Alliance Facebook followers [n = 495]) and a haematology clinic in Vermont (n = 24). Patients were 83% females and on average (±standard deviation [SD]) 45.7 ± 13.1 years; 65% self-reported warfarin as their initial VTE treatment and 35% a DOAC. Proportions reporting being extremely concerned about the following outcomes were as follows: recurrent VTE 33%, major bleeding 21%, moderate bleeding 16% and all-cause death 29%. When asked about oral anticoagulant characteristics, patients strongly preferred anticoagulants that are reversible (53%), and for which blood drug levels can be monitored (30%). Lower proportions agreed with statements that regular blood testing is inconvenient (18%), that they are comfortable using the newest drug versus an established drug (15%) and that it is difficult to change their diet to accommodate their anticoagulant (17%). In multivariable-adjusted models, patients tended to have had as their initial treatment, and to currently be taking, the oral anticoagulant option they personally preferred. Patients held the greatest concern for recurrent VTE and mortality, regardless of which treatment they were prescribed. Potential weaknesses of warfarin (e.g., dietary restrictions, regular monitoring) were generally not considered onerous, while warfarin's advantages (e.g., ability to monitor) were viewed favourably.


Psychometric properties and norm scores of the sleep self report in Dutch children.
Psychometrically robust questionnaires to assess self-reported sleep problems in children are important since sleep problems can have a major impact on child development. The Sleep Self Report (SSR) is a 26-item self-report tool measuring different sleep domains in children aged 7-12 years. This study aims to evaluate the psychometric properties of the SSR and to provide Dutch norm scores. Children aged 7-12 years from the general population were recruited through a professional market research agency. In this population, structural validity was assessed with confirmatory and exploratory factor analyses, internal consistency was assessed with the Cronbach's alpha coefficient and norm scores were provided. Additionally, children attending outpatient sleep clinics (clinical population) were invited to participate. SSR scores of the general population and the clinical population were compared to establish discriminative validity. In total, 619 children (mean age: 9.94 ± 1.72 years) from the general population and 34 children (mean age: 9.21 ± 1.63 years) from sleep clinics participated. The 1-factor structure of the SSR was not confirmed with factor analysis. Exploratory analyses did also not yield an appropriate multidimensional structure. Internal consistency of the total score was adequate (Cronbach's alpha: 0.76). The total score distinguished the clinical population from the general population (39.07 ± 5.31 versus 31.61 ± 5.31; P < 0.01). An appropriate structure of the SSR was not found with factor analyses in this Dutch population. The adequate internal consistency indicates that the total score can be interpreted as a measure of overall sleep problems. The SSR also shows good discriminative validity. We recommend the total score to assess overall sleep problems and item scores to evaluate specific sleep issues and to follow up children's sleep longitudinally, as opposite changes in different item scores may not reflect in the total score. Further research on the development of multidimensional psychometrically sound pediatric sleep self-reports is of major importance.


Predictive model for delayed graft function based on easily available pre-renal transplant variables.
Identification of pre-transplant factors influencing delayed graft function (DGF) could have an important clinical impact. This could allow clinicians to early identify dialyzed chronic kidney disease (CKD) patients eligible for special transplant programs, preventive therapeutic strategies and specific post-transplant immunosuppressive treatments. To achieve these objectives, we retrospectively analyzed main demographic and clinical features, follow-up events and outcomes registered in a large dedicated dataset including 2,755 patients compiled collaboratively by four Italian renal/transplant units. The years of transplant ranged from 1984 to 2012. Statistical analysis clearly demonstrated that some recipients' characteristics at the time of transplantation (age and body weight) and dialysis-related variables (modality and duration) were significantly associated with DGF development (p ≤ 0.001). The area under the receiver-operating characteristic (ROC) curve of the final model based on the four identified variables predicting DGF was 0.63 (95 % CI 0.61, 0.65). Additionally, deciles of the score were significantly associated with the incidence of DGF (p value for trend <0.001). Therefore, in conclusion, in our study we identified a pre-operative predictive model for DGF, based on inexpensive and easily available variables, potentially useful in routine clinical practice in most of the Italian and European dialysis units.


Factors Associated with the Prevalence of Thyroid Nodules and Goiter in Middle-Aged Euthyroid Subjects.
The aim of the present study was to determine associations of thyroid hormone levels and different metabolic parameters and anthropometric measurements with volume of nodular and nonnodular thyroid as well as with prevalence of goiter and thyroid nodules in middle-aged euthyroid subjects. Methods. The study consisted of 317 euthyroid subjects aged 48-49 from the Kaunas Cardiovascular Risk Cohort study. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), and antithyroid peroxidase antibody (ATPO) levels, as well as anthropometric and metabolic parameters and smoking information, were evaluated. Results. In subjects with and without thyroid nodules, thyroid volume correlated with components of metabolic syndrome, body mass index (BMI), smoking, and TSH levels. In the nonnodular thyroid group, thyroid volume was also positively related to serum insulin and HOMA-IR, whereas a negative correlation between thyroid volume and leptin was identified in the nodular thyroid group. The goiter was identified in 12.3% of subjects. Female gender, thyroid nodules, smoking, BMI, and levels of TSH were independent predictors for goiter. Thyroid nodules were found in 31.2% of participants. Female gender, higher TSH levels, and thyroid volume were independent risk factors for thyroid nodules. Conclusions. Female gender, thyroid nodules, smoking, BMI, and TSH levels were identified as potential predictors of goiter. Female gender, TSH levels, and thyroid volume predicted the presence of thyroid nodules.


