Antibiotic Prescriptions Targeting Bacterial Respiratory Infections in Admitted Patients with COVID-19: A Prospective Observational Study.
Although bacterial co- and superinfections are rarely present in patients with COVID-19, overall antibiotic prescribing in admitted patients is high. In order to counter antibiotic overprescribing, antibiotic stewardship teams need reliable data concerning antibiotic prescribing in admitted patients with COVID-19. In this prospective observational cohort study, we performed a quantitative and qualitative evaluation of antibiotic prescriptions in patients admitted to the COVID-19 ward of a 721-bed Belgian university hospital between 1 May and 2 November 2020. Data on demographics, clinical and microbiological parameters and antibiotic consumption were collected. Defined daily doses (DDD) were calculated for antibiotics prescribed in the context of a (presumed) bacterial respiratory tract infection and converted into two indicators: DDD/admission and DDD/100 hospital bed days. A team of infectious disease specialists performed an appropriateness evaluation for every prescription. A driver analysis was performed to identify factors increasing the odds of an antibiotic prescription in patients with a confirmed COVID-19 diagnosis. Of 403 eligible participants with a suspected COVID-19 infection, 281 were included. In 13.8% of the 203 admissions with a COVID-19 confirmed diagnosis, antibiotics were initiated for a (presumed) bacterial respiratory tract co-/superinfection (0.86 DDD/admission; 8.92 DDD/100 bed days; 39.4% were scored as 'appropriate'). Five drivers of antibiotic prescribing were identified: history of cerebrovascular disease, high neutrophil/lymphocyte ratio in male patients, age, elevated ferritin levels and the collection of respiratory samples for bacteriological analysis. In the studied population, the antibiotic consumption for a (presumed) bacterial respiratory tract co-/superinfection was low. In particular, the small total number of DDDs in patients with confirmed COVID-19 diagnosis suggests thoughtful antibiotic use. However, antibiotic stewardship programmes remain crucial to counter unnecessary and inappropriate antibiotic use in hospitalized patients with COVID-19. The study is registered at ClinicalTrials.gov (NCT04544072).


Young Adults' Hopes Regarding Noncommunicable Disease (NCD) Prevention and Management After the SARS-CoV-2 Virus Pandemic: Reflections From the NCD Child #YouthCOVIDCHAT Campaign.
The SARS-CoV-2 virus pandemic has left a massive global death toll in its wake. Associated restrictions, precautions and lockdowns have disrupted daily routines, which has been associated with social isolation and major health implications for the world's youth. This paper shares young adults' visions for life beyond the pandemic as it relates to the prevention and management of noncommunicable diseases (NCDs). NCD Child hosted a global Twitter campaign for young adults, some of whom are living with NCDs, to express their reflections on life beyond the pandemic. Contributions were subjected to qualitative thematic analysis. 52 responses from the campaign described six main themes: Health system strengthening; Access to care; Issues of sustainability, including the environment and the economy; Human rights, equity, and social issues; Mental health, and NCD prevention. Young adults expressed optimism about postpandemic life and emphasized the importance of comprehensive intersectoral approaches to create resilient health systems.


Estimation of volume density of interdental papilla components in patients with chronic periodontitis and interleukin-6 (-174G/C) gene polymorphisms.
The association between interleukin-6 (IL-6) (-174G/C) gene polymorphisms and level of tissue breakdown and periodontal disease progression is unknown. The present study investigated quantitative parameters of interdental papilla in chronic periodontitis (CP) patients with IL-6 (-174G/C) gene polymorphisms. Sixty gingival samples were studied. After determination of IL-6 (-174G/C) gene polymorphisms using a tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) technique, 45 gingival tissue samples of CP patients (GG and GC+CC genotypes) were considered as case groups. Fifteen control samples were also collected from healthy individuals. After tissue processing, interdental gingival tissues were exhaustively sectioned into 4 μm-thick sections. Ten to thirteen sections were sampled by systematic uniform random sampling and stained with Masson trichrome, and the volume density (Vv) of the gingival components was estimated using Cavalier's point counting method. Statistical analysis was performed by Student t-test to compare differences between groups. The significance level was set at P < 0.05. There were statistically significant differences in the Vv of epithelium, connective tissue, collagenous and non-collagenous matrix, and blood vessels between the control and CP groups (P < 0.0001). There were no statistically significant differences in the Vv of epithelium, connective tissue of gingiva, collagenous and non-collagenous matrix, and blood vessels among GG, GC, and CC genotypes in CP patients (P > 0.05). Results of the current study showed that there was no association between IL-6 (-174G/C) gene polymorphisms and quantitative parameters of interdental papilla in CP patients.


Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives.
The mitochondria are directly involved in cell survival and death. Drugs that protect mitochondria viability and prevent apoptotic cascade mechanisms involved in mitochondrial permeability transition pore (MPTp) will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor, anti-Parkinson drug. Unlike selegiline, rasagiline is not derived from amphetamine, is not metabolized to neurotoxic l-methamphetamine derivative, nor does it have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to L-dopa for patients with early and late Parkinson's disease (PD), and adverse events do not occur with greater frequency in subjects receiving rasagiline than those on placebo. Controlled studies indicate that it might have a disease-modifying effect in PD that may be related to neuroprotection. Its S-isomer, TVP1022, is a relatively inactive MAO inhibitor. However, both drugs have similar neuroprotective activities in neuronal cell cultures in response to various neurotoxins and in vivo (global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a pre-requisite for neuroprotection. Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase. The neuroprotective activity of propargylamine has led us to develop novel bifunctional neuroprotective iron-chelating MAO-inhibiting drugs possessing propargyl moiety for the treatment of other neurodegenerative diseases.


From a sequential pattern, temporal adjustments emerge in hummingbird traplining.
Animals that feed from resources that are constant in space and that refill may benefit from repeating the order in which they visit locations. This is a behavior known as traplining, a spatial phenomenon. Hummingbirds, like other central-place foragers, use short traplines when moving between several rewarding sites. Here we investigated whether traplining hummingbirds also use relevant temporal information when choosing which flowers to visit. Wild rufous hummingbirds that were allowed to visit 3 artificial flower patches in which flowers were refilled 20 min after they had been depleted repeated the order in which they visited the 3 patches. Although they tended to visit the first 2 patches sooner than 20 min, they visited the third patch at approximately 20-min intervals. The time between visits to the patches increased across the experiment, suggesting that the birds learned to wait longer before visiting a patch. The birds appeared to couple the sequential pattern of a trapline with temporal regularity, to some degree. This suggests that there is a temporal component to the repeated spatial movements flown by foraging wild hummingbirds.


Effects of macromolecular crowding on the association of E. coli ribosomal particles.
The equilibrium for the binding reaction between the 30 S and 50 S ribosomal subunits of E. coli is shifted towards formation of 70 S ribosomes in the presence of a variety of polymers. The polymers also increase a further interaction between 70 S particles to form the 100 S dimer. The requirement for relatively high concentrations of non-specific polymers indicates that the shifts in equilibria arise from excluded volume effects. Analysis using scaled particle theory is consistent with this mechanism. The effects of high concentrations of polymers on the interactions between ribosomal species may make important changes in the function of ribosomes under the crowded conditions which occur in vivo.


Application of color Doppler ultrasound in the study of small pleural effusion.
To compare the results of gray scale ultrasound with those of color Doppler ultrasound in order to evaluate the minimal pleural effusion and to differentiate the minimal pleural effusion from pleural thickening. We prospectively analyzed 86 patients who, according to their chest radiographs, were suspected of having minimal pleural effusion. All patients were examined by ultrasonography on gray scale and color Doppler and the presence or absence of pleural effusion was confirmed by thorax CT. Using the color Doppler examination we analyzed the fluid color sign of pleural effusion. In our study, the ultrasonography on gray scale in real time detected pleural effusion with 60% specificity, 100% sensitivity and 88.37% accuracy. By applying the color Doppler the specificity of the method is higher (specificity 100%, sensitivity 96.72% and accuracy 97.57%). The evidence of pleural effusion on grayscale ultrasound has a greater sensitivity than that of color Doppler ultrasound, but has a smaller specificity. Therefore, color Doppler ultrasound proved to be a useful diagnostic aid in gray-scale ultrasound for the assessment of minimal effusion, having the highest accuracy.


