Synthesis of confined Ag nanowires within mesoporous silica via double solvent technique and their catalytic properties.
Ag nanowires within the channels of mesoporous silica have been successfully synthesized via a double solvent technique, in which n-hexane is used as a hydrophobic solvent to disperse mesoporous silica and an AgNO(3) aqueous solution is used as a hydrophilic solvent to fill mesochannels. The morphology of the obtained Ag (nanowires, nanoparticles or nanorods) can be controlled by adjusting the concentration of AgNO(3) solution and the template pore size. HRTEM images demonstrate extensive Ag nanowires with several to tens of hundreds nanometers in length are deposited along the long axis of mesochannels when the atomic AgNO(3)/Si ratio is 0.090. When the atomic AgNO(3)/Si ratio is 0.068 or 0.11, there is a combination of Ag nanoparticles and nanowires; nanoparticles are mainly formed when the atomic AgNO(3)/Si ratio is higher than 0.14. Further, the catalytic results of the oxidation of styrene show that styrene oxide and benzaldehyde are the main products of the reaction, and the morphology and diversity of Ag in Ag/mesoporous silica composites have an effect on the conversion of styrene and selectivity of styrene oxide.


Computer systems for the prediction of xenobiotic metabolism.
The aim of pharmaceutical research and development is to ensure a continuing pipeline of new chemical entities (NCEs) displaying high therapeutic efficacy with few or no side effects. Failure of promising lead candidates late in the drug discovery processes is regarded as commercially unacceptable in today's increasingly competitive business environment. An inappropriate ADME/Toxicity profile in humans is the major cause of failure of lead candidates in late clinical stages of drug development. Combinatorial chemistry techniques coupled with high throughput screening protocols means that pharmaceutical companies are now dealing with an unprecedented number of NCEs on an annual basis. As a consequence, screening for undesirable ADME/Toxicity properties in the early stages of drug development, preferably pre-synthesis, is now considered the essential paradigm. In silico assessment of NCEs is rapidly emerging as the next wave of technology for early ADME/Toxicity prediction. In this review, we discuss the major commercially available products for the assessing the potential metabolic activity of xenobiotic substances in mammalian systems.


Coriolus versicolor suppresses inflammatory bowel disease by Inhibiting the expression of STAT1 and STAT6 associated with IFN-γ and IL-4 expression.
To investigate the effects of Coriolus versicolor extract (CVE) on infl ammatory bowel disease (IBD), ulcerative colitis was induced in male BALb/c mice by administering drinking water containing dextran-sulfate sodium (DSS). The mice were divided into the following four experimental groups: control, DSS-induced colitis, CVE treatment and CVE treatment + DSS-induced colitis. Mice receiving DSS treatment developed clinical and macroscopic signs of ulcerative colitis. However, treatment with CVE relieved the symptoms of IBD, including the decrease in body and organ weight. The levels of serum, spleen and mesenteric lymph node IgE in the CVE-treated groups was lower compared with the untreated groups. The antiinfl ammatory response upon CVE treatment correlated with the reduced expression of TNF-α, IL-1β and IL-6. Also, there was a significant reduction in the expression of STAT1 and STAT6 molecules, thereby leading to lower IFN-γ and IL-4 expression. Therefore, the antiinfl ammatory effects of Coriolus versicolor can be explained by its ability to inhibit certain proinflammatory cytokines.


[A training diary as a strategy for reflection about practice during initial and continuous training of Mental Health specialists].
This article presents a Training Diary as a strategy for professional training under the framework of a thoughtful practice. As such, it is a tool that allows access to knowledge through narrative thinking, favoring the organization of experience by integrating cognitive, affective, and practical aspects. This work proposes a necessary dialogue between narrative and logical-scientific thinking, while exposing the theoretical foundations of the Diary as well as some suggestions for its implementation.


Cognitive trajectories following onset of psychosis: a meta-analysis.
Cognitive impairment is a core feature of schizophrenia, associated with poor functional outcomes. The course of cognitive function in the years following illness onset has remained a subject of debate, with a previous analysis finding no worsening, providing support for the neurodevelopmental model of schizophrenia. Since then, many more studies have reported on longitudinal cognitive performance in early psychosis, with some indicating deterioration, which does not align with this view. This study aims to quantitatively review the literature on the longitudinal trajectory of cognitive deficits in the years following psychosis onset, in comparison with healthy controls. It is the first to also synthesise longitudinal data on social cognition. Electronic databases ('PubMed', 'PsycInfo' and 'Scopus') were searched (to end September 2021). Meta-analyses of 25 longitudinal studies of cognition in early psychosis were conducted (1480 patients, 789 health controls). Unlike previous analyses, randomised controlled trials and those with multiple cognitive testing periods within the first year were excluded to minimise bias (PROSPERO, ID: CRD42021241525). Small improvements were observed for global cognition (g = 0.25, 95% CI 0.17-0.33) and individual cognitive domains, but these were comparable with healthy controls and likely an artefact of practice effects. There is no evidence of continued cognitive decline or improvement in the early years following psychosis onset, with a need for more studies over longer follow-up periods. Practice effects highlight the importance of including control samples in longitudinal and intervention studies. Further data are needed to evaluate the course of social cognition subdomains.


Unraveling metabolic alterations in transgenic mouse model of Alzheimer's disease using MALDI MS imaging with 4-aminocinnoline-3-carboxamide matrix.
Revealing the metabolic abnormalities of central and peripheral systems in Alzheimer's disease (AD) mouse model is of paramount importance for understanding AD disease. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is a powerful label-free technique that has been extensively utilized for the interrogation of spatial changes of various metabolites in neurodegenerative disease. However, technical limitations still exist in MALDI MS, and there is a need to improve the performance of traditional MALDI for a deeper investigation of metabolic alterations in the AD mouse model. In this work, 4-aminocinnoline-3-carboxamide (4-AC) was developed into a novel dual-polarity MALDI matrix. Compared with traditionally used MALDI matrices such as 2,5-dihydroxybenzoic acid (DHB) and 9-aminoacridine (9-AA), 4-AC exhibited superior performance in UV absorption at 355 nm, ion yields, background interference, and vacuum stability, making it an ideal MALDI matrix for comprehensive evaluation of metabolic alteration in the brain and serum of APP/PS1 transgenic mouse model of AD. In total, 93 metabolites exhibited different levels of regional changes in the brain of AD mice as compared to the age-matched controls. Moreover, in the serum of AD mice, 81 altered metabolites distinguishing the AD group from the control were observed by using multivariate statistical analysis. It is expected that the application of the MALDI MSI method developed in this work to visualize the spatio-chemical change of various metabolites may improve our understanding of the etiopathogenesis of AD.


Damaging effects of TiO2 nanoparticles on the ovarian cells of Bombyx mori.
As a new type of biologically compatible material, TiO2 NPs are widely used in the industry as additives, drug carriers, and components of skin care products. Due to their wide use, residual TiO2 NPs in the environment are a safety concern that has attracted extensive attention. In this study, the ovarian cell line BmN of the model organism Bombyx mori was used to reveal the damaging effects of TiO2 NPs exposure. The results demonstrated that TiO2 NPs exhibited a dose-dependent effect on the relative cell viability, with significant toxic effects being observed above 20 mg/L. Oxidative damage analysis showed that ROS accumulated significantly in BmN cells after exposure to TiO2 NPs (P ≤ 0.05) and induced DNA damage. Further analysis revealed that the transcriptional levels of key superoxide dismutase genes (SOD) decreased significantly, while the transcriptions of key genes of the MAPK/NF-κB signaling pathway (P38, MEK, ERK and REL) and the downstream inflammatory factor genes (IL6 and TNFSF5) were all significantly up-regulated (P ≤ 0.05). Overall, our results indicate that exposure to TiO2 NPs leads to reduced transcription of antioxidant genes, accumulation of peroxides, and inflammation. These findings provide valuable data for the safety evaluation of environmental residues of TiO2 NPs.


High-throughput analysis of testosterone in serum samples by on-line solid phase extraction liquid chromatography-tandem mass spectrometry.
Liquid chromatography tandem-mass spectrometer (LC-MS/MS) techniques are more and more common in the measurement of testosterone concentrations in biological samples. However, LC-MS/MS methods are more laborious than streamlined automated immunochemistry methods because of the need for tedious pre-purification of the sample before the mass spectrometric analysis. We therefore developed a robust and rapid sample clean-up method to improve the throughput of the whole LC-MS/MS analysis procedure by applying an automated on-line solid-phase extraction (SPE) technique instead of the still widely used conventional liquid-liquid extraction. Testosterone was purified by the on-line SPE-column-switching technique after rapid precipitation of serum samples by zinc sulphate/internal standard solution before LC-MS/MS analysis. The results were compared with those of our previous routine LC-MS/MS method using liquid-liquid extraction with tert-butyl methyl ether for the pre-purification of the samples. The tested on-line SPE-LC-MS/MS method reached the specifications of the previous method with liquid-liquid extraction. The precision of the new method was notably better, especially in the lower concentration range, than with the former method; the total variation was below 10% in the whole quantitation range of 0.25-35 nmol/L. The new method liberates more than 50% of hands-on time of laboratory technicians as well as expensive instrument time for other applications compared with the older method. The on-line SPE-pre-purification technique tested in long-term use offers a rapid and reliable technique in the LC-MS/MS analysis of serum testosterone and is a valuable tool in the improvement of efficiency in the laborious steroid analytics.


Diminishing hERG inhibitory activity of aminopiperidine-naphthyridine linked NBTI antibacterials by structural and physicochemical optimizations.
Novel bacterial topoisomerase inhibitors (NBTIs) are an important new class of antibacterials targeting bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Notwithstanding their potent antibacterial activity, they suffer from a detrimental class-related hERG blockage. In this study, we designed and synthesized an optimized library of NBTIs comprising different linker moieties that exhibit reduced hERG inhibition and retain inhibitory potencies on DNA gyrase and topoisomerase IV of Staphylococcus aureus and Escherichia coli, respectively, as well as potent antibacterial activities. Substitution of the linker's tertiary amine with polar groups outcome in diminished hERG inhibition. Compound 17 expresses nanomolar enzyme inhibitory potency and antibacterial activity against both Gram-positive and Gram-negative bacteria as well as reduced hERG inhibition relative to our previously published NBTI analogs. Here, we point to some important NBTI's structural features that influence their hERG inhibitory activity.