Mesenteric panniculitis: an unusual cause of dyspepsia in a hemodialysis patient.
Many patients with chronic renal failure have dyspeptic symptoms. However, mesenteric panniculitis as a cause of dyspepsia has not been described in this patient group. We report a 78-year-old hemodialysis patient who was admitted because of intractable dyspepsia. Investigations with ultrasonography, endoscopy and barium studies were all inconclusive. Computed tomography of the abdomen demonstrated a large encapsuled soft-tissue mass in the root of mesentery. Percutaneous biopsy confirmed the diagnosis of mesenteric panniculitis. Percutaneous drainage was performed when liquefaction of the mesenteric mass lesion was noted on follow-up computed tomography 1 month later. Improvement of gastrointestinal symptoms occurred soon after drainage of the fluid component of the mesenteric mass. Microbiologic and cytologic studies of the drainage specimens were negative. Follow-up computed tomography 3 months later showed reduction in the size of the mesenteric mass.


Stereotype Embodiment: A Psychosocial Approach to Aging.
Researchers have increasingly turned their attention from younger individuals who hold age stereotypes to older individuals who are targeted by these stereotypes. The refocused research has shown that positive and negative age stereotypes held by older individuals can have beneficial and detrimental effects, respectively, on a variety of cognitive and physical outcomes. Drawing on these experimental and longitudinal studies, a theory of stereotype embodiment is presented here. It proposes that stereotypes are embodied when their assimilation from the surrounding culture leads to self-definitions that, in turn, influence functioning and health. The theory has four components: The stereotypes (a) become internalized across the life span, (b) can operate unconsciously, (c) gain salience from self-relevance, and (d) utilize multiple pathways. The central message of the theory, and the research supporting it, is that the aging process is, in part, a social construct.


Evaluation and treatment of the infected foot in a community teaching hospital.
More inpatient hospital days are used for the care of diabetic foot infection than for any other diabetic sequela. Both the number of lower extremity amputations and the overall treatment cost of treating diabetic infections may be reduced by using a team approach in the care of the infected diabetic pedal wound. The authors propose an evaluation and treatment protocol of infected pedal ulcerations in an urban, community teaching institution when admitted to an established, multidisciplinary diabetic foot care team. The hospital course of 111 patients admitted with a primary diagnosis of infected pedal ulceration are retrospectively reviewed. Results revealed an average-length hospital stay of 7.4 days with a 96% limb-salvage rate. The authors suggest that in the treatment of the infected pedal wound, a diabetic foot care team with a well developed treatment protocol may yield a consistently favorable outcome and a cost-effective hospital course.


Rapid review of suspected adverse drug events due to remdesivir in the WHO database; findings and implications.
Objectives: Remdesivir has shown promise in the management of patients with COVID-19 although recent studies have shown concerns with its effectiveness in practice. Despite this there is a need to document potential adverse drug events (ADEs) to guide future decisions as limited ADE data available before the COVID-19 pandemic. Methods: Interrogation of WHO VigiBase® from 2015 to 2020 coupled with published studies of ADEs in COVID-19 patients. The main outcome measures are the extent of ADEs broken down by factors including age, seriousness, region and organ. Results: A total 1086 ADEs were reported from the 439 individual case reports up to July 19, 2020, in the VigiBase®, reduced to 1004 once duplicates were excluded. Almost all ADEs concerned COVID-19 patients (92.5%), with an appreciable number from the Americas (67.7%). The majority of ADEs were from males > 45 years and were serious (82.5%). An increase in hepatic enzymes (32.1%), renal injury (14.4%), rise in creatinine levels (11.2%), and respiratory failure (6.4%) were the most frequently reported ADEs. Conclusions: Deterioration of liver and kidney function are frequently observed ADEs with remdesivir; consequently, patients should be monitored for these ADEs. The findings are in line with ADEs included in regulatory authority documents.


Subarachnoid Hemorrhage Induces Gliosis and Increased Expression of the Pro-inflammatory Cytokine High Mobility Group Box 1 Protein.
Subarachnoid hemorrhage (SAH) following cerebral aneurysm rupture is associated with high rates of morbidity and mortality. Surviving SAH patients often suffer from neurological impairment, yet little is currently known regarding the influence of subarachnoid blood on brain parenchyma. The objective of the present study was to examine the impact of subarachnoid blood on glial cells using a rabbit SAH model. The astrocyte-specific proteins, glial fibrillary acidic protein (GFAP) and S100B, were up-regulated in brainstem from SAH model rabbits, consistent with the development of reactive astrogliosis. In addition to reactive astrogliosis, cytosolic expression of the pro-inflammatory cytokine, high-mobility group box 1 protein (HMGB1) was increased in brain from SAH animals. We found that greater than 90% of cells expressing cytosolic HMGB1 immunostained positively for Iba1, a specific marker for microglia and macrophages. Further, the number of Iba1-positive cells was similar in brain from control and SAH animals, suggesting the majority of these cells were likely resident microglial cells rather than infiltrating macrophages. These observations demonstrate SAH impacts brain parenchyma by activating astrocytes and microglia, triggering up-regulation of the pro-inflammatory cytokine HMGB1.


Understanding trophic interactions of Orius spp. (Hemiptera: Anthocoridae) in lettuce crops by molecular methods.
The aphid Nasonovia ribisnigri (Mosley) (Hemiptera: Aphididae) and the thrips Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae) are common pests in Mediterranean lettuce crops, where Orius spp. are common generalist predators. Predation by Orius spp. was studied in a lettuce plot by conventional polymerase chain reaction (PCR) and real-time PCR analyses using specific primers of both main pests. Also, high-throughput sequencing was used to have a wider approach of the diet of these predators in natural field conditions. Molecular analyses indicated a higher predation on N. ribisnigri in spring and on F. occidentalis in summer. Predation on alternative prey, like Collembola, was also found in both seasons. Real-time PCR was more sensitive than conventional PCR in showing the target trophic links, whereas high-throughput sequencing revealed predation on other natural enemies - intraguild predation (IGP), showing other trophic interactions of Orius majusculus within the studied ecosystem. This study gives important information about the trophic relationships present in Mediterranean lettuce crops in different periods of the year. The detected predation by Orius spp. on alternative prey, as well as on other natural enemies, should be further investigated to clarify whether it adds or detracts to the biological control of N. ribisnigri and F. occidentalis.