A magnetic resonance (MR) microscopy system using a microfluidically cryo-cooled planar coil.
We present the development of a microfluidically cryo-cooled planar coil for magnetic resonance (MR) microscopy. Cryogenically cooling radiofrequency (RF) coils for magnetic resonance imaging (MRI) can improve the signal to noise ratio (SNR) of the experiment. Conventional cryostats typically use a vacuum gap to keep samples to be imaged, especially biological samples, at or near room temperature during cryo-cooling. This limits how close a cryo-cooled coil can be placed to the sample. At the same time, a small coil-to-sample distance significantly improves the MR imaging capability due to the limited imaging depth of planar MR microcoils. These two conflicting requirements pose challenges to the use of cryo-cooling in MR microcoils. The use of a microfluidic based cryostat for localized cryo-cooling of MR microcoils is a step towards eliminating these constraints. The system presented here consists of planar receive-only coils with integrated cryo-cooling microfluidic channels underneath, and an imaging surface on top of the planar coils separated by a thin nitrogen gas gap. Polymer microfluidic channel structures fabricated through soft lithography processes were used to flow liquid nitrogen under the coils in order to cryo-cool the planar coils to liquid nitrogen temperature (-196 °C). Two unique features of the cryo-cooling system minimize the distance between the coil and the sample: (1) the small dimension of the polymer microfluidic channel enables localized cooling of the planar coils, while minimizing thermal effects on the nearby imaging surface. (2) The imaging surface is separated from the cryo-cooled planar coil by a thin gap through which nitrogen gas flows to thermally insulate the imaging surface, keeping it above 0 °C and preventing potential damage to biological samples. The localized cooling effect was validated by simulations, bench testing, and MR imaging experiments. Using this cryo-cooled planar coil system inside a 4.7 Tesla MR system resulted in an average image SNR enhancement of 1.47 ± 0.11 times relative to similar room-temperature coils.


[Geometry of eccentric vascular stenoses in various projections--significance for angiographic assessment of the degree of stenosis, especially using digital subtraction angiography].
A mathematical model is used to predict the angiographic appearance of plaque-like lesions and eccentric vascular stenoses. The virtual stenotic areas and the degree of stenosis are calculated for different projection angles varying between 0 degree--x-ray beam tangential to the lesion--and 90 degrees--x-ray beam incidental to the lesion. Eccentric stenoses are underestimated if the lesion is not tangential to the x-ray beam. Eccentric stenoses can be overestimated if automated programmes are based on a circular configuration of both the normal and the stenotic lumens. In this model the best estimation is obtained if the stenotic lumen is assumed to be elliptic, and if biplane rectangular projections are available.


Multiple myeloma: a paradigm for translation of the cancer stem cell hypothesis.
Despite recent advances in drug development, multiple myeloma (MM) remains incurable for the majority of patients due to relapse and disease progression. The cancer stem cell (CSC) hypothesis may provide an explanation for these clinical findings. It suggests that the long-term proliferative potential responsible for disease initiation, maintenance, and relapse is contained within specific subpopulations of biologically distinct tumor cells. Data in MM suggest that CSCs represent a rare cell population phenotypically resembling normal memory B cells. Compared to MM plasma cells, MM CSCs also appear to be relatively resistant to a wide variety of standard anti-cancer agents suggesting they may persist following treatment and mediate tumor re-growth and relapse. A unique property CSCs share with their normal counterparts is the potential for self-renewal that likely maintains the malignant clone over time. The development of therapeutic strategies targeting the signaling elements contributing to cancer cell self-renewal has been limited primarily because the cellular processes involved are poorly understood. However, it is common that the signaling pathway components regulating normal stem cell self-renewal are aberrantly activated in human cancers and may serve as potential therapeutic targets. One class of shared regulatory pathways are those active during normal embryonic patterning and organ formation such as Hedgehog (Hh), Notch and Wingless (Wnt), and emerging data suggest that these may play a role in CSCs. Here we review the identification and characterization of MM CSCs, the role of Hh in MM, and issues to be considered during the early clinical testing of CSC targeting agents.


European Sero-Epidemiology Network 2: standardisation of immunoassay results for pertussis requires homogeneity in the antigenic preparations.
A standardisation process, already developed during the earlier European Sero-Epidemiology Network (ESEN) project, was employed with a more robust algorithm to harmonise results of pertussis serological assays performed in 12 European and non-European countries. Initially, results from each country's own assay were compared with those obtained at the reference laboratory by means of an in-house pertussis toxin (PT)-based ELISA: seven countries used in-house or commercial PT-ELISAs; the other countries used assays based on Bordetella pertussis whole cell extracts (WCE) (three countries) or on combined PT-FHA (filamentous haemagglutinin) antigenic preparations (two countries). The WCE assays, although admitted for diagnostic purposes, confirmed their low correlation with the PT-ELISAs and their results could not be used for standardisation; the PT-FHA ELISAs gave results that were suitable for standardisation in one country but unsatisfactory in the other; the use of purified PT in serological assays confirmed its better reliability than other preparations and all PT-ELISAs results could be calibrated against those of the reference centre. In the standardisation process two high-titre cut-offs indicative of likelihood of recent infection (from within 4 weeks of disease onset up to 1 year after) were included for evaluations as they are suggested to be more useful, for the sero-epidemiological assays of immunity to pertussis, than the cut-off of protection, commonly employed, but still not defined for pertussis. Providing PT-ELISAs are used, standardisation of pertussis assay results is always possible and, when standardisation is performed, evaluation and comparison of the impact of different interventions can be also allowed, by measuring at the distribution of high antibody titres in the populations.