A head-worn display ("smart glasses") has adverse impacts on the dynamics of lateral position control during gait.
Head-worn displays (e.g., "smart glasses") are an emerging technology to provide information, and in many situations they might be used while walking. However, little evidence exists regarding the effects of head-worn displays on walking performance. We found earlier that "smart glasses" had smaller adverse effects on measures of gait variability in the anterior-posterior direction vs. other types of information displays. Participants, however, complained about motion sickness and perceived instability while using smart glasses. Were the participants' complaints a result of adverse effects of the smart glasses on the dynamics of lateral stepping and gait stability? Twenty individuals walked on a treadmill in four different conditions; single-task walking, and three dual-task walking conditions, the latter using smart glasses, smartphone, and a paper-based system to provide secondary cognitive tasks. We assessed the dynamics of lateral stepping and gait stability using the goal equivalent manifold and maximum Lyapunov exponent, respectively. The dynamics of the lateral stepping were more adversely affected using smart glasses compared to the other types of information displays. However, stability measures revealed that the participants were more unstable when they used the smartphone and paper-based system. Promising results in terms of stability and adaptability suggest that head-worn display technology is a potentially useful alternative to smartphones and other types of information displays for reducing the risk of a fall. Results regarding perceptions of instability and a loss of control over lateral stepping, however, imply that this technology requires further development prior to real-work implementations.


Health status of prevalent cancer cases as measured by mortality dynamics (cancer vs. noncancer): Application to five major cancers sites.
Cancer prevalence is heterogeneous because it includes individuals who are undergoing initial treatment and those who are in remission, experiencing relapse, or cured. The proposed statistical approach describes the health status of this group by estimating the probabilities of death among prevalent cases. The application concerns colorectal, lung, breast, and prostate cancers and melanoma in France in 2017. Excess mortality was used to estimate the probabilities of death from cancer and other causes. For the studied cancers, most deaths from cancer occurred during the first 5 years after diagnosis. The probability of death from cancer decreased with increasing time since diagnosis except for breast cancer, for which it remained relatively stable. The time beyond which the probability of death from cancer became lower than that from other causes depended on age and cancer site: for colorectal cancer, it was 6 years after diagnosis for women (7 years for men) aged 75-84 and 20 years for women (18 years for men) aged 45-54 years, whereas cancer was the major cause of death for women younger than 75 years whatever the time since diagnosis for breast and for all patients younger than 75 years for lung cancer. In contrast, deaths from other causes were more frequent in all the patients older than 75 years. Apart from breast cancer in women younger than 55 years and lung cancer in women older than 55 years and men older than 65 years, the probability of death from cancer among prevalent cases fell below 1%, with varying times since diagnosis. The authors' approach can be used to better describe the burden of cancer by estimating outcomes in prevalent cases.


Annual trends in Google searches provides insights related to rhinosinusitis exacerbations.
Temporal trends of disease-specific internet searches may provide novel insights into seasonal dynamics of disease burden and, by extension, disease pathophysiology. The aim of this study was to define the temporal trends in rhinosinusitis-specific internet searches. This was a cross sectional analysis of search volume for predefined search terms. Google trends was used to explore the volume of searches for five specific search terms related to rhinosinusitis: nose, mucus, sinus, sinusitis, chronic sinusitis, which were entered into Google web search between 2004 and 2019. Results were analyzed within search "context" which included temporally associated related searches. Relative search volume (RSV) was analyzed for English and non-English speaking countries from the Northern and Southern hemispheres. Analysis of seasonality was performed using the cosinor model. The five specific search terms were most related to rhinosinusitis-related search contexts, indicating that they were appropriately reflective of internet queries by patients for rhinosinusitis. The RSV for rhinosinusitis-related terms and more general search terms increased with each passing year indicating constant interest in rhinosinusitis. Cosinor time series analysis revealed inquiry peaks in winter months for all five specific rhinosinusitis-related search terms independent from the hemisphere. Over a 15-year period, Google searches with rhinosinusitis-specific search terms consistently peaked during the winter around the world. These findings indirectly support the model of viral infection or exposure as the predominant cause of acute rhinosinusitis and acute exacerbations of chronic rhinosinusitis.


Neutron guide optimization for the Moroccan PGAA system.
The Moroccan TRIGA Mark II research reactor is to be equipped with a PGAA (Prompt Gamma Activation Analysis) facility to assist the country's progression in socioeconomic areas such as the environment and geochemistry, agriculture, health, industry, cultural heritage, and human sciences. The requirements of the PGAA facility include a very high thermal to fast neutron flux ratio and a focused, thin beam. Supermirror neutron guides are generally used to meet such requirements due to their ability to reflect neutrons with a specific energy and scattering angle. This study was undertaken to determine a suitable neutron guide for achieving optimal performance for the PGAA facility, where such a determination needs to be made according to both the available space and the minimum performance needed for PGAA analysis. To better parameterize the neutron guide, a set of simulations were performed with the aim of establishing the best guide specifications. Three types of neutron guides were studied, namely straight, curved, and bender. McStas code was used in this study, and the simulations showed that the guides must be 6 m long and that the coating value m must be equal to 5 for the bender and straight guides and 6 for the curved guide. Among the three guide types, the thermal/epithermal (Фth/Фep) and thermal/fast (Фth/Фfast) ratios were found to be much better when using the curved guide.


Metallic Co Nanoarray Catalyzes Selective NH3 Production from Electrochemical Nitrate Reduction at Current Densities Exceeding 2 A cm-2.
Electrochemical nitrate reduction (NITRR) offers a promising alternative toward nitrogen recycling and ammonia production under ambient conditions, for which highly active and selective electrocatalyst is desired. In this study, metallic cobalt nanoarrays as facilely prepared from the electrochemical reduction of Co(OH)2 nanoarrays (NAs) are demonstrated to exhibit unprecedented NH3 producing capability from catalyzing NITRR. Benefitting from the high intrinsic activity of Co0, intimate contact between active species and conductive substrate and the nanostructure which exposes large number of active sites, the Co-NAs electrode exhibits current density of -2.2 A cm-2 and NH3 production rate of 10.4 mmol h-1 cm-2 at -0.24 V versus RHE under alkaline condition and significantly surpasses reported counterparts. Moreover, the close-to-unity (≥96%) Faradaic efficiency (FE) toward NH3 is achieved over wide application range (potential, NO3 - concentration and pH). Density function theory calculation reveals the optimized adsorption energy of NITRR intermediates on Co surface over Co(OH)2. Furthermore, it is proposed that despite the sluggish kinetics of Volmer step (H2O → *H + *OH) which provides protons in conventional hydrogenation mechanism, the proton-supplying water dissociation process on Co surface is drastically facilitated following a concerted water dissociation-hydrogenation pathway.


Ceroid-containing histiocytic granuloma of the endometrium.
In an endometrial curettage specimen, taken from a 67-year-old woman with post-menopausal bleeding, the endometrium was replaced by aggregates of swollen histiocytes filled with yellowish-brown pigment. Histochemical and ultrastructural examination of the specimen revealed that the pigment was of ceroid nature. Previously reported cases with similar findings are reviewed, and the distinction of this type of endometrial lesion from 'foam cell reaction' is briefly discussed.


Effect of contralateral auditory stimuli on active cochlear micro-mechanical properties in human subjects.
The present study investigates the possibility that contralateral auditory stimulation along medial efferent system pathways may alter active cochlear micromechanics and hence affect evoked oto-acoustic emissions in humans. A first experiment, involving 21 healthy subjects showed reduction of oto-acoustic emission amplitude under low intensity contralateral white noise (from 30 dB SPL, 10 dB SL, upwards). The effect is found for intensities below the acoustic reflex threshold (85.2 dB HL). A second experiment, involving 10 of the above 21 subjects, sought to rule out any technical artefact. Recording was again carried out, but after sealing of the contralateral ear with a silicon putty plug. No contralateral intensity effect on oto-acoustic emission amplitude was found for contralateral intensities below 65 dB SPL. In subjective perception terms (dB SL) an effect was found under sealing when the sound reached or passed above the 10 dB SL level. These two findings confirm the preceding experiment. The third experiment investigated the role of transcranial transmission of the contralateral auditory stimulus. 16 subjects having total unilateral deafness and one healthy ear were tested by the same procedure as above. No fall-off in oto-acoustic emission amplitude was found for contralateral stimuli equal to or less than 80 dB SPL. There is thus a contralateral auditory stimulus effect on active cochlear micromechanics. The most appropriate explanation involves the medial cochlear efferent system, excited at brainstem level via the afferent auditory pathways. Alteration of active cochlear micromechanics seems promising at a basic level, pointing, as it does, to an interactive cochlear functioning which can be investigated by simple, non-intrusive, objective techniques which can be used with human subjects. We have here a model for functional exploration of the medial olivocochlear efferent system.


Cefuroxime: mechanisms of action, antimicrobial activity, pharmacokinetics, clinical applications, adverse reactions and therapeutic indications.
Cefuroxime is a second generation cephalosporin with a broad antimicrobial activity against both Gram-positive and Gram-negative organisms. It has excellent in vitro activity against staphylococcal strains, streptococcal strains (other than enterococci), N. gonorrhoeae, H. influenzae and N. meningitidis. It also has excellent in vitro activity against members of the Enterobacteriaceae with the exception of Serratia and indole-positive Proteus. Ps. aeruginosa and B. fragilis are resistant. Cefuroxime is relatively free of serious side effects. It is metabolically stable, and most of it is excreted unchanged in the urine. Three fourths of it are distributed in the extravascular compartment. Blood levels exceed the in vitro minimum inhibitory concentrations for many important gram negative pathogens. Clinical studies have shown cefuroxime to be effective therapy for infections of soft tissue, respiratory tract, urinary tract, genital tract (caused by N. gonorrhoeae) and the central nervous system. Superinfections with Ps. aeruginosa and enterococcal strains may present a problem. In spite of excellent diffusion into bone and joint tissues, the available clinical data are too limited to make a recommendation for its use in bone and joint infections.