Frequency dependence of specific airway resistance in a commercialized plethysmograph.
Specific airway resistance (sRaw) measured by body plethysmography has been shown to decrease markedly with decreasing breathing frequency when the inspired air is not conditioned to body temperature, atmospheric pressure and saturation with water vapour (BTPS). The phenomenon has been attributed to noninstantaneous gas warming and wetting in the airways. The aim of this investigation was to assess whether the phenomenon was also present in a commercialized plethysmograph featuring an "electronic BTPS correction". Airway resistance (Raw) and sRaw were measured in 15 healthy subjects at six breathing frequencies ranging 0.25-3 Hz, using a constant volume plethysmograph in which a correction for non-BTPS gas conditions was applied by electronically flattening the box pressure-airway flow loop (Jaeger Masterscreen Body, version 4.0). The temperature and water vapour saturations in the box averaged 26.5 +/- 1.3 degrees C and 59 +/- 6%, respectively. Raw and sRaw exhibited a clear positive frequency dependence in all but one subject. From 0.25 to 3 Hz Raw increased from (mean+/-SD) 0.62 +/- 0.55 to 1.71 +/- 0.76 hPa x s x L-1 (p<0.001), and sRaw from 2.34 +/- 1.90 to 7.55 +/- 3.08 hPa x s (p<0.001). The data are consistent with a simple model, in which gas conditioning in the airways and external dead space occurred with a time constant of 0.39 s. We conclude that the electronic BTPS correction of the instrument was inadequate, probably because it is assumed that gas conditioning in the airways is instantaneous. We recommend that, with similar instruments, airway resistance be measured using as high a panting frequency as feasible.


A comprehensive analysis of PAX8 expression in human epithelial tumors.
PAX8 is a paired-box gene important in embryogenesis of the thyroid, Müllerian, and renal/upper urinary tracts, and expression of PAX8 has been previously described in carcinomas from each of these sites. However, a large study including a wide variety of epithelial neoplasms from multiple organ sites other than the thyroid, kidney, or Müllerian system has not been performed. The goal of this study was to evaluate the utility of PAX8 immunostaining based on the evaluation of a wide range of epithelial tumors. PAX8 immunohistochemistry was performed on 1357 tumors (486 tumors in whole-tissue sections and 871 tumors in tissue microarrays, predominantly epithelial) from multiple organs. Only nuclear staining was scored as positive, and tumors were evaluated for the extent and intensity of staining. Western blot analysis with PAX8 was also performed on multiple tumor cell lines. Nuclear PAX8 staining was present in 91% (60 of 66) of thyroid tumors, 90% (158 of 176) of renal cell carcinomas (RCCs), 81% (13 of 16) of renal oncocytomas, 99% (164 of 165) of high-grade ovarian serous carcinomas, 71% (32 of 49) of nonserous ovarian epithelial neoplasms, 91% (10 of 11) of cervical epithelial lesions, and 98% (152 of 155) of endometrial adenocarcinomas. Of the remaining 719 evaluated tumors, only 30 cases (4%), including 12 thymic neoplasms, 3 bladder urothelial carcinomas, 4 lung squamous cell carcinomas, 2 esophageal adenocarcinomas, 1 pancreatic adenocarcinoma, 2 cholangiocarcinomas, 1 ovarian Sertoli-Leydig cell tumor, 1 ovarian sex cord stromal tumor, 3 testicular mixed germ cell tumors, and 1 acinic cell carcinoma, showed at least weak or focal PAX8 positivity. The unexpected finding was diffuse, moderate staining of PAX8 in a subset of thymomas and thymic carcinomas. The 689 remaining tumors, including but not limited to those from the prostate, colon, stomach, liver, adrenal gland, and head and neck, and small cell carcinomas from the lung, cervix, and ovary, were PAX8 negative. PAX8 specificity was confirmed by Western blot analysis, as expression was detected only in ovarian and RCC cell lines. These results show that PAX8 is a highly sensitive marker for thyroid, renal, Müllerian, and thymic tumors. Importantly, all lung adenocarcinomas, breast and adrenal neoplasms, and the majority of gastrointestinal tumors were negative for PAX8. Therefore, PAX8 is an excellent marker for confirming primary tumor site. In a subset of cases, additional markers, including but not limited to thyroid transcription factor-1, RCC, and Wilms tumor-1, may be needed to distinguish between the 3 most common PAX8-positive tumors.


Low-grade non-Hodgkin lymphoma at advanced stage: a case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, retinoids, and melatonin.
Low-grade non-Hodgkin lymphomas (NHLs) at advanced stage are still incurable, and treatment may include chemotherapy with a single drug or a combination of different drugs. With a combination of cyclophosphamide, somatostatin, bromocriptin, retinoids, melatonin, and adrenocorticotropic hormone, we already reported 100% of global response (50% complete response and 50% partial response) in 12 patients with low-grade NHL at advanced stage: 4 previously untreated patients and 8 with relapse of disease after single or combined chemotherapy and therapy free time >or=6 months. This provided the rationale to treat a patient affected by low-grade NHL stage 4, with cyclophosphamide, somatostatin, bromocriptin, retinoids, and melatonin (adrenocorticotropic hormone was not administered for high blood pressure). The patient was treated for at least 2 months. After this period, if he had stable or responding disease, he received an additional 3 months of treatment, and if he was stable or responding after 5 months he was treated for 3 months and more. After 2 months the patient had a partial response, and after 5 months he achieved a complete response. Today, 18 months after the beginning of treatment, the patient is in complete remission. Treatment had very good tolerance, and the patient carried on at home doing his normal activities.