It's Your Game-Tech: Toward Sexual Health in the Digital Age.
Adolescent sexually transmitted infection (STI) and birth rates indicate a need for effective middle school HIV/STI, and pregnancy prevention curricula to delay, or mitigate consequences of, early sexual activity. Individual and organizational barriers to adoption, implementation, and maintenance, however, can hamper dissemination of evidence-based sexual health curricula, adversely impacting fidelity and reach. Internet-based approaches may help mitigate these barriers. This paper describes the development and feasibility testing of It's Your Game (IYG)-Tech, a stand-alone 13-lesson Internet-based sexual health life-skills curriculum adapted from an existing effective sexual health curriculum-It's Your Game… Keep it Real (IYG). IYG-Tech development adaptation steps were to: 1) Select a suitable effective program and gather the original program materials; 2) Develop "proof of concept" lessons and test usability and impact; 3) Develop the program design document describing the core content, scope, and methods and strategies; and 4) produce the new program. Lab- and school-based tests with middle school students demonstrated high ratings on usability parameters and immediate impact on selected psychosocial factors related to sexual behavior-perceptions of friends' beliefs, reasons for not having sex, condom use self-efficacy, abstinence intentions, negotiating with others to protect personal rules, and improved knowledge about what constitutes healthy relationships (all p < .05). Youth rated IYG-Tech is favorably compared to other learning channels (>76.2% agreement) and rated the lessons as helpful in making healthy choices, selecting personal rules, detecting challenges to those rules, and protecting personal rules through negotiation and refusal skills (89.5% - 100%). Further efficacy testing is indicated for IYG-Tech as a potential strategy to deliver effective HIV/STI, and pregnancy prevention to middle school youth.


Accurate Sex Identification of Ancient Elephant and Other Animal Remains Using Low-Coverage DNA Shotgun Sequencing Data.
Sex identification of ancient animal biological remains can benefit our understanding of historical population structure, demography and social behavior. Traditional methods for sex identification (e.g., osteological and morphometric comparisons) may be ineffective when animal remains are not well preserved, when sex distinguishing characteristics have not yet developed, or where organisms do not exhibit sex-associated phenotypic dimorphisms. Here we adapt a method developed for human sex determination so that it can be used to identify the sex of ancient and modern animal taxa. The method identifies sex by calculating the ratio of DNA reads aligning to the X chromosome to DNA reads aligning to autosomes (termed the Rx ratio). We tested the accuracy of this method using low coverage genomes from 15 modern elephants (Loxodonta africana) for which sex was known. We then applied this method to ancient elephant ivory samples for which sex was unknown, and describe how this method can be further adapted to the genomes of other taxa. This method may be especially useful when only low-coverage genomic data are obtainable. Furthermore, because this method relies on only the X and not the Y chromosome, it can be used to determine the sex of organisms for which a reference genome was obtained from a female or for which only the X chromosome is reported. Such taxa include the domestic cat, sheep, goat, and horse; and non-domesticated animals such as the Sumatran orangutan, western lowland gorilla and meerkat.


[Splenic rupture and anticoagulant therapy].
Splenic rupture associated with anticoagulant therapy is a rare entity. We report a case of spontaneous splenic rupture in a 62-year-old man who was treated by acenocoumarol orally after an aortic-valve replacement. Unrecognised, minor trauma may lead to splenic haemorrhage in patients receiving anticoagulant therapy. The symptoms and signs may mimic those of acute myocardial infarction and cardiogenic shock. Early diagnosis is essential. Reversal of the anticoagulant and emergent splenectomy are the treatments of choice.


Inhibitor resistance and in situ capability of nanoparticle based gene quantification.
We have demonstrated the preliminary results of the in situ monitoring capability of an inhibitor resistant gene quantification assay using magnetic bead (MB) and quantum dot (QD) nanoparticles (hereafter "MB-QD assay") for the detection of E. coli O157:H7 in environmental samples. The selectivity of the MB-QD assay was demonstrated via the discrimination of the target bacteria in the presence of nonspecific microbial populations. The effect of temperature on the assay was examined to evaluate the necessity of elevated temperature incubation. The reagents (i.e., particle complex and particle-DNA conjugate) were also shown to have a stability of at least 10 days without refrigeration, therefore enabling prior preparation and the subsequent storage of these reagents. In addition, it was found that the MB-QD assay was resistant to the presence of naturally occurring inhibitors (i.e., humic acids, Ca(2+)) and residual reagents from DNA extraction (i.e., surfactant, ethanol). Overall the results indicated that the MB-QD assay is potentially suitable for further development as an in situ bacteria monitoring method for working with inhibitor laden samples without requiring additional purification steps and elevated temperature processes.