[Monitor of ECG signal and heart rate using a mobile phone with Bluetooth communication protocol].
To develop a portable signal monitoring equipment for electrocardiography (ECG) and heart rate (HR), communicated with a mobile phone using the Bluetooth (BT) communication protocol for display of the signal on screen. A monitoring system was designed in which the electronic section performs the ECG signal acquisition, as well as amplification, filtering, analog to digital conversion and transmission of the ECG and HR using BT. Two programs were developed for the system. The first one calculates HR through QRS identification and sends the ECG signals and HR to the mobile, and the second program is an application to acquire and display them on the mobile screen. We developed a portable electronic system powered by a 9 volt battery, with amplification and bandwidth meeting the international standards for ECG monitoring. The QRS complex identification was performed using the second derivative algorithm, while the programs allow sending and receiving information from the ECG and HR via BT, and viewing it on the mobile screen. The monitoring is feasible within distances of 15 m and it has been tested in various mobiles telephones of brands Nokia®, Sony Ericsson® and Samsung®. This system shows an alternative for mobile monitoring using BT and Java 2 Micro Edition (J2ME) programming. It allows the register of the ECG trace and HR, and it can be implemented in different phones.


Efficacy of ganglioside treatment in reducing functional alterations induced by vincristine in rabbit peripheral nerves.
Vincristine (VCR) administration to rabbits resulted in severe electrophysiologic alterations of peripheral nerves. Sciatic nerve conduction velocity, compound action potential (CAP) amplitude, and area under the CAP waveform were all reduced in a dose-dependent fashion. In addition, the pattern of conduction velocity of both motor and sensory fibers was altered and shifted toward slow conduction classes. Simultaneous treatment with gangliosides limited significantly the changes in electrophysiologic parameters induced by VCR. It is suggested that gangliosides be given in the clinical setting as protection for the peripheral nerves against the side effects of antiblastic therapy.


Human lung cell growth is not stimulated by lead ions after lead chromate-induced genotoxicity.
Chromate compounds are known human lung carcinogens. Water solubility is an important factor in the carcinogenicity of these compounds with the most potent carcinogenic compounds being water-insoluble or 'particulate'. Previously we have shown that particulate chromates dissolve extracellularly releasing chromium (Cr) and lead (Pb) ions and only the Cr ions induce genotoxicity. Pb ions have been considered to have epigenetic effects and it is thought that these may enhance the carcinogenic activity of lead chromate, perhaps by stimulating Cr-damaged cells to divide. However, this possibility has not been directly tested. Accordingly, we investigated the ability of Pb ions to stimulate human lung cells and possibly force lead chromate-damaged cells to grow. We found that at concentrations of lead chromate that induced damage, human lung cells exhibited cell cycle arrest and growth inhibition that were very similar to those observed for sodium chromate. Moreover, we found that soluble Pb ions were not growth stimulatory to human lung cells and in fact induced progressive mitotic arrest. These data indicate that lead chromate-generated Cr ions cause growth inhibition and cell cycle arrest and that Pb does not induce epigenetic effects that stimulate chromate-damaged cells to grow.


Perioperative and long-term outcome after ascending aortic and arch repair with elephant trunk and open thoracoabdominal aortic aneurysm repair.
To describe the outcome of open thoracoabdominal aortic aneurysm (TAAA) repair following previous aortic arch repair including elephant trunk (ET) or frozen elephant trunk (FET) for acute and chronic pathologies. This was a retrospective, observational, multicenter study including 32 patients treated between 2006 and 2019 in two aortic centers using identical surgical protocols. Assessment focused on perioperative and long-term outcome, namely in-hospital morbidity and mortality, as well as procedure-related reintervention rate and aortic-related mortality rate. Kaplan-Meier curves with 95% confidence intervals were used to analyze the overall survival after surgery within the cohort. Thirty-two patients (mean age, 45.0 ± 13.6 years; 20 males [62.5%]) were treated because of acute (34.38% [n = 11]) or chronic (65.62% [n = 21]) aortic pathologies, including residual dissection following acute, symptomatic type A dissection (n = 7) and symptomatic mega aortic syndrome (n = 4), as well as post-dissection TAAA (n = 18) and asymptomatic mega aortic syndrome (n = 3). Twenty-eight patients (87.5%) received type II repair, and 4 patients (12.5%) received type III repair after previous ascending aorta and arch repair including ET/FET. Concomitant infrarenal and iliac vessel repair was performed in 38.7% (n = 12) and 29.4% (n = 10), respectively. The in-hospital mortality rate was 18.75% (n = 6). Spinal cord ischemia occurred in two cases, both after one-stage emergency procedure with one case of permanent paraplegia. Temporary acute kidney injury occurred in 41.94% (n = 13). The estimated 1-year survival rate was 78.1% (95% confidence interval, 63.9%-95.6%), with a median follow-up time of 1.29 years (interquartile range, 0.26-3.88 years). No procedure-related reinterventions and one case of aortic-related mortality, namely sepsis because of graft infection, was observed. Open TAAA repair following aortic arch repair including ET or FET because of acute or chronic aortic pathologies is associated with a relevant perioperative morbidity and mortality rate. During follow-up, a low aortic-related mortality rate and procedure-related reintervention rate were observed.


Skull x-ray criteria endorsed by the Food and Drug Administration: some flaws and proposed modifications.
Some skull fractures may be overlooked if the current FDA-endorsed criteria for ordering roentgenograms of the skull are followed strictly. Such cases raise the issues of the applicability of the criteria to children, the omission from the criteria of factors that are associated with skull fracture, and the fact that the criteria as currently written seem to miss certain types of occult open and depressed fractures. Modifications of two of the criteria are suggested.


Effectiveness of eHealth-based cognitive behavioural therapy on depression: A systematic review and meta-analysis.
To systematically appraise the effects of eHealth cognitive behavioural therapy on depression and anxiety severity, quality of life, adherence and attrition rates observed in adults with clinically diagnosed depression. eHealth-based cognitive behavioural therapy is an increasingly popular intervention on depression, but current reviews investigating the effects of eHealth interventions on depression are not exclusive to the clinically depressed. A systematic review and meta-analysis. Following the PRISMA guidelines, a systematic search of randomised controlled trials related to eHealth cognitive behavioural therapy published from inception from six databases and three trial registries was undertaken. A total of 15 studies were included in this systematic review. The meta-analysis revealed that, when compared to passive comparators, eHealth cognitive behavioural therapy had a statistically significant effect on depression (d = -0.62, 95% CI: -0.96 to -0.28, p = .0003) and anxiety severity (d = -0.65, 95% CI: -1.10 to -0.21, p = .004) but not for quality of life (d = 0.30, 95% CI: -0.09 to 0.07, p = .13). When compared to active comparators, a statistically significant effect on depression (d = -0.31, 95% CI: -0.55 to -0.07, p = .01) and anxiety severity (d = -0.50, 95% CI: -0.81 to -0.19, p = .002) was observed, but not for quality of life (d = 0.22, 95% CI: -0.04 to 0.48, p = .10). Weighted averages for adherence and attrition rates were low. eHealth cognitive behavioural therapy showed effectiveness in reducing depression and anxiety severity, but not quality of life. Further research is required to culturally adapt CBT interventions and explore the long-term benefits of eHealth cognitive behavioural therapy. The use of eHealth-based cognitive behavioural therapy could potentially bridge treatment gaps and serve as an adjunct to active treatment plans or an alternative for those without access to treatment.


The use of sym-triazine trichloride in RNA-protein cross-linking studies with Escherichia coli ribosomal subunits.
The reagent sym-triazine trichloride is used as a bifunctional reagent to generate RNA-protein cross-links within intact ribosomal subunits from E. coli. The reaction takes place in a stepwise manner, involving substitution of one chlorine atom at 12 degrees and pH 8, and substitution of the second at 40 degrees and pH 6. The cross-linked proteins are analysed by two-dimensional electrophoresis, and the existence of a stable cross-linkage is demonstrated by isolating protein-oligonucleotide complexes from 32P-labelled subunits. The proteins cross-linked are S3 and S4 in the 30S subunit, and L2 in the large subunit, together with smaller amounts of other proteins. The reagent should prove useful in topographical studies of the E. coli ribosome as it is a rigid molecule and generates very short cross-links.


Selective destruction and regeneration of rat Leydig cells in vivo. A new method for the study of seminiferous tubular-interstitial tissue interaction.
The effect of a single i.p. administration of ethane dimethanesulphonate (EDS) upon rat testicular histology was studied by light microscopy and morphometry up to 4 weeks after treatment. One day after injection the interstitial tissue exhibited degenerating Leydig cells, abundant pyknotic interstitial cells, deposition of cellular debris and extensive networks of fibrillar material. Macrophages contained greatly increased numbers of cytoplasmic inclusion bodies. From 3 to 7 days morphometric analysis showed that Leydig cells and cellular debris had disappeared from the interstitial tissue, leaving only macrophages, fibroblasts and lymphatic endothelial tissue. A very small number of new Leydig cells were seen on day 14, often located in peritubular or perivascular positions. Regeneration of foetal-like Leydig cells occurred by 4 weeks, their cytoplasm containing large lipid inclusions and, numerous Leydig cells were often observed closely applied to the walls of the seminiferous tubules. The observations suggest that, after experimental destruction and depletion of Leydig cells, an interstitial precursor cell, as yet unidentified, gives rise to a new Leydig cell population. EDS thus offers a valuable opportunity to study further the interactions between the seminiferous tubules and the interstitial tissue following the destruction and subsequent regeneration of the Leydig cells.


Acamprosate does not induce a conditioned place preference and reveals no state-dependent effects in this paradigm.
To evaluate the putative rewarding properties of the anticraving substance acamprosate, male rats learned to associate injections of vehicle and acamprosate (200 mg/kg ip) with two visually contrasting compartments in a place conditioning paradigm. The degree of preference for the acamprosate-associated compartment was determined, in both a postconditioning test with undrugged animals and a consecutive test with drugged animals, to rule out the possibility that a putatively rewarding effect of acamprosate may have been masked by state-dependent effects. The animals did not show any preference for the substance-paired compartment, neither in the undrugged nor in the drugged state. In conclusion, acamprosate has no rewarding properties as shown in place preference. Therefore, it may prevent a relapse in detoxified alcoholics in a way other than by simply substituting the rewarding effects of ethanol. This adds to the therapeutic value of acamprosate in the treatment of drug craving.