Physician Burnout: Are We Treating the Symptoms Instead of the Disease?
Despite increasing recognition of physician burnout, its incidence has only increased in recent years, with nearly half of physicians suffering from symptoms of burnout in the most recent surveys. Unfortunately, most burnout research has focused on its profound prevalence rather than seeking to identify the root cause of the burnout epidemic. Health care organizations throughout the United States are implementing committees and support groups in an attempt to reduce burnout among their physicians, but these efforts are typically focused on increasing resilience and wellness among participants rather than combating problematic changes in how medicine is practiced by physicians in the current era. This report provides a brief review of the current literature on the syndrome of burnout, a summary of several institutional approaches to combating burnout, and a call for a shift in the focus of these efforts toward one proposed root cause of burnout.


Stereochemical analysis of 3,4-methylenedioxymethamphetamine and its main metabolites in human samples including the catechol-type metabolite (3,4-dihydroxymethamphetamine).
3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a designer drug commonly misused in large segments of young populations. MDMA is usually formulated in tablets of its racemate (1:1 mixture of its enantiomers) in doses ranging from 50 to 200 mg. MDMA has an enantioselective metabolism, the (S)-enantiomer being metabolized faster than the (R)-enantiomer. Different pharmacologic properties have been attributed to each enantiomer. The carbon responsible for MDMA chirality is preserved along its metabolic disposition. An analytical method has been developed to determine MDMA enantiomers and those from its major metabolites, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymeth-amphetamine (HHMA), and 4-hydroxy-3-methoxymethamphet-amine (HMMA). It has been applied to the analysis of plasma and urine samples from healthy recreational users of MDMA who participated voluntarily in a clinical trial and received 100 mg (R,S)-MDMA. HCl orally. (R)/(S) ratios both in plasma (0-48 h) and urine (0-72 h) for MDMA and MDA were >1 and <1, respectively. Ratios corresponding to HHMA and HMMA, close to unity, deviate from theoretical expectations and are most likely explained by the ability of MDMA to autoinhibit its own metabolism. The short elimination half-life of (S)-MDMA (4.8 h) is consistent with the subjective effects and psychomotor performance reported in subjects exposed to MDMA, whereas the much longer half-life of the (R)-enantiomer (14.8 h) correlates with mood and cognitive effects experienced on the next days after MDMA use.


Improving student-perceived benefit of academic advising within education of occupational and physical therapy in the United States: a quality improvement initiative.
Academic advising is a key role for faculty in the educational process of health professionals; however, the best practice of effective academic advising for occupational and physical therapy students has not been identified in the current literature. The purpose of this quality improvement initiative was to assess and improve the faculty/student advisor/advisee process within occupational and physical therapy programs within a school of allied health professions in the United States in 2015. A quality improvement initiative utilizing quantitative and qualitative information was gathered via survey focused on the assessment and improvement of an advisor/advisee process. The overall initiative utilized an adaptive iterative design incorporating the plan-do-study-act model which included a three-step process over a one year time frame utilizing 2 cohorts, the first with 80 students and the second with 88 students. Baseline data were gathered prior to initiating the new process. A pilot was conducted and assessed during the first semester of the occupational and physical therapy programs. Final information was gathered after one full academic year with final comparisons made to baseline. Defining an effective advisory program with an established framework led to improved awareness and participation by students and faculty. Early initiation of the process combined with increased frequency of interaction led to improved student satisfaction. Based on student perceptions, programmatic policies were initiated to promote advisory meetings early and often to establish a positive relationship. The policies focus on academic advising as one of proactivity in which the advisor serves as a portal which the student may access leading to a more successful academic experience.


[Structural and bioindicative aspects of fluctuated asymmetry of bilateral organisms].
We have proposed and validated a method for quantitative assessment of phenotypic diversity of natural populations. Method is based on the fluctuated asymmetry (FA) indices of bilateral organisms, and it is applicable for biondicative investigations. Convolution of functions was proposed to estimate the mean (population) value of FA complex of features. This function could be written as finit sum [formula: see text] where eta is power of sample invariance (symmetry) for m individuals (i = 1, m). Eta is characterized by n asymmetric characteristics (j = 1, n) for the left (L) and the right (R) sides of the body. We have validated applicability of generalized function of desirability [formula: see text] (where di is partial desirability function [0,1]) for cumulative characterization of environment quality with results of bioindicative investigations. The value of function coincides with the value of symmetry of indicating species in this case.


Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by human cytochrome P4501A1, P4501A2 and P4501B1.
While the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by N-hydroxylation has been well documented, the relative roles of the human cytochrome P450 (CYP) enzymes that catalyze this reaction have not been established. Previous studies indicated that the mutagenic activation product, 2-hydroxyamino-PhIP (N2-OH-PhIP), is produced primarily by CYP1A2, and to a lesser extent by CYP1A1. We recently reported that human CYP1B1 also produces N2-OH-PhIP (Carcinogenesis, 18, 1793-1798, 1997). In the present study, we examined PhIP metabolism by microsomes containing recombinant human CYP1A1, 1A2 or 1B1 expressed in Sf9 insect cells and compared the kinetic values for PhIP metabolite formation. PhIP metabolites were analyzed by high pressure liquid chromatography with fluorescence and absorbance detection. Vmax values for N2-OH-PhIP formation were 90, 16 and 0.2 nmol/min/nmol P450, and the apparent Km values were 79, 5.1 and 4.5 microM for human CYP1A2, 1A1 and 1B1, respectively. The non-mutagenic metabolite, 4'-hydroxy-PhIP, was also formed by all three CYP enzymes with Vmax values of 1.5, 7.8 and 0.3 nmol/ min/nmol P450 and apparent Km values of 43, 8.2 and 2.2 microM for human CYP1A2, 1A1 and 1B1, respectively. Although the Vmax for N2-OH-PhIP production was highest for CYP1A2, the catalytic efficiency (Vmax/Km) of CYP1A1 was greater than that of CYP1A2. These results suggest that, for humans, extrahepatic CYP1A1 may be more important than previously thought for the metabolic activation of the dietary carcinogen PhIP.


Diagnosis and management of cystic pancreatic tumours with mucin production.
To aid selection of the most appropriate treatment for intraductal tumours (IDTs) and mucinous cystic tumours (MCTs) of the pancreas, this study describes the clinical and diagnostic features of these tumours and compares the clinicodiagnostic features of malignant and benign tumours and hyperplasia. The clinical features of 28 IDTs (four cases of hyperplasia, six adenomas and 18 adenocarcinomas) and six MCTs (four adenomas and two adenocarcinomas) were studied. An IDT was found in 24 men and four women with a mean age of 64.5 years, whereas all patients with an MCT were women, with a mean age of 50.8 years. Twenty IDTs were located in the pancreatic head, whereas all MCTs were in the pancreatic body-tail. The mean size of IDTs was smaller than that of MCTs (4.4 versus 7.7 cm). The mean size of hyperplastic lesions, adenomas and adenocarcinomas in IDTs were 1.7, 2.9 and 5.4 cm respectively. Hyperplastic IDT lesions were smaller than 2 cm without either mural nodules or dilatation of the main pancreatic duct. IDTs larger than 3 cm with mural nodules and mucin secretion from an enlarged papilla orifice and dilatation of the main pancreatic duct were often adenocarcinomas. Although follow-up of intraductal hyperplasia is a reasonable approach, other types of IDT and MCT require surgical treatment.


A Josephson junction-coupled neuron with double capacitive membranes.
The channel currents have distinct magnetic field effect and any changes of the electromagnetic field or electirc stimulus will change the membrane potential effectively. A feasible neuron model considers the distinct physical characteristic is more suitable to mimic the neural activities accompanying with shift in energy level. A Josephson junction (JJ) is connected to a neural circuit for estimating the effect of external magnetic field and two capacitors are connected via a linear resistor for mimicing the capacitive field beside two sides of the cell membrane. Its equivalent Hamilton energy is calculated to show the relation between firing mode and energy level. Noisy disturbance is imposed to predict the occurrence of coherence resonance, and the biophysical neuron is excited to present higher energy level. This new neuron model can address the field effect and the biophysical property of cell membrane considered as combination of capacitive fields in double capacitors. It can mimic the physical property of outer and inner membranes, and energy exchange across the double membranes explains the energy mechanism in neural activities. Time-varying energy diveristy between capacitive field is crucial for supporting continuous firing activities. The JJ channel discerns slight changes in external magnetic field and regularity is stabilized under coherence resonance in presence of noisy excitation on the membrane or ion channels.


Effect of genotype and environment on five bioactive components of cultivated licorice (Glycyrrhiza uralensis) populations in northern China.
Methods to improve the bioactive component content of cultivated licorice have become the bottleneck of industrial licorice extraction for pharmaceutical use. To evaluate the effects of genotype, environment and their interaction on major bioactive components, we analyzed the five bioactive components: liquiritin (LQ), liquiritigenin (LQG), glycyrrhizin (GL), isoliquiritin (ILQ) and isoliquiritigenin (ILQG) of four diverse licorice varieties grown in four distinct environments in northern China during 2010-11. Analysis of variance showed that environmental and genotypic effects were significant (p<0.01) for all five bioactive components. Additionally, their interaction was significant (p<0.05) for GL in the 2-year study period. LQ and ILQ were mainly affected by genetic factors and have great potential for genetic improvement, whereas LQG and ILQG were mainly affected by environmental factors. GL was similarly affected by environmental and genetic factors. Biplot of the principal component analysis showed that for quality breeding, G2 (WNT-1) and G3 (JX-1) are two relatively preferable genotypes, and E2 (Chifeng) location is suitable for accumulation of the bioactive components of these two genotypes. Stepwise regression analysis showed that sunshine and rainfall are the dominant environmental factors for licorice bioactive component accumulation; increased duration of sunshine is advantageous to GL accumulation whereas declining rainfall is conducive to LQG and ILQG accumulation. These results provide a theoretical basis for initiating licorice breeding programs with increased bioactive components and improved quality.


[Health security--GMOs in therapeutics].
The recent progress in human therapeutics has been made possible thanks to molecular biology and its use in producing proteins having the same sequence and structure as that of human proteins. The use of GMOs allows production of proteins with high added value in therapeutics, which are of satisfactory quality. GMOs may also be directly administered to patients as gene therapy vectors. However, the use of GMOs in therapeutics must take into consideration some risks, particularly those of microbiological contamination, of neo-antigenicity as well as environmental risks with regard to the way of use of the GMO. Nevertheless, those risks are taken in due consideration in the development of these new medicinal products; solutions have been found to allow their use in therapeutics with a very positive benefit/risk ratio. Medicinal products from biotechnology have enabled considerable therapeutic progress without compromising health security.