Effect of Reflexology on the Constipation Status of Elderly People.
The current literature shows that one of the alternative therapies used to control constipation is reflexology. This study was conducted to assess the effect of reflexology on the constipation status of elderly people. This study was randomized clinical trial conducted from at the private nursing home in the Ankara Province. At the nursing home, 60 eligible elderly people were randomly assigned into experimental (n = 30) and control (n = 30) groups. The experimental group received foot reflexology massage for 1 month three times per week for 30 min. Reflexology was initiated from the patient's right foot. The foot was relaxed primarily by applying effleurage followed by shaking, rotation, and stretching methods. The practice ended by applying solar plexus pressure on both feet. For elderly people in the control group foot surface massage without pressure was applied to simulate the interventions similar to the experimental group. The scale scores before and after reflexology were noted for the experimental group, and those for the control group, which did not receive any reflexology massage, were also determined. After the implementation of reflexology, the rate of emptying bowels on alternate days increased in the experimental group as opposed to that in the control group (P < 0.001). In this study, reflexology was found to improve the quality of life of the elderly and decrease the severity of constipation. Foot reflexology massage was found to be effective in relieving the constipation of elderly people. Therefore, reflexology is recommended as part of nursing care to reduce the constipation status of elderly people.


Changes in the Ca2+-activation characteristics of demembranated rat single muscle fibres after prolonged incubation at room temperature in the presence and absence of DTT and protease inhibitors.
Prolonged incubation (24 h) of chemically skinned rat muscle preparations in rigor solutions at room temperature and in the absence of reducing agents and protease inhibitors modified the Ca2+-activation characteristics of the contractile machinery. In the absence of reducing agents and protease inhibitors, the contraction threshold for incubated fibres was shifted to lower Ca2+ concentrations and the steepness of the steady-state force-pCa (-log10)[Ca2+]) curve was decreased compared to that of control muscle fibres. Mean myosin ATPase activity under these conditions was significantly lowered by a factor of 2.7. Fibres incubated in the presence of 10 mM dithiothreitol (DTT) and protease inhibitors (100 microM pepstatin A/200 microM leupeptin) produced a maximum Ca2+-activated force per cross-sectional area that compared favourably with that of freshly dissected muscle fibres and there were no changes in the other contractile activation characteristics. Intermediate responses were obtained when fibres were incubated in the presence of either DTT or protease inhibitors. MgATPase activities of incubated preparations increased significantly following the addition of protease inhibitors and/or DTT to the incubation medium. Taken together, these results suggest that in the presence of DTT and protease inhibitors, most contractile properties are maintained at levels seen in fresh mechanically skinned fibres. The extended viability of this preparation and its closely related properties with fresh muscle fibres make it a useful model for experiments requiring longer term incubations with biological agents.


Active particles bound by information flows.
Self-organization is the generation of order out of local interactions. It is deeply connected to many fields of science from physics, chemistry to biology, all based on physical interactions. The emergence of collective animal behavior is the result of self-organization processes as well, though they involve abstract interactions arising from sensory inputs, information processing, storage, and feedback. Resulting collective behaviors are found, for example, in crowds of people, flocks of birds, and swarms of bacteria. Here we introduce interactions between active microparticles which are based on the information about other particle positions. A real-time feedback of multiple active particle positions is the information source for the propulsion direction of these particles. The emerging structures require continuous information flows. They reveal frustrated geometries due to confinement to two dimensions and internal dynamical degrees of freedom that are reminiscent of physically bound systems, though they exist only as nonequilibrium structures.


Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1).
Proliferation and apoptosis are increased in many types of inflammatory diseases. A role for the cyclin kinase inhibitor p27(Kip1) (p27) in limiting proliferation has been shown. In this study, we show that p27(-/-) mesangial cells and fibroblasts have strikingly elevated rates of apoptosis, not proliferation, when deprived of growth factors. Apoptosis was rescued by restoration of p27 expression. Cyclin A-cyclin-dependent kinase 2 (CDK2) activity, but not cyclin E-CDK2 activity, was increased in serum-starved p27(-/-) cells, and decreasing CDK2 activity, either pharmacologically (Roscovitine) or by a dominant-negative mutant, inhibited apoptosis. Our results show that a new biological function for the CDK inhibitor p27 is protection of cells from apoptosis by constraining CDK2 activity. These results suggest that CDK inhibitors are necessary for coordinating the cell cycle and cell-death programs so that cell viability is maintained during exit from the cell cycle.