Acute malignant obstruction in patients with peritoneal carcinomatosis: The role of palliative surgery.
Patients with peritoneal carcinomatosis who do not have curative treatment options often develop acute obstructive symptoms and when conservative management fails, surgical treatment is the remaining option. However, palliative surgery is associated with high morbidity and mortality and the chance of success is unclear. The aim of this study was to evaluate outcomes of palliative surgery and to provide guidance for surgeons, medical oncologists and patients in their decision-making. All consecutive patients who underwent palliative surgery for acute obstruction caused by peritoneal carcinomatosis between January 2005 and October 2017 where identified. In total 148 patients underwent surgery. Primary malignancy was colorectal cancer (28.4%), neuroendocrine tumor (20.3%), ovarian cancer (14.2%) or 'other' (37.2%). Median length of postoperative hospital stay was 16 days (IQR 9-24). More than half (58.1%) of the patients developed postoperative complications, 29.1% developed ≥2 complications. In-hospital mortality was 8.8%. Readmission (56.1%) and re-obstruction (35.0%) were common. Median overall survival was 119 days (IQR 48-420). Patients with a neuroendocrine tumor had a significantly better overall survival compared to other primary malignancies (p < 0.001). Patients who developed an obstruction during or within 6 months after treatment with chemotherapy had a worse overall survival (p < 0.001), compared to patients treated with chemotherapy longer than 6 months ago, or patients not treated with chemotherapy. Palliative surgery is associated with high rates of complications and readmission and re-obstruction are common. Comfort care is often a better option than surgery, especially in patients with disease progression under recent treatment with chemotherapy.


[Inspiratory muscle training during pulmonary rehabilitation].
Inspiratory muscle training (IMT) is part of the management of patients with pulmonary diseases during rehabilitation. Since the last recommendations of the Société de pneumologie de langue française, several studies have focused on the role of inspiratory muscle training during pulmonary rehabilitation. IMT, in comparison to standard care or sham-IMT, improves the strength and endurance of the inspiratory muscles, decreases dyspnoea during the activities of daily living, improves walking distance and quality of life. However, the different studies did not show an additional effect of IMT during a pulmonary rehabilitation program compared to a rehabilitation program without IMT, with regard to improvement of exercise capacity and quality of life. One study showed an improvement in dyspnoea of effort, but these results are yet to be confirmed. Finally, it seems appropriate to associate IMT with an exercise-training program before chest or abdominal surgery, even if further studies are necessary. During a pulmonary rehabilitation program, IMT does not provide additional benefits. However, when patients cannot perform a global exercise training, IMT has shown benefit. IMT provides additional benefits in pre-operative programs.


Thai women's experiences of and responses to domestic violence.
Domestic violence has been linked to many health consequences. It can impact women's mental, physical, sexual, and reproductive health, and all of these effects can be long lasting. Despite the growing awareness of the deleterious effects of domestic violence in Thailand, there have been few nation-wide studies that have examined the issue and its consequences. In fact, Thailand has not examined intimate partner violence incidence for the past 20 years. This study aimed to investigate the consequences of domestic violence across the country. A cross-sectional study was conducted in four areas of Thailand: central, southern, northern, and northeastern. One province in each area was selected by simple random sampling techniques. One thousand four hundred and forty-four married or cohabiting females in a heterosexual union, aged 20-59 years, were included in the sample and were interviewed about their experiences of psychological, physical, and sexual violence by their male partners. One thousand four hundred and forty-four women completed the interviews. Sixteen percent of respondents encountered domestic violence in its various psychological, physical, or sexual forms. In the majority of cases, all forms of domestic violence were exerted repeatedly. Four-fifths of women who faced domestic violence reported that it had an impact on their physical and mental health as well as employment. This study also found that half of the domestic violence survivors reported their children had witnessed violent situations. These women exercised four coping strategies to deal with their domestic violence: 1) counseling; 2) requesting help from others; 3) fighting back; and 4) running away from home. The findings confirm that domestic violence has implications that extend beyond health and result in the deterioration of the quality of women's lives. These results underscore that domestic violence is a serious problem that must be addressed in Thai society.


Comparison of microplate- and bottle-based methods to age yeast for chronological life span assays.
This study compared the chronological life span and survival of Saccharomyces cerevisiae aged in a microplate or bottle, under different aeration and calorie restriction conditions. Our data shows that limited aeration in the microplate-aged culture contributed to slower outgrowth but extended yeast CLS compared to the bottle-aged culture.


Standard -20 °C freezer storage protocols may cause substantial plasma renin cryoactivation.
To assess the appropriate preanalytical process for storage of plasma for renin concentration analysis. This study was initiated due to the wide variation in preanalytical handling of samples observed within our network, particularly with respect to freezing for longer term storage. Pooled plasma from patient samples was analysed immediately post separation for renin concentration (n=30, concentration 4.0-204 mIU/L). Aliquots from these samples were frozen in a -20 °C freezer and then analysed, with the renin concentration compared to the respective baseline concentration. Comparisons were also made to: aliquots snap frozen using a dry ice/acetone bath, aliquots stored at room temperature, and aliquots stored at 4 °C. Subsequent experiments investigated the potential sources of cryoactivation observed in these initial studies. Substantial and highly variable cryoactivation was observed in samples frozen using a -20 °C freezer, with renin concentration increasing over 300% from baseline in some samples (median 21.3%). This cryoactivation could be prevented by snap freezing samples. Subsequent experiments determined that long term storage in a -20 °C freezer could prevent cryoactivation provided samples were initially frozen rapidly in a -70 °C freezer. Rapid defrosting of samples was not required to prevent cryoactivation. Standard -20 °C freezers may not be appropriate for freezing samples for renin analysis. Laboratories should consider snap freezing their samples using a -70 °C freezer or similar to avoid cryoactivation of renin.


Prespecified Risk Criteria Facilitate Adequate Discharge and Long-Term Outcomes After Transfemoral Transcatheter Aortic Valve Implantation.
Background Despite the availability of guidelines for the performance of transcatheter aortic valve implantation (TAVI), current treatment pathways vary between countries and institutions, which impact on the mean duration of postprocedure hospitalization. Methods and Results This was a prospective, multicenter registry of 502 patients to validate the appropriateness of discharge timing after transfemoral TAVI, using prespecified risk criteria from FAST-TAVI (Feasibility and Safety of Early Discharge After Transfemoral [TF] Transcatheter Aortic Valve Implantation), based on hospital events within 1-year after discharge. The end point-a composite of all-cause mortality, vascular access-related complications, permanent pacemaker implantation, stroke, cardiac rehospitalization, kidney failure, and major bleeding-was reached in 27.0% of patients (95% CI, 23.3-31.2) within 1 year after intervention; 7.5% (95% CI, 5.5-10.2) had in-hospital complications before discharge and 19.6% (95% CI, 16.3-23.4) within 1 year after discharge. Overall mortality within 1 year after discharge was 7.3% and rates of cardiac rehospitalization 13.5%, permanent pacemaker implantation 4.2%, any stroke 1.8%, vascular-access-related complications 0.7%, life-threatening bleeding 0.7%, and kidney failure 0.4%. Composite events within 1 year after discharge were observed in 18.8% and 24.3% of patients with low risk of complications/early (≤3 days) discharge and high risk and discharged late (>3 days) (concordant discharge), respectively. Event rate in patients with discordant discharge was 14.3% with low risk but discharged late and increased to 50.0% in patients with high risk but discharged in ≤3 days. Conclusions The FAST-TAVI risk assessment provides a tool for appropriate, risk-based discharge that was validated with the 1-year event rate after transfemoral TAVI. Registration URL: https://www.ClinicalTrials.gov; Unique identifier: NCT02404467.


A phase I study of combined docetaxel and repeated high activity 186Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial).
Bone-seeking radiopharmaceuticals have palliative benefit in castration-resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and (186)Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity. A dose escalation schedule was designed consisting of four dose levels with a standard dosage of docetaxel (75 mg/m(2) 3-weekly). (186)Re-HEDP was given in increasing activities (1,250 MBq up to 2,500 MBq) after the third and sixth cycle of docetaxel. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity lasting more than 7 days or any grade 3 toxicity that did not recover within 10 days. Three patients were planned for each dose level expanding to six if a DLT occurred. Fourteen patients were recruited with a median age of 64.6 years. One DLT, grade 3 thrombocytopenia lasting >10 days, occurred at dose level 3 leading to expansion of this group to six. One of these patients had an episode of acute renal failure which resolved. Because of production problems of (186)Re-HEDP dose level 4 was not started. Combined therapy with docetaxel and (186)Re-HEDP is generally well tolerated in patients with CRPC metastatic to bone. We will conduct a randomized phase II study using three cycles of docetaxel 75 mg/m(2) 3-weekly followed by (188)Re-HEDP 40 MBq/kg body weight, followed by another three cycles of docetaxel 75 mg/m(2), followed by (188)Re-HEDP 20 MBq/kg body weight.


Self-loving in the epidemic years: Carmen Machado's rhetoric of woundedness.
This article explores Carmen Machado's Her Body and Other Parties (2017) as articulating generative unmaking of bodies. Mobilizing that which I examine as rhetoric of woundedness, a thread of Latina rhetoric wherein wounds are strategically positioned to emphasize flesh as space of conflict, Machado writes body horrors to provoke dis-ease in audiences. Specifically, Machado highlights pervasive discursive discomforts that decentralize narratives about women's body (un)wellness. It is important to note, however, that Machado's attention to the corporal becomes, in part, rejection of body, a de-composition of physicality-sometimes reached through sexual ecstasy, other times through violence and epidemics-to re-compose self. Such a tactic recalls conversations advanced in Cherríe Moraga's writings and Yvonne Yarbro-Bejarano's embodied theories, both included in Carla Trujillo's landmark anthology, Chicana Lesbians: The Girls Our Mothers Warned Us About (1991). Moraga and Yarbro-Bejarano investigate textual dismemberment of female physique to re-imagine and reclaim body for enactments of Chicana desire. What marks Machado as distinct is her resistance to reclaim body. Often, Machado's characters manifest phantom states that quarantine body from toxic physical and social spaces. Concurrently, characters lose rights to body due to self-hate within that toxicity. Machado's characters find clarity only when freed from physicality, at which point they may re-compose themselves according to their testified truths. I see this distinction as a progression of works contained in Trujillo's anthology as Machado envisions a worldmaking process that one composes through autonomous self-love and self-partnership to nurture female narrative and solidarity.