Cost-effectiveness analysis of primary treatments for localised prostate cancer: A population-based Markov analysis using real-world evidence.
We evaluate cost-effectiveness of primary treatments for localised prostate cancer by uniquely combining prospectively collected real-world outcomes and costs from UCSF Cancer of Prostate Strategic Urologic Research Endeavor (CaPSURE™). Markov models assessed cost-effectiveness of radical prostatectomy (RP), brachytherapy, electron beam radiation therapy (EBRT) and brachytherapy with EBRT by risk from US payers perspective over 8 years. Treatment costs included office visits, hospitalisation, procedures, medication and long-term care. Patients' surveyed HRQoL were mapped into utilities. Incremental cost-effectiveness ratios (ICERs) used cost per quality-adjusted life years (QALYs) and willingness-to-pay of $150,000/QALY. Cost-effectiveness analysis (CEA) showed for low-risk prostate cancer, EBRT dominated the lowest cost brachytherapy, but RPns and brachytherapy plus EBRT were cost-effective compared to brachytherapy with ICERs of $18,926 and $41,662 per QALY. In medium-risk patients, RP, EBRT and brachytherapy plus EBRT all were cost-effective compared with brachytherapy, with ICERs of $30,604, $22,588 and $21,627/QALY. In high-risk, brachytherapy dominated all treatments. Procedure cost and utility are driving ICER, but probabilistic sensitivity analysis showed the model was robust across variables. This first CEA combining prospective real-world evidence for HRQOL outcomes with costs shows cost-effectiveness of treatments vary by risk groups, providing new evidence for treatment decisions.


No evidence of genetic mediation in the association between birthweight and academic performance in 2,413 Danish adolescent twin pairs.
Evidence of a positive association between birthweight and IQ has been established in several studies. Analyses of within twin pair differences in birthweight and IQ have been used to shed light on the basis of the association. The strength of this approach is the possibility of controlling for both unmeasured common childhood-environmental factors as well as genetic factors shared by the co-twins. Two twin studies suggest the existence of genetic mediation between birthweight and IQ, that is, common genetic factors influence both fetal growth and IQ in childhood, while two other twin studies find no evidence of such mediation. In the present study we use a large population-based national register study of 2,413 Danish twin-pairs from birth cohorts 1986-1990, of which we have zygosity information on 74%. We perform individual level as well as intra-pair analyses of birthweight and school achievements at age 16. For both sexes we observed a monotonic increase in academic performance with increasing percentiles of birthweight. However, we did not find that this association is due to genetic mediation.


Technological Prospection on Nanotechnologies Applied to the Petroleum Industry.
This paper presents a technological prospection on nanotechnologies applied to the petroleum industry through the creation of a worldwide overview regarding scientific paper publications and patents concerning that business, with the purpose of identifying the main trends on research and development (R&D), the annual evolution, as well as the key agents and countries involved. In this research, it was possible to verify the presence of services oil companies, like Baker, Schlumberger and Halliburton. In scientific paper publications, it was possible to observe university departments, related to petroleum studies, from different countries, as Thailand, China, USA, Iran.


Betulinic acid protects mice from cadmium chloride-induced toxicity by inhibiting cadmium-induced apoptosis in kidney and liver.
Cadmium exposure is closely associated with a variety of diseases including cancers and the accumulation of cadmium has been long recognized as a public health problem. It is therefore of high importance to find methods to reduce cadmium accumulation in the human body. Herein, we report that administration of betulinic acid (BA) protects mice from cadmium chloride (CdCl2)-induced toxicity by inhibiting cadmium-induced apoptosis in both kidney and liver. Mice were given oral doses of 3 mg/kg, 10 mg/kg and 30 mg/kg of BA daily for ten consecutive days, and were injected with one dose of 1 mg/kg CdCl2 after one hour of BA administration every day. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and blood urea nitrogen (BUN) were assessed by ELISA. Residual cadmium was determined by atomic absorption analysis. Protein expression was evaluated by western blotting. Pretreatment with BA significantly reduced residual cadmium levels in the liver, kidney and testis, increased the cadmium output in urine, and reduced tissue damage induced by CdCl2. Moreover, BA prevented body weight loss by CdCl2 in a dose dependent manner. Furthermore, BA treatment increased the expression levels of B-cell lymphoma 2 (Bcl-2), decreased Bcl-2-associated X (Bax), and inhibited the levels of active caspase-3. Importantly, BA within a dose of 30 mg/kg did not induce any signs of toxicity, and protected mice from the toxicity induced by CdCl2 in a dose-dependent manner. Our findings suggest that BA inhibits CdCl2 induced apoptosis in the kidney and liver, and BA may be an effective agent for the prevention and treatment of cadmium-induced diseases in humans.


Atmospheric Constraints on the Surface UV Environment of Mars at 3.9 Ga Relevant to Prebiotic Chemistry.
Recent findings suggest that Mars may have been a clement environment for the emergence of life and may even have compared favorably to Earth in this regard. These findings have revived interest in the hypothesis that prebiotically important molecules or even nascent life may have formed on Mars and been transferred to Earth. UV light plays a key role in prebiotic chemistry. Characterizing the early martian surface UV environment is key to understanding how Mars compares to Earth as a venue for prebiotic chemistry. Here, we present two-stream, multilayer calculations of the UV surface radiance on Mars at 3.9 Ga to constrain the surface UV environment as a function of atmospheric state. We explore a wide range of atmospheric pressures, temperatures, and compositions that correspond to the diversity of martian atmospheric states consistent with available constraints. We include the effects of clouds and dust. We calculate dose rates to quantify the effect of different atmospheric states on UV-sensitive prebiotic chemistry. We find that, for normative clear-sky CO2-H2O atmospheres, the UV environment on young Mars is comparable to young Earth. This similarity is robust to moderate cloud cover; thick clouds (τcloud ≥ 100) are required to significantly affect the martian UV environment, because cloud absorption is degenerate with atmospheric CO2. On the other hand, absorption from SO2, H2S, and dust is nondegenerate with CO2, meaning that, if these constituents build up to significant levels, surface UV fluence can be suppressed. These absorbers have spectrally variable absorption, meaning that their presence affects prebiotic pathways in different ways. In particular, high SO2 environments may admit UV fluence that favors pathways conducive to abiogenesis over pathways unfavorable to it. However, better measurements of the spectral quantum yields of these pathways are required to evaluate this hypothesis definitively. Key Words: Radiative transfer-Origin of life-Mars-UV radiation-Prebiotic chemistry. Astrobiology 17, 687-708.