Cementless fixation in Oxford unicompartmental knee replacement: a multicentre study of 1000 knees.
The Cementless Oxford Unicompartmental Knee Replacement (OUKR) was developed to address problems related to cementation, and has been demonstrated in a randomised study to have similar clinical outcomes with fewer radiolucencies than observed with the cemented device. However, before its widespread use it is necessary to clarify contraindications and assess the complications. This requires a larger study than any previously published. We present a prospective multicentre series of 1000 cementless OUKRs in 881 patients at a minimum follow-up of one year. All patients had radiological assessment aligned to the bone-implant interfaces and clinical scores. Analysis was performed at a mean of 38.2 months (19 to 88) following surgery. A total of 17 patients died (comprising 19 knees (1.9%)), none as a result of surgery; there were no tibial or femoral loosenings. A total of 19 knees (1.9%) had significant implant-related complications or required revision. Implant survival at six years was 97.2%, and there was a partial radiolucency at the bone-implant interface in 72 knees (8.9%), with no complete radiolucencies. There was no significant increase in complication rate compared with cemented fixation (p = 0.87), and no specific contraindications to cementless fixation were identified. Cementless OUKR appears to be safe and reproducible in patients with end-stage anteromedial osteoarthritis of the knee, with radiological evidence of improved fixation compared with previous reports using cemented fixation.


A deep learning-based model for screening and staging pneumoconiosis.
This study aims to develop an artificial intelligence (AI)-based model to assist radiologists in pneumoconiosis screening and staging using chest radiographs. The model, based on chest radiographs, was developed using a training cohort and validated using an independent test cohort. Every image in the training and test datasets were labeled by experienced radiologists in a double-blinded fashion. The computational model started by segmenting the lung field into six subregions. Then, convolutional neural network classification model was used to predict the opacity level for each subregion respectively. Finally, the diagnosis for each subject (normal, stage I, II, or III pneumoconiosis) was determined by summarizing the subregion-based prediction results. For the independent test cohort, pneumoconiosis screening accuracy was 0.973, with both sensitivity and specificity greater than 0.97. The accuracy for pneumoconiosis staging was 0.927, better than that achieved by two groups of radiologists (0.87 and 0.84, respectively). This study develops a deep learning-based model for screening and staging of pneumoconiosis using man-annotated chest radiographs. The model outperformed two groups of radiologists in the accuracy of pneumoconiosis staging. This pioneer work demonstrates the feasibility and efficiency of AI-assisted radiography screening and diagnosis in occupational lung diseases.


Pre-Conceptional Exposure to Glyphosate Affects the Maternal Hepatic and Ovarian Proteome.
Exposure to glyphosate (GLY), a commonly used herbicide, is supported by urinary detection and associated with shortened gestation in women. This study tested the hypothesis that chronic low-dose pre-conceptional GLY exposure would affect maternal ovarian function mid- and post-gestation. Mice (C57BL/6; n = 40) were exposed per os to saline vehicle control (CT; n = 20) or GLY (2 mg/kg; n = 20) daily for 10 weeks starting at 7 weeks of age. Post-exposure, females were impregnated and euthanized at gestation day 14 (GD14) or post-weaning (PW). Pregnancy success was reduced from 75% to 55% by GLY exposure. No treatment effect (p > .05) on body weight, maternal serum 17β-estradiol, or litter size was noted. Ovarian weight was unaffected or reduced (p < .05) by GLY in GD14 and PW dams, respectively. Exposure to GLY decreased (p < .05) PW ovarian secondary follicle number with no other follicle composition impacts. Protein abundance analysis by LC-MS/MS identified that GLY altered (p < .05) 26 ovarian and 41 hepatic proteins in GD14 dams and 39 hepatic proteins in PW dams. In GD14 dams, GLY increased ovarian protein abundance of SEC16A (p < .05; 29-fold) and hepatic RPS27L and GM4952 (p < .05; ∼4-fold). In both GD14 and PW dams, GLY exposure increased (p < .05) hepatic RPS4 and decreased (p < .05) ECHDC3. Pathway analysis using DAVID identified 10 GLY hepatic pathway targets with FDR ≤ 0.07 in GD14 dams.