Nemaline bodies of skeletal muscle fibers of the neck in a case of pharyngeal cancer.
Nemaline bodies were found in the regenerating muscle fibers of the neck of a 74-year-old Japanese male with pharyngeal cancer. Histologically, the nemaline bodies were needle-shaped structures and hematoxophilic with phosphotungstic acid-hematoxylin stain. Electron microscopic examination suggested that they arise as extensions of the Z bands. Although nemaline bodies occur in a variety of pathological conditions other than nemaline myopathy, their occurrence in regenerating skeletal muscle fibers invaded by cancer has not been reported previously. The pathogenesis of the nemaline body formation in the present case is discussed.


Central nervous system relapse in diffuse large B lymphoma: a retrospective cohort study
CNS relapse in patients with LDCGB is a poor prognosis event. The incidence of relapse is variable according to the literature. Data in Latin America is lacking. In order to establish the incidence of CNS relapse in our cohort, time to CNS relapse and the impact of CNS relapse risk factors, a retrospective cohort study was performed, from January 2012 to June 2017. One hundred and forty seven patients were analyzed. The median age was 66 years (ICR 56-76); 76 patients (51.70%) were men. The IPI was low or intermediate/low in 115 (78.2%) cases. The CNS IPI was intermediate in 77 (52.4%) and high in 14 (9.5%) of cases. Thirty-five (23.81%) patients received intrathecal prophylaxis. No patient received systemic prophylaxis. During the follow-up, 8 (4.59%) patients had CNS relapse, none of them with high IPI. The median time to relapse was 6.5 months (ICR 5.5-10). Seven (87.5%) patients relapsed within the year of diagnosis. We found no risk factors for CNS involvement in the bivariate analysis. The incidence of relapse was 2.7% (CI 0.2% -4.6%), 4.8% (CI 1.8% -8.9%) and 5.4% (CI 4.5- 8.9%) at 6, 12 and 24 months, respectively. The incidence of CNS relapse was similar to that described in the international series. Our study confirms that the majority of patients relapse during the first year of follow up. We must carry out broader collaborative work to better establish the risk factor for CNS relapse.


Brief Report: Retrospective Evaluation on the Efficacy of Lopinavir/Ritonavir and Chloroquine to Treat Nonsevere COVID-19 Patients.
The effectiveness of lopinavir/ritonavir (LPV/r) and chloroquine treatment for COVID-19 has not been verified. We conducted a retrospective study to summarize the clinical practices of nonsevere patients with COVID-19 receiving the standard care, LPV/r or chloroquine in Beijing Ditan Hospital from January 20 to March 26, 2020. The main outcome measurements include the changes of cycle threshold values of open reading frame 1 ab (ORF1ab) and nucleocapsid (N) genes by reverse transcriptase-polymerase chain reaction assay from day 1 to 7 after admission for patients receiving standard care or after treatment being initiated for patients receiving either LPV/r or chloroquine. The proportion of developing severe illness, fever duration and the time from symptom onset to chest computer tomography improvement, and negative conversion of nucleic acid were compared. Of the 129 patients included in the study, 59 received the standard care, 51 received LPV/r, and 19 received chloroquine. The demographics and baseline characteristics were comparable among the 3 groups. The median duration of fever, median time from symptom onset to chest computer tomography improvement, and negative conversion of the nucleic acid were similar among the 3 groups. The median increase in cycle threshold values of N and ORF1ab gene for patients receiving LPV/r or chloroquine or the standard care during the treatment course was 7.0 and 8.5, 8.0, and 7.6, 5.0, and 4.0, respectively. These figures were not found significantly different among the 3 groups. Antiviral therapy using LPV/r or chloroquine seemed not to improve the prognosis or shorten the clinical course of COVID-19.


Multiple-Choice Tests: A-Z in Best Writing Practices.
Multiple-choice tests are the most used method of assessment in medical education. However, there is limited literature in medical education and psychiatry to inform the best practices in writing good-quality multiple-choice questions. Moreover, few physicians and psychiatrists have received training and have experience in writing them. This article highlights the strategies in writing high-quality multiple-choice items and discusses some common flaws that can impact validity and reliability of the assessment examinations.


Green valorization of end-of-life toner powder to iron oxide-nanographene nanohybrid as a recyclable persulfate activator for degrading emerging micropollutants.
The sustainable management of toner waste (T-raw) was performed via carbonization at 500 °C (T-500) and 600 °C (T-600) to produce iron oxide-nanographene nanohybrid (FeO-NG) for activating persulfate (PS) to efficiently degrade dyes (methylene blue, MB), antibiotics (sulfamethazine, SMZ), and pesticides (diazinon, DZN). Morphology, crystallinity, chemical structure, chemical composition, surface area, and pore size distribution of the synthesized materials were investigated using various analyses. High degradation ratios of MB were attained over a wide pH range (2-7), and the optimum operating conditions were determined. The FeO-NG/PS system was tested in different water matrices. MB degradation efficiency dropped from 80.13% to 78.56% after five succeeding experiments, proving the high stability of T-500. Trapping experiments proved the major role of sulfate radicals and the minor contribution of singlet oxygen. The toxicity evaluation of the treated and untreated MB solutions was conducted via measuring the cell viability, showing an increase in cell viability ratio after the degradation of MB. The degradation efficiencies of DZN and SMZ were 97.54% and 83.7%, respectively and the mineralization ratios were 74.08% and 60.37% at initial concentrations of sulfamethazine and diazinon of 50 and 100 mg/L, respectively. The high degradation efficiency of emerging micropollutants as well as the inexpensiveness, and facile synthesis of the catalyst boost the prospect of applying the proposed system on an industrial scale.


Three-dimensional analysis of the structure and composition of CA3 branched dendritic spines and their synaptic relationships with mossy fiber boutons in the rat hippocampus.
This paper is the third in a series to quantify differences in the composition of subcellular organelles and three-dimensional structure of dendritic spines that could contribute to their specific biological properties. Proximal apical dendritic spines of the CA3 pyramidal cells receiving synaptic input from mossy fiber (MF) boutons in the adult rat hippocampus were evaluated in three sets of serial electron micrographs. These CA3 spines are unusual in that they have from 1 to 16 branches emerging from a single dendritic origin. The branched spines usually contain subcellular organelles that are rarely found in adult spines of other brain regions including ribosomes, multivesicular bodies (MVB), mitochondria, and microtubules. MVBs occur most often in the spine heads that also contain smooth endoplasmic reticulum, and ribosomes occur most often in spines that have spinules, which are small nonsynaptic protuberances emerging from the spine head. Most of the branched spines are surrounded by a single MF bouton, which establishes synapses with multiple spine heads. The postsynaptic densities (PSDs) occupy about 10-15% of the spine head membrane, a value that is consistent with spines from other brain regions, with spines of different geometries, and with immature spines. Individual MF boutons usually synapse with several different branched spines, all of which originate from the same parent dendrite. Larger branched spines and MF boutons are more likely to synapse with multiple MF boutons and spines, respectively, than smaller spines and boutons. Complete three-dimensional reconstructions of representative spines with 1, 6, or 12 heads were measured to obtain the volumes, total surface areas, and PSD surface areas. Overall, these dimensions were larger for the complete branched spines than for unbranched or branched spines in other brain regions. However, individual branches were of comparable size to the large mushroom spines in hippocampal area CA1 and in the visual cortex, though the CA3 branches were more irregular in shape. The diameters of each spine branch were measured along the cytoplasmic path from the PSD to the origin with the dendrite, and the lengths of branch segments over which the diameters remained approximately uniform were computed for subsequent use in biophysical models. No constrictions in the segments of the branched spines were thin enough to reduce charge transfer along their lengths.(ABSTRACT TRUNCATED AT 400 WORDS)


Loneliness in mid-life and older adults from ethnic minority communities in England and Wales: measure validation and prevalence estimates.
We investigated the prevalence of loneliness among 1206 adults aged 40 + from six minority communities in England and Wales: Black Caribbean, Black African, Indian, Pakistani, Bangladeshi and Chinese. Replicating the approach from the previous studies, we demonstrate robust acceptability, reliability and validity for both the six-item De Jong Gierveld (DJG) and single-item loneliness scales in our six ethnic groups. The prevalence of loneliness using a single-item question (loneliness reported as often/always) ranges from 5% (Indian) to 14% (Chinese) compared with approximately 5% for the general population aged 40 + in Britain. Levels of loneliness are very much higher using the DJG scale. Using a loneliness threshold score of 5 +, the percentage ranged from 13% (Indian) to 36% (Chinese). We explored the importance of six established loneliness vulnerability factors for our sample using regression modelling. Three factors were not associated with loneliness-number of children, gender and health rating, and three factors were protective: younger age, being married and low financial strain. The addition of ethnicity did not change these relationships or enhance statistical power of our models. Being a member of the African Caribbean group was protective against loneliness but not for the other groups included in our study. We suggest that exposure to loneliness vulnerability factors rather than ethnicity per se or measurement artefact underpins differences in loneliness across ethnic groups.