MRI after removal of central venous access device reveals a high number of asymptomatic thromboses in children with haemophilia.
Central venous access devices (CVADs) are often required in children with haemophilia to secure venous access for prophylactic treatment or immune tolerance therapy. Complications of CVADs include infections, thrombosis and mechanical problems. This study sought to determine the outcome of the vessels by magnetic resonance imaging (MRI) in children with haemophilia and to assess risk factors for development of catheter-related deep venous thrombosis (DVT). After the removal of CVAD an MRI of the chest and neck was performed to 20 boys with haemophilia who each had 1-3 (total number 27) CVADs placed. MRI revealed DVT in five children (25%). As their CVADs were functional at the time of the removal, the DVTs were clinically silent. However, there had been suspicion of DVT leading to replacement of the CVAD in one case. All the children with DVT had their CVADs inserted initially below the age of 1 year. The clinical signs of mild post-thrombotic syndrome (PTS) were common: dilated chest wall veins were observed in 11 (55%) children and were associated with DVT in three cases. Arm circumference discrepancy was observed in one child with DVT. No correlation between the duration or number of CVADs and DVT was detected. None of the patients had subjective symptoms of PTS. Silent DVT is a common complication of CVAD. Catheter insertion at a young age seems to predispose to thrombosis. The long-term consequences of the DVTs remain unknown.


Laser beamsteering using the photorefractive effect.
A new configuration for laser beamsteering based on the photorefractive effect is presented. This method has the potential to produce several thousand beam positions, with a random access time of <1 msec. The method has a theoretical efficiency approaching 100%. The principles of device operation are presented, including a writing beam geometry which will allow the efficiency to be maintained over a wide field of view. A scheme for generating the required writing beams and results of a proof-of-concept experiment are presented.


Pharmacokinetics of gentamicin in newborn to 30-day-old foals.
Gentamicin sulfate, equivalent to 4 mg of gentamicin base/kg of body weight, was administered IV to 6 Thoroughbred foals on day 1 (12 to 24 hours of age) and at 5, 10, 15, and 30 days after birth. On day 40 after parturition, gentamicin was given to the mares at a dosage similar to that used in foals. Decay of serum gentamicin concentrations was best described by a 2-compartment model. Among foals, the overall elimination rate constant at 30 days of age was significantly (P less than 0.05) greater than at days 1, 10, and 15. There was, however, no difference in the overall elimination rate constant between foals and mares. The volume of distribution (Vd), determined on the basis of total area under the disposition curve, did not change between day 1 and day 30. Mean values of Vd of foals were between 1.5 and 2.5 times higher than the mean Vd of the mares; however, only values from the foals at days 5 and 10 were significantly greater. Both age and interindividual differences were reflected in the total body clearance (ClB) of gentamicin. Total body clearance of gentamicin of foals on day 1 was less than that of foals on days 5, 10, and 30. Additionally, C1B of gentamicin on day 15 was less than that on day 30. There was no significant difference between ClB of foals and mares except for the day-30 group, which had a higher clearance rate than did the adults. Protein binding of gentamicin was less than 30% in all groups, and there were no apparent age-related differences.


The federal deficit: how does it matter?
Government deficits and debt are surpluses and assets of the private sector of the economy that stimulate private spending. Official measures of deficits are misleading, however, for failing to distinguish public investment from current spending and for failing to adjust for inflation. Correctly measured real deficits have contributed to the growth of gross national product, consumption, and imports, and to investment as well. Optimal policy consistent with balanced growth calls not for elimination of the nominal deficit but rather for prudent deficit reduction accompanied by and stemming at least partly from sufficient monetary stimulus to achieve and sustain relatively full employment.


TMC-95A, B, C, and D, novel proteasome inhibitors produced by Apiospora montagnei Sacc. TC 1093. Taxonomy, production, isolation, and biological activities.
In our course of screening for novel proteasome inhibitors, TMC-95A and its diastereomers, TMC-95B to D, were isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093. TMC-95A inhibited the chymotrypsin-like (ChT-L), trypsin-like (T-L), and peptidylglutamyl-peptide hydrolyzing (PGPH) activities of 20S proteasome with IC50 values of 5.4nM, 200nM, and 60nM, respectively. TMC-95B inhibited these activities to the same extent as TMC-95A, while the inhibitory activities of TMC-95C and D were 20 to 150 times weaker than that of TMC-95A and B. TMC-95A did not inhibit m-calpain, cathepsin L, and trypsin at 30 microM, suggesting its high selectivity for proteasome. Taxonomy of the producing strain is also described.