Nociceptin/orphanin FQ modulation of rat midbrain dopamine neurons in primary culture.
Previous microdialysis studies have identified a suppressive effect of the novel opioid peptide nociceptin (also known as orphanin FQ) on dopamine release from mesolimbic neurons. In order to further evaluate the locus of this action, we investigated nociceptin's action in an in vitro model system, namely midbrain dopamine neurons in primary culture. Immunohistochemical analysis revealed abundant tyrosine hydroxylase- and GABA-immunoreactive neurons, with a strong correlation between tyrosine hydroxylase content and basal endogenous dopamine release. Nociceptin (0.01-100 nM) suppressed basal dopamine release by up to 84% (EC50=0.65 nM). This action was reversible by drug removal and attenuated by co-application of the non-peptidergic ORL1 antagonist, Compound B. Nociceptin had no significant effect on dopamine release evoked by direct depolarization of the terminals with elevated extracellular K+, suggesting that nociceptin suppresses dopamine release by modulating the firing rate of the dopamine neurons. Nociceptin also suppressed GABA release from the cultures (45% maximal inhibition; EC50=1.63 nM). Application of the GABA-A antagonist, bicuculline, elevated extracellular dopamine concentrations but the dopamine release inhibiting property of nociceptin persisted in the presence of bicuculline. The NMDA receptor antagonist, D(-)-2-amino-5-phosphononpentanoic acid (AP-5) had no effect on basal dopamine release and failed to modify nociceptin's inhibitory effects. Thus, nociceptin potently modulates dopamine release from midbrain neurons most likely as a result of a direct suppression of dopamine neuronal activity.


[A case of malignant fibrous histiocytoma occurring in the retroperitoneum with giant pyonephrosis].
A case of malignant fibrous histiocytoma (MFH) occurring in th retroperitoneum with giant pyonephrosis is reported. The patient was a 45-year-old male and his chief complaint was an abdominal mass. The abdominal fullness progressed so rapidly that he was admitted to our hospital. After examination, this case was diagnosed as a malignant tumor with left hydronephrosis, and an operation was performed on August 5, 1982. At operation, the left kidney contained about 11,000 ml of a pus-like fluid and in the retroperitoneum was found a hen-egg-sized solid tumor which was invading into the left kidney and the feeding vessels of the descending colon. So the tumor, left kidney and a part of the descending colon were resected en bloc. Pathological diagnosis was malignant fibrous histiocytoma. Chemotherapy (PPM regimen) and immunotherapy (OK-432) were administered after the operation, but multiple metastases appeared in the liver and bilateral lungs within 3 months. Then, the CY-VA-DIC regimen was followed. But, local recurrence was found in about 5 months, and the patient died on the 174 th day after the operation. Local recurrence and metastases in the liver, bilateral lungs, pleura and bones were confirmed at autopsy. Besides our case, a review of case reports of retroperitoneal MFH in Japan and comments are presented.


Polarity reversal lowers activation time during diastolic field stimulation of the rabbit ventricles: insights into mechanisms.
To fully characterize the mechanisms of defibrillation, it is necessary to understand the response, within the three-dimensional (3D) volume of the ventricles, to shocks given in diastole. Studies that have examined diastolic responses conducted measurements on the epicardium or on a transmural surface of the left ventricular (LV) wall only. The goal of this study was to use optical imaging experiments and 3D bidomain simulations, including a model of optical mapping, to ascertain the shock-induced virtual electrode and activation patterns throughout the rabbit ventricles following diastolic shocks. We tested the hypothesis that the locations of shock-induced regions of hyperpolarization govern the different diastolic activation patterns for shocks of reversed polarity. In model and experiment, uniform-field monophasic shocks of reversed polarities (cathode over the right ventricle is RV-, reverse polarity is LV-) were applied to the ventricles in diastole. Experiments and simulations revealed that RV- shocks resulted in longer activation times compared with LV- shocks of the same strength. 3D simulations demonstrated that RV- shocks induced a greater volume of hyperpolarization at shock end compared with LV- shocks; most of these hyperpolarized regions were located in the LV. The results of this study indicate that ventricular geometry plays an important role in both the location and size of the shock-induced virtual anodes that determine activation delay during the shock and subsequently affect shock-induced propagation. If regions of hyperpolarization that develop during the shock are sufficiently large, activation delay may persist until shock end.