Self-monitoring of blood glucose and insulin dose alteration in type 1 diabetes mellitus.
The purpose of this study was to evaluate the relationship between proper use of self-monitoring of blood glucose (SMBG) including knowledge and application of specific algorithms and metabolic control in a group of randomly selected insulin-dependent diabetic patients. We studied 80 patients responding to the following criteria: intensive conventional insulin therapy and SMBG for at least 6 months using a reflectance meter, and previous 5-day hospital education period. The practical knowledge of the guidelines was evaluated by a questionnaire simulating 8 metabolic situations. A computer analysis of the SMBG data for the 3 months preceding the study allowed us to evaluate patient compliance with SMBG (number of blood glucose determinations) and patients' application of the guidelines (percentage of insulin doses modified according to the guidelines). Fifty-nine patients (79%) were compliant with SMBG and had better metabolic control than the non-compliers (HbA1c: 6.7 +/- 1.1% vs. 7.5 +/- 1.9, P < 0.05). Twenty-eight out of the 59 compliant subjects had good knowledge of the guidelines but without patent improvement of glycemic control. Seventeen of these 28 correctly used the algorithms to modify insulin dosage; their HbA1c levels were lower than those of the 11 patients who did not use the algorithms (6.1 +/- 0.9 vs. 7.1 +/- 0.9%, P < 0.05). The percentage of insulin dose modification consistent with the guidelines and the level of HbA1c was negatively correlated in the good-knowledge group. The conclusion is that good metabolic control is linked not only with the degree of knowledge but also with the application of this knowledge.


Translational and pharmacokinetic-pharmacodynamic application for the clinical development of GDC-0334, a novel TRPA1 inhibitor.
GDC-0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC-0334 were evaluated in this first-in-human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC-0334 in guinea pigs, rats, dogs, and monkeys. Human PK and PK-PD of GDC-0334 were characterized after single and multiple oral dosing using a population modeling approach. The ability of GDC-0334 to inhibit dermal blood flow (DBF) induced by topical administration of allyl isothiocyanate (AITC) was evaluated as a target-engagement biomarker. Quantitative models were developed iteratively to refine the parameter estimates of the dose-concentration-effect relationships through stepwise estimation and extrapolation. Human PK analyses revealed that bioavailability, absorption rate constant, and lag time increase when GDC-0334 was administered with food. The inhibitory effect of GDC-0334 on the AITC-induced DBF biomarker exhibited a clear sigmoid-Emax relationship with GDC-0334 plasma concentrations in humans. This study leveraged emerging preclinical and clinical data to enable iterative refinement of GDC-0334 mathematical models throughout the FIH study for dose selection in subsequent cohorts throughout the study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GDC-0334 is a novel, small molecule TRPA1 inhibitor and a pharmacokinetic-pharmacodynamic (PK-PD) modeling strategy could be implemented in a systematic and step-wise manner to build and learn from emerging data for early clinical development. WHAT QUESTION DID THIS STUDY ADDRESS? Can noncompartmental and population-based analyses be used to describe the PK and PD characteristics of GDC-0334 in preclinical and clinical studies? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? GDC-0334 exposure generally increased with dose in rats, dogs, and monkeys. The starting dose (25 mg) in the clinical study was determined based on the preclinical data. GDC-0334 exhibited linear PK in humans and the bioavailability was increased with food. The inhibitory effect of GDC-0334 on dermal blood flow induced by the TRPA1 agonist allyl isothiocyanate in humans indicates a clear PK-PD relationship. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The models developed based on TRPA1 agonist-induced dermal blood flow inhibition data can be used to predict PK-PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1.


Improved management of grade B biliary leaks after complex liver resections using gadoxetic acid disodium-enhanced magnetic resonance cholangiography.
Bile leaks occurring after complex liver resection and lasting >1 week (grade B) usually are managed by means of invasive cholangiography either endoscopic or percutaneous, with a substantial risk of procedure-related complications. The aim of this study was to investigate the ability of gadoxetic acid disodium-enhanced magnetic resonance cholangiography to detect postoperative biliary leaks and avoid invasive cholangiography in case of peripheral location of the fistula. Patients with grade B biliary leak after complex liver resection from January 2018 to March 2020 underwent magnetic resonance cholangiography to guide the management of the leak (study group). The primary endpoint was the ability of magnetic resonance cholangiography to reduce the need for invasive cholangiography with respect to similar posthepatectomy leaks collected in the previous 2 years and approached with upfront invasive cholangiography (controls). A series of in-hospital outcomes also were compared. Out of 533 liver resections, 11 study patients versus 11 control patients with grade B leaks were compared. Magnetic resonance cholangiography achieved 100% accuracy in detection and location of the leak. Five out of 6 peripheral leaks healed without invasive cholangiography. Overall, 50% reduction in the use of invasive cholangiography was observed in the study versus control patients. Median healing time and hospital stay were 38 and 40 days in patients undergoing invasive cholangiography versus 10 and 11 days in patients treated conservatively (P = .007 and 0.012, respectively). Infection rate and other complications rate were 82% vs 20% (P = .01) and 35% vs 40% (P = .5), respectively. Magnetic resonance cholangiography is a safe, precise, noninvasive tool to detect posthepatectomy bile leaks that can help clinicians in decision-making on conservative versus invasive treatment of fistulas.


A homeostasis criterion for limit cycle systems based on infinitesimal shape response curves.
Homeostasis occurs in a control system when a quantity remains approximately constant as a parameter, representing an external perturbation, varies over some range. Golubitsky and Stewart (J Math Biol 74(1-2):387-407, 2017) developed a notion of infinitesimal homeostasis for equilibrium systems using singularity theory. Rhythmic physiological systems (breathing, locomotion, feeding) maintain homeostasis through control of large-amplitude limit cycles rather than equilibrium points. Here we take an initial step to study (infinitesimal) homeostasis for limit-cycle systems in terms of the average of a quantity taken around the limit cycle. We apply the "infinitesimal shape response curve" (iSRC) introduced by Wang et al. (SIAM J Appl Dyn Syst 82(7):1-43, 2021) to study infinitesimal homeostasis for limit-cycle systems in terms of the mean value of a quantity of interest, averaged around the limit cycle. Using the iSRC, which captures the linearized shape displacement of an oscillator upon a static perturbation, we provide a formula for the derivative of the averaged quantity with respect to the control parameter. Our expression allows one to identify homeostasis points for limit cycle systems in the averaging sense. We demonstrate in the Hodgkin-Huxley model and in a metabolic regulatory network model that the iSRC-based method provides an accurate representation of the sensitivity of averaged quantities.


Analysis of real-world data on growth hormone therapy adherence using a connected injection device.
Poor adherence to long-term recombinant human growth hormone (r-hGH) treatment can lead to suboptimal clinical outcomes; consequently, supporting and monitoring adherence is a crucial part of patient management. We assessed adherence to r-hGH treatment in children with growth disorders over 48 months using a connected monitoring device (easypod™), which automatically transmits adherence data via an online portal (easypod™ connect); both sit within an adherence decision support system (ADSS). We also investigated the effect of age and sex on adherence. Data from children transmitting over 10 injections between January 2007 and February 2019 were analyzed. Adherence (mg injected/mg prescribed) was categorized as high (≥85%), intermediate (> 56-84%) or low (≤56%) and assessed at seven time points from the start of treatment up to 48 months. Adherence was investigated over time and stratified by puberty status and sex. Mean transmission rate in each adherence category (total number of transmissions/total number of children) at each time point was calculated as a proxy measure of engagement in disease and treatment management. Descriptive analyses were performed. Longitudinal records were available for 13,553 children. Overall, 71% (n = 9578) had high adherence, 22% (n = 2989) intermediate and 7% (n = 986) low. The proportion of children with high adherence decreased over time from 87% (n = 12,964) to 65% (n = 957) and was higher in pre-pubertal than pubertal children (girls: 80% [n = 1270] vs 70% [n = 4496]; boys 79% [n = 2573] vs 65% [n = 5214]). Children with high adherence had a higher mean number of transmissions (12.5 [SD 24.9]) than children with intermediate (7.2 [SD 15.3]) or low (3.5 [SD 5.7]) adherence. High adherence was seen in patients administering r-hGH using the connected device. Children with high adherence were most likely to regularly transmit data. Pubertal children showed lower adherence. We show the potential to develop an ADSS to analyze trends in real-world adherence data. This may prove useful to direct interventions to improve adherence while the ability to readily share data with healthcare professionals may itself improve adherence.


A pilot study to explore the predictive validity of 4 measures of falls risk in frail elderly patients.
To test the hypothesis that scores on 4 falls risk measures will differ significantly in patients reporting recurrent falls compared with those who do not; and to explore the validity of each measure to predict such falls status. A convenience sample was tested to establish the sensitivity and specificity of the Functional Reach Test, Timed Up & Go test, one-leg stance test (OLST), and balance subsection of the Performance Oriented Mobility Assessment (B-POMA). A 12-month retrospective falls history was used to identify recurrent fallers. A day hospital for the elderly. Convenience sample of 30 day hospital patients. The inclusion criteria were: ability to rise from a chair and walk 6m; no severe cognitive impairment or blindness; age 65 years or older. Not applicable. Scores on the 4 tests and retrospective falls histories. Scores on the B-POMA and OLST showed significant differences between fallers and nonfallers (P<.05). An OLST time of 1.02 seconds or less (odds ratio [OR]=15.2; 95% confidence interval [CI], 1.72-133.95) and B-POMA score of 11 or less (OR=18.5; 95% CI, 2.05-167.79) were predictive of day hospital patients having a history of recurrent falls. OLST and B-POMA both have potential as screening tools for risk of falls, but this observation requires confirmation in a prospective study.


Development of UHPLC-MS/MS methods to quantify 25 antihypertensive drugs in serum in a cohort of patients treated for hypertension.
We developed three ultra-high pressure liquid chromatography coupled to mass spectrometry detection (UHPLC-MS/MS) methods to quantify 25 antihypertensive drugs in serum samples. Patient-reported drug lists were collected, and drug concentrations were analysed in samples from 547 patients, half with uncontrolled hypertension, and all treated with ≥ 2 antihypertensive drugs. For sample preparation, serum was mixed with deuterated internal standards and acetonitrile and precipitated. Aliquots of the supernatant were injected on UHPLC-MSMS with a C18 reversed phase column. The mobile phase was 0.1 % HCOOH (formic acid) in water and 0.1 % HCOOH in acetonitrile (except in methanol for spironolactone/canrenone) at a flow rate of 0.4 mL/min. The calibrators and internal controls were prepared in Autonorm™. The calibration ranges were wide, and the models were linear or quadratic with squared correlation coefficients ≥ 0.97. The limits of detection and quantification, specificity, carry-over, and matrix effects were acceptable. The accuracy of the internal controls was in the range 85-121 %, and the intermediate precision for all drugs was 4-28 %. The patient-reported antihypertensive drug use and the detected serum drug concentrations were in accordance with that most frequently prescribed nationally. The percent non-detectable level was 5-10 % for bendroflumethiazide, doxazosin, nifedipine, and ramipril. Often the drug dose chosen was lower than the recommended maximum daily dose. We report the maximum (Cmax) and minimum (Cmin) drug concentrations after drug intake. The inter-individual pharmacokinetic variability at Cmin was 18-fold for hydrochlorothiazide, 22-fold for losartan carboxyl acid, 26-fold for amlodipine, 44-fold for candesartan, and 50-fold for valsartan. Our methods are suitable for measuring antihypertensive drugs in patient serum for therapy control.