[The importance of correct policy options for oncologic patient care].
During recent years, a growing number of papers have been published, showing how the treatment of malignant disease can meet, in various centres, with varying degrees of success. Doubtlessly, many more such papers would reach the journals hut for the lack of reliable follow-up data concerning survival, staging, type of treatment, selection criteria, etc. This article summarizes some data of 7 examples derived from observations in continental Europe, the UK, Canada and the US. Their most remarkable feature are the far from negligible differences in outcome (either in survival or in related "administrative" parametres such as treatment waiting time). Most of these studies stress the importance for oncologic patient care, of factors that are not directly related to primary clinical and/or scientific competence, but to policy and management aspects of the problem such as: providing adequate staff and technical infrastructure, creating cooperative networks and, last hut not least, organizing possibilities to collect, as widely as possible, enough data allowing a reliable appraisal of what has, or has not, been achieved.


Heme transport and detoxification in nematodes: subproteomics evidence of differential role of glutathione transferases.
In contrast to their mammalian hosts, parasitic nematodes are heme auxotrophs and require pathways for the uptake and transport of exogenous heme for incorporation into hemoproteins. Phase II detoxification Nu-class glutathione transferase (GST) proteins have a proposed role as heme-binding ligandins in parasitic nematodes. The genome-verified free-living nematode Caenorhabditis elegans also cannot synthesize heme and is an ideal functional genomics model to delineate the role of individual nematode GSTs in heme trafficking and heme detoxification. In this study, C. elegans was exposed to externally controlled heme concentrations ranging from 20-fold suboptimal growth levels to 10-fold supra-optimal growth levels to mimic fluctuations in blood- and tissue-feeding parasitic cousins from the same nematode group. A new heme-responsive GST (GST-19) was identified by subproteomics approaches. Functional characterization of this and two other C. elegans GSTs revealed that they all have high affinity for heme compounds similar to mammalian soluble heme carrier proteins such as HBP23 ( K d approximately 10 (-8) M). In the genomics-predicted absence of orthologous mammalian soluble heme-binding proteins in nematodes, we propose that Nu-class GSTs are candidates in the cellular processing of heme compounds. Toxic heme binding may be coupled to enzymatic protection from its breakdown as several GSTs possess glutathione peroxidase activity.


A novel self-assembled Na{Cu12Zn4} multifunctional material: first report of a discrete coordination compound for detection of Ca2+ ions and selective adsorption of cationic dyes in water.
A novel metal directed discrete self-assembled compound, Na2O[Cu12Zn4(μ-OH)8(H4btp)8](ClO4)8·26H2O (1), was synthesized employing a flexible aminoalcohol ligand, 2,2'-(propane-1,3-diyldiimino)bis-[2-(hydroxylmethyl)propane-1,3-diol] (H6btp), and mixed metal ions (CuII and ZnII) in order to explore it as a multifunctional material. The molecular cluster is characterized by spectral and analytical techniques, single crystal X-ray diffraction and magnetic studies. Crystallography reveals the presence of eight peripheral CuII centers in octahedral environments, while four interior CuII and ZnII centers are present in tetrahedral systems. The ligand is coordinated in the dianionic form (H4btp2-) with copper and zinc metal ions through various bridging modes. Magnetic data suggest the presence of strong antiferromagnetic coupling between the twelve Cu(ii) centers (C = 4.31 cm3 K mol-1 and θ = -120.44 K). Interestingly, the eight ligands present in the system have eight free hydroxyl groups at the periphery of the cluster, which could be employed in molecular recognition for the analytes under investigation. One of the sodium cations of the lattice sodium oxide [Na2O or Na+(Na+O2-)] is encapsulated in the {Cu12Zn4} cavity and held through electrostatic interactions with the oxygen atoms, forming a Na{Cu12Zn4} core. Taking advantage of this entrapped cation, we have used the present assembly in the sensing of various s-block cations. Interestingly, the cluster shows a sensitive and selective sensing ability towards Ca2+ ions through cation exchange. The selectivity towards Ca2+ can be rationalized in terms of the identical size of the sodium and calcium ions and the HSAB principle. Hard sodium is exchanged with the hard Ca2+ ion, which effectively interacts with the hard oxygen donor, giving rise to a stable hard-hard interaction. Moreover the Na{Cu12Zn4} cluster shows excellent selectivity towards the adsorption of cationic dyes, specifically methylene blue (MB), via non-covalent interactions. An abundance of free O-H groups in the cluster gives rise to the existence of O-Hπ interactions with the dye for enhanced adsorption. Thus, the present report is the first example of any heterometallic coordination compound (in contrast to complex systems like polymeric frameworks/nanocomposites) with discriminating sensing of Ca2+ ions with ultra-low detection limit (4 nM) and with high efficiency in the selective adsorption and separation of methylene blue.


A comprehensive model of treatment participation in chronic disease allowed prediction of opioid substitution treatment participation in Zurich, 1992-2012.
Chronic diseases are often associated with cycling in and out of treatment. We used data of a large opioid substitution treatment case register to (1) identify associated factors and (2) integrate retention and readmission into a model of overall participation over subsequent treatment episodes of various groups. Data of all 9,407 patients undergoing 26,545 methadone or buprenorphine substitution treatment episodes between 1992 and 2012 in the canton of Zurich, Switzerland, were analyzed. We used extended survival analysis to estimate the duration of, and time between, treatment episodes, with the number of episodes, gender, nationality, administration route, age at onset of first regular heroin use, and provider type as independent variables. A similar analysis was applied to estimate overall participation (the probability of being in treatment at a given day after first entry independent of current number of treatment episode) and to test for group differences. The time between treatment episodes shortened with the increasing number of episodes. Retention slightly increased after the first episode and then shortened for later treatment episodes. Effect sizes were generally rather weak (odds ratio ≤ 1.47). Effects were usually equal for all episodes, and if changing, weakened for later episodes. The complex process of leaving and entering treatment as well as the daily probability of being in treatment independent of treatment episode can be predicted by comprehensible statistical models applied to patient-period data sets.