Characterization of calcium-independent forms of protein kinase C-beta in phorbol ester-treated rabbit platelets.
The subcellular distribution, size, and activation state of protein kinase C (PKC) were studied after short term exposure of rabbit platelets to a saturating dose of 12-O-tetradecanoylphorbol 13-acetate (TPA). Cytosolic and Nonidet P-40-solubilized particulate extracts prepared from TPA-treated platelets were subjected to analytical column chromatography on Mono Q, hydroxylapatite, and Superose 6/12. PKC activity was assayed according to the ability of the enzyme to phosphorylate (i) histone H1 in the presence of the activators calcium, diacylglycerol, and phosphatidylserine; (ii) histone H1 after proteolytic activation of PKC with trypsin; and (iii) protamine in the absence of calcium and lipid. Within 1 min of TPA treatment of platelets, greater than 95% of the PKC activity was particulate associated, as assessed by all three methods. The particulate PKC activity from 1-min TPA-treated cells eluted from Mono Q with approximately 0.35 M NaCl (peak I), and it was highly dependent upon Ca2+ and lipid for optimal histone H1 phosphorylation. With longer exposure times of platelets to TPA, the disappearance of the Mono Q peak I form of PKC was correlated with the production of new PKC species that were released from Mono Q with approximately 0.4 M NaCl (peak II), approximately 0.5 M NaCl (peak III), and approximately 0.6 M NaCl (peak IV). These last forms of PKC were still lipid activated but exhibited little Ca2+ dependence. The Mono Q peak III form displayed a particularly high level of histone H1 phosphorylating activity in the absence of lipid and Ca2+. All of these forms behaved as approximately 65-kDa proteins on Superose 6/12, but on sodium dodecyl sulfate-polyacrylamide gels, Western blotting with anti-PKC-beta antibodies revealed immunoreactive polypeptides of approximately 79 kDa (Mono Q peaks I, II, and IV) and approximately 100-kDa (Mono Q peak III). Hydroxylapatite column chromatography permitted partial resolution of the Mono Q peaks I and II forms, which were eluted within a concentration range of potassium phosphate (100-150 mM) which was typical of the beta isozyme of PKC. Treatment of the Mono Q peak III and IV PKC forms with alkaline phosphatase resulted in the production of the peak I form, which implicated protein phosphorylation in the interconversion of the various PKC forms.


EMA401, an angiotensin II type 2 receptor antagonist blocks visceral hypersensitivity and colonic hyperpermeability in rat model of irritable bowel syndrome.
Visceral hypersensitivity and impaired gut barrier are crucial pathophysiology of irritable bowel syndrome (IBS), and injection of lipopolysaccharide or corticotropin-releasing factor, and repeated water avoidance stress simulate these gastrointestinal changes in rat (IBS models). We previously demonstrated that losartan, an angiotensin II type 1 (AT1) receptor antagonist prevented these changes, and we attempted to determine the effects of EMA401, an AT2 receptor antagonist in the current study. EMA401 blocked visceral hypersensitivity and colonic hyperpermeability in these models, and naloxone reversed the effects by EMA401. These results suggest that EMA401 may improve gut function via opioid signaling in IBS.


Extended release lipophilic indomethacin microspheres: formulation factors and mathematical equations fitted drug release rates.
Extended release liphophilic microspheres of indomethacin were prepared using cetostearyl alcohol (CsA), stearyl alcohol (SA) and cetyl alcohol (CA) in the various drug-lipid ratios. The release of indometacin was studied on the basis of USP criteria and the effects of drug-lipid ratio, the size of microspheres and carboxymethylcellulose sodium (CMC-Na) added as a hydrophilic polymer on the drug release were investigated. In vitro dissolution studies were performed using USP XXIII apparatus I at pH 6.2. Release profiles were evaluated according to first order, Higuchi square root of time and Hixson-Crowell cube root models. The best fit was found with the square root of time model (r2=0.991) for the microspheres (125-250 microm) prepared in 1:4:1 drug-lipid-copolymer ratio using stearyl alcohol. With a further regression analysis, an excellent equation (Release%=-10.721+42.549*square root of (t)-4.027*t) was developed for empirical drug estimation (r2=0.998).


Mitochondria and polarity in the egg ofSmittia spec. (Diptera, Chironomidae): UV irradiation, respiration measurements, ATP determination and application of inhibitors.
1) The development of the head end in the embryo ofSmittia is determined by cytoplasmic components in the anterior region of the egg. Experimental inactivation or removal of these determinants results in the formation of "double abdomens". In embryos with this aberrant metameric pattern, head and anterior segments are replaced by an additional set of posterior segments joined in mirror image symmetry to the original abdomen. Several types of experiment were carried out to determine whether mitochondria act as determinants of the anterior pole in the embryo. 2) The following observations are compatible with a determinative rôle of mitochondria: mitochondria are more abundant in the anterior tip of theSmittia egg which responds most effectively in experiments inducing double abdomens by local UV irradiation. UV irradiation inflicts visible damage upon mitochondria in the irradiated egg region, and significantly decreases the oxygen consumption of the eggs. 3) The following data argue against a determinative rôle of mitochondria: photoreverting treatment after UV irradiation did not cause a significant increase of oxygen uptake. The ATP content of whole eggs and anterior egg halves was significantly increased after UV irradiation of the anterior egg quarter. Localized application of dinitrophenol and ethidium bromide via puncture of the anterior pole, as well as irradiation with intense red light after sensitization of mitochondria with Janus Green B, did not produce double abdomens. 4) After UV irradiation during intravitelline cleavage, photoreverting treatment can be delayed for several hours without diminishing its efficiency; the deadline for photoreversal coincides perfectly with the deadline for UV induction, i.e. with blastoderm formation. This result suggests that the effective targets are metabolically inactive from egg-laying until blastoderm-formation. 5) The results are considered as evidence that mitochondria and the determinants of anterior pole in theSmittia embryo are not identical despite their apparently similar cellular localization.


Soil from a Hexachlorocyclohexane Contaminated Field Site Inoculates Wheat in a Pot Experiment to Facilitate the Microbial Transformation of β-Hexachlorocyclohexane Examined by Compound-Specific Isotope Analysis.
β-Hexachlorocyclohexane (β-HCH) is a remnant from former HCH pesticide production. Its removal from the environment gained attention in the last few years since it is the most stable HCH isomer. However, knowledge about the transformation of β-HCH in soil-plant systems is still limited. Therefore, experiments with a contaminated field soil were conducted to investigate the transformation of β-HCH in soil-plant systems by compound specific isotope analysis (CSIA). The results showed that the δ13C and δ37Cl values of β-HCH in the soil of the planted control remained stable, revealing no transformation due to a low bioavailability. Remarkably, an increase of the δ13C and δ37Cl values in soil and plant tissues of the spiked treatments were observed, indicating the transformation of β-HCH in both the soil and the plant. This was surprising as previously it was shown that wheat is unable to transform β-HCH when growing in hydroponic culture or garden soil. Thus, results of this work indicate for the first time that a microbial community of the soil inoculated the wheat and then facilitated the transformation of β-HCH in the wheat, which may have implications for the development of phytoremediation concepts. A high abundance of HCH degraders belonging to Sphingomonas sp., Mycobacterium sp., and others was detected in the β-HCH-treated bulk and rhizosphere soil, potentially supporting the biotransformation.


Driving appliances for upper limb amputees.
The advice given to upper limb amputees in the United Kingdom with regard to the use of driving appliances has often been somewhat variable. At best a full rehabilitation package has been provided, including the fitting of the appliances to the person's vehicle and contact with the driver's instructor, to the other extreme of issuing driving appliances to patients with no instruction at all. Though upper limb amputations are not a relevant or prospective disability, all drivers with a "limb disability" are legally required, in the UK, to declare changes in their physical state to the Driver and Vehicle Licensing Agency. This study examines the current usage of driving appliances. It was found that the level of upper limb loss has little effect on where the driving appliance is placed or on any other aspect of driving method used.


Regulation of apoptosis by BH3 domains in a cell-free system.
The Bcl-2 family of proteins plays a key role in the regulation of apoptosis. Some family members prevent apoptosis induced by a variety of stimuli, whereas others promote apoptosis. Competitive dimerisation between family members is thought to regulate their function. Homologous domains within individual proteins are necessary for interactions with other family members and for activity, although the specific mechanisms might differ between the pro-apoptotic and anti-apoptotic proteins. Using a cell-free system based on extracts of Xenopus eggs, we have investigated the role of the Bcl-2 homology domain 3 (BH3) from different members of the Bcl-2 family. BH3 domains from the pro-apoptotic proteins Bax and Bak, but not the BH3 domain of the anti-apoptotic protein Bcl-2, induced apoptosis in this system, as determined by the rapid activation of specific apoptotic proteases (caspases) and by DNA fragmentation. The apoptosis-inducing activity of the BH3 domains requires both membrane and cytosolic fractions of cytoplasm, involves the release of cytochrome c from mitochondria and is antagonistic to Bcl-2 function. Short peptides, corresponding to the minimal sequence of BH3 domains required to bind anti-apoptotic Bcl-2 family proteins, also trigger apoptosis in this system. The BH3 domains of pro-apoptotic proteins are sufficient to trigger cytochrome c release, caspase activation and apoptosis. These results support a model in which pro-apoptotic proteins, such as Bax and Bak, bind to Bcl-2 via their BH3 domains, inactivating the normal ability of Bcl-2 to suppress apoptosis. The ability of synthetic peptides to reproduce the effect of pro-apoptotic BH3 domains suggests that such peptides may provide the basis for engineering reagents to control the initiation of apoptosis.


New insights into molecular changes in skeletal muscle aging and disease: Differential alternative splicing and senescence.
Progressive loss of muscle mass and function due to muscle fiber atrophy and loss in the elderly and chronically ill is now defined as sarcopenia. It is a major contributor to loss of independence, disability, need of long-term care as well as overall mortality. Sarcopenia is a heterogenous disease and underlying mechanisms are not completely understood. Here, we newly identified and used Tmem158, alongside Cdkn1a, as relevant senescence and denervation markers (SDMs), associated with muscle fiber atrophy. Subsequent application of laser capture microdissection (LCM) and RNA analyses revealed age- and disease-associated differences in gene expression and alternative splicing patterns in a rodent sarcopenia model. Of note, genes exhibiting such differential alternative splicing (DAS) are mainly involved in the contractile function of the muscle. Many of these splicing events are also found in a mouse model for myotonic dystrophy type 1 (DM1), underscoring the premature aging phenotype of this disease. We propose to add differential alternative splicing to the hallmarks of aging.


Congenital adrenal calcifications as the first clinical indication of sphingosine lyase insufficiency syndrome: A case report and review of the literature.
Sphingosine Lyase Insufficiency Syndrome (SPLIS) or SGPL1 Deficiency is a newly described entity that is characterized by steroid-resistant nephrotic syndrome, primary adrenal insufficiency, lymphopenia, ichthyosis, and/or endocrine and neurologic abnormalities. The earliest identification of SGPL1 pathogenic variants in association with this syndrome was reported in 2017. Since then, at least 36 patients have been reported with this pediatric syndrome. Here, we report a new patient with SPLIS who had a prenatal finding of adrenal calcifications, congenital nephrotic syndrome, and abnormal newborn screening concerning for Severe Combined Immunodeficiency. We conclude that SPLIS is a clinically recognizable condition with prenatal onset. This case should increase awareness of SPLIS in the differential diagnosis for adrenal calcifications. We present a case on the severe end of the clinical spectrum of SPLIS, and a review of the literature.


Knee pain in people aged 80 years and older is not associated with gait parameter and functional performance.
We evaluated the differences in gait and functional performance between two groups of elderly people, one consisting of people between 65 and 79 years of age and the other consisting of people over 80 years of age. We analysed whether knee pain affected gait and looked at the functional performance of the timed 'up and go' (TUG) and functional reach (FR) tests. In 247 community-dwelling people aged 65 years and older, consisting of 90 men and 157 women with a mean age of 80 years (range 65-94 years), 47% had knee pain. Shorter stride, shorter step, slower speed, longer TUG and shorter FR were seen in the group aged 80 years and over compared with the group aged 65-79 years. Knee pain was associated with TUG, especially in the group aged 65-79 years. In the group aged 65-79 years with knee pain, a shorter stride and step length, a longer time required to hold a double stance, a slower walking speed and a longer TUG were shown. However, in the group aged 80 years and over, there was no significant difference between participants with and without knee pain for these parameters.


A novel immunohistochemical technique for the detection of human oral carcinomas transplanted in nude mice using mouse monoclonal antibodies.
We have developed a new immunostaining technique specifically for the detection of human tumors transplanted into nude mice using mouse monoclonal antibodies (MoAbs) produced in our laboratory. The formation of a molecular complex consisting of three components (mouse MoAb or hybridoma supernatant, biotin-labeled anti-mouse immunoglobulins, and normal nude mouse serum) markedly reduced background staining and enhanced specific reaction with the transplanted tumors in nude mice. When MoAb production by electrofusion was screened with this new method, the incidence of hybridoma supernatant reactive with sections of transplanted tumor was 2.3 per 100 wells immunostained. These results suggest that production of MoAbs using transplanted tumors is immunohistochemically possible and that this method may provide a new means for developing useful tumor markers.


[Ultrastructure of the nasal mucosa cilia in the Kartagener syndrome].
The authors draw the attention on the existence of an "Immotile-cilia Syndrome" in patients with chronic respiratory infections of unknown origin. The study of the ultra structure of the ciliae (TEM, SEM) in a case of Kartagener Syndrome supports the existence of an "Immotile-cilia Syndrome".


Posterior urethral valves diagnosed by bedside ultrasound in the ED.
Posterior urethral valves are the most common cause of urinary obstruction in male children. Presentations of posterior urethral valves beyond the neonatal period include urinary tract infection, abdominal mass, renal failure,diminished urinary stream, crying during micturition,incontinence, dysuria, hematuria, or failure to thrive. Early diagnosis is imperative because early surgical relief of the obstruction is believed to help prevent the progression to endstage renal disease.This case serves to remind us that, in the male child who presents with urinary symptoms and/or abdominal symptoms,the bedside sonogram is a valuable tool that can clarify the diagnosis and expedite care.


The coronary sinus conduit function: anatomical study (relationship to adjacent structures).
The mitral valve annulus (MVA) is anchored antero-medially to the aorta. Dilatation of the MVA primarily affects its postero-lateral aspect, which is related to the coronary sinus (CS). The CS and its tributaries have been used for pacing the left ventricle in patients with intractable heart failure. The aim of this study was to determine anatomical relations between the CS and its adjacent structures in 40 adult normal cadaveric heart specimens. In 32 specimens, longitudinal sections were made along the free circumference of the MVA in 6 separate regions, 36 degrees between each, with the 0 degree marked by a line joining the centre of the CS ostium and that of the MV. In each section, the relations of the CS to the circumflex artery and the MVA were determined. CS diameter and its distance from the endocardium, just below the MVA, were also measured by a digital calliper. The great cardiac vein (GCV) diameter is 5.6 +/- 1.6 mm. As it leaves the interventricular groove, it curves to the left forming the base of the triangle of "Brocq and Mouchet" with the two branches of the left coronary artery, having a triple relationship with the circumflex artery. It then continues as the CS (diameter 9.3 +/- 5.3 mm) in the inferior atrioventricular groove. The end part of the GCV crosses superficial to the left circumflex artery at the level of the left marginal vein. The shortest distance between the wall of the CS and the endocardium adjacent to the MVA at the level of the anterolateral commissure is 5.2 +/- 1.6 mm, i.e. beyond the Vieussens valve. Thus, together with the CS the great cardiac vein, form a semicircular venous channel at the postero-lateral aspect of the MVA. In 37/40 hearts, this venous channel arches upwards in its middle part to be in direct contact with the left atrium. This study demonstrates an intimate proximity between the coronary sinus, at its beginning and end, and the mitral valve annulus. It also highlights the close relationship between the great cardiac vein, the annulus and the left ventricular free wall. Assessing the same relationship using the currently available imaging techniques should aid in the successful cannulation of the coronary sinus for various cardiological interventions.


Wecomedon Jarrett & Bousfield, 1982, a replacement name for the amphipod genus Psammonyx Bousfield, 1973 (Crustacea, Amphipoda, Tryphosidae), preoccupied by Psammonyx Döderlein, 1892 (Foraminifera, Astrorhizida, Ammovolummidae).
Wecomedon Jarrett & Bousfield, 1982 is reintroduced as a replacement name for Psammonyx Bousfield, 1973 (Crustacea: Amphipoda: Tryphosidae) which is a junior homonym of Psammonyx Döderlein, 1892 (Foraminifera: Astrorhizida: Ammovolummidae).


Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity.
Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aβ levels and Aβ half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aβ clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aβ metabolism and defining a potential new therapeutic target in AD.


Evaluation of the acute toxicity of perfluorinated carboxylic acids using eukaryotic cell lines, bacteria and enzymatic assays.
The acute biological activity of a homologous series of perfluorinated carboxylic acids - perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) - was studied. To analyze the potential risk of the perfluorinated acids to humans and the environment, different in vitro toxicity test systems were employed. The cytotoxicity of the chemicals towards two different types of mammalian cell lines and one marine bacteria was investigated. The viability of cells from the promyelocytic leukemia rat cell line (IPC-81) and the rat glioma cell line (C6) was assayed calorimetrically with WST-1 reagent. The evaluation was combined with the Vibrio fischeri acute bioluminescence inhibition assay. The biological activity of the compounds was also determined at the molecular level with acetylcholinesterase and glutathione reductase inhibition assays. This is the first report of the effects of perfluorinated acids on the activity of purified enzymes. The results show these compounds have a very low acute biological activity. The observed effective concentrations lie in the millimole range, which is well above probable intracellular concentrations. A relationship was found between the toxicity of the perfluorinated carboxylic acids and the perfluorocarbon chain length: in every test system applied, the longer the perfluorocarbon chain, the more toxic was the acid. The lowest effective concentrations were thus recorded for perfluorononanoic and perfluorodecanoic acids.


Respiratory neuroplasticity: Mechanisms and translational implications of phrenic motor plasticity.
Widespread appreciation that neuroplasticity is an essential feature of the neural system controlling breathing has emerged only in recent years. In this chapter, we focus on respiratory motor plasticity, with emphasis on the phrenic motor system. First, we define related but distinct concepts: neuromodulation and neuroplasticity. We then focus on mechanisms underlying two well-studied models of phrenic motor plasticity: (1) phrenic long-term facilitation following brief exposure to acute intermittent hypoxia; and (2) phrenic motor facilitation after prolonged or recurrent bouts of diminished respiratory neural activity. Advances in our understanding of these novel and important forms of plasticity have been rapid and have already inspired translation in multiple respects: (1) development of novel therapeutic strategies to preserve/restore breathing function in humans with severe neurological disorders, such as spinal cord injury and amyotrophic lateral sclerosis; and (2) the discovery that similar plasticity also occurs in nonrespiratory motor systems. Indeed, the realization that similar plasticity occurs in respiratory and nonrespiratory motor neurons inspired clinical trials to restore leg/walking and hand/arm function in people living with chronic, incomplete spinal cord injury. Similar application may be possible to other clinical disorders that compromise respiratory and non-respiratory movements.