The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer.
It is now well established that cancer cells exhibit a number of genetic defects in the machinery that governs programmed cell death and that sabotage of apoptosis is one of the principal factors aiding in the evolution of the carcinogenic phenotype. A number of studies have implicated aberrant DNA methylation as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many processes including apoptosis. To date, studies on the methylation profile of apoptotic genes have largely focused on cancers of the breast, colon and stomach, with only limited data available on prostate cancer. Here we discuss the major developments in the field of DNA methylation and its role in the regulation of aberrant apoptosis in prostate cancer. The most significant advances have involved the discovery of apoptotic gene targets of methylation, including XAF1, (fragile histidine triad (FHIT ), cellular retinol binding protein 1 (CRBP1), decoy receptor 1(DCR1), decoy receptor 2 (DCR2 ), target of methylation-induced silenceing 1 (TMS1), TNF receptor superfamily, member 6 (FAS), Reprimo (RPRM) and GLI pathogenesis-related 1 (GLIPR1). These genes are reported to be hypermethylated in prostate cancer and some offer potential as diagnostic and prognostic markers. We also introduce the concept of an 'apoptotic methylation signature' for prostate cancer and evaluate its potential in a diagnostic, prognostic and therapeutic setting.


C-MYC modulation induces responsiveness to paclitaxel in adrenocortical cancer cell lines.
C-MYC is overexpressed in many types of cancer linked to poor prognosis. We examined the c-Myc protein expression in adrenocortical cancer (ACC) cells to investigate the role of this protein in the neoplasm, its involvement in chemotherapy and finally to determine whether c-Myc could be considered a prognostic factor in patients with ACC. H295R and SW13 cell lines were treated with paclitaxel. c-Myc overexpressing cell clones were achieved by transfecting the H295R cell line with the pcDNA3-hMYC plasmid expressing the full-lengh C-MYC coding sequence. The SW13 cell line was transfected with siRNA oligonucleotides for C-MYC. Cell cycle analysis was evaluated by flow cytometry. c-Myc, cyclin B1 and pro caspase expression levels were evaluated by western blot analysis. We found that expression of c-Myc was highly expressed in the SW13 cells, whereas the protein was undetectable in the H295R cells. Different doses of paclitaxel were required in the two ACC cell line to induce a block in the G2 phase, characterized by increased cyclin B1 levels and to induce apoptosis by pro-caspase-3 activation. Interestingly, the silencing of C-MYC mRNA prevented paclitaxel induced apoptosis in SW13 cells, whereas in the H295R cells the overexpression of C-MYC rendered the cells more prone to growth inhibition after paclitaxel exposure. The present study directly demonstrates that C-MYC plays a central role in controlling proliferation in ACC cells after paclitaxel treatment and that c-Myc could be considered as a marker for predicting response to chemotherapeutic agents in ACC cell lines.


Interleukin-10 promoter polymorphism in multiple sclerosis: association with disease progression.
Interleukin-10 (IL-10) is a potent anti-inflammatory and immunosuppressive cytokine that modulates disease expression in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In previous studies, two dinucleotide repeat elements (microsatellites G and R) were identified, respectively located about 1.1 and 4.0 kb upstream of the IL-10 gene transcription initiation site. Several of their alleles were found to be associated with the level of IL-10 production. The aim of our study was to determine whether sequence variations in the IL-10 gene were associated with MS susceptibility and progression. To do so, we analyzed the distribution of IL-10.R and IL-10.G alleles and genotype polymorphisms in MS patients and healthy controls. We then correlated our findings with disease severity in MS patients using the progression index (PI). Patients were classified as experiencing mild (PI < 0.5) or severe (PI > 0.5) disease progression. Our results show no association between the IL-10.R microsatellite and MS, regardless of disease severity. However, IL-10.G microsatellite genotyping showed that IL-10.G9/9, G10/13, G11/13 and G13/14 were more frequently found in patients with mild disease progression (p = 0.005). We also found that in patients with severe disease progression, IL-10.G9/10, G9/11, G9/13 and G12/13 were over-represented (p = 0.002). Our study indicates that neither the IL-10.R or the IL-10.G alleles are associated with predisposition to MS. However, several IL-10.G genotypes might emerge as markers of disease progression.


Elder Abuse and Neglect Risk Alleviation in Protective Services.
Little is known about conditions associated with favorable elder mistreatment (EM) case outcomes. The fundamental goal of EM protective service programs is to alleviate risk associated with substantiated cases of elder abuse and neglect. Using the EM socio-cultural model, this study examined victim, perpetrator, victim-perpetrator relationship, social embeddedness, and socio-cultural factors predicting risk alleviation of EM cases. Data from a random sample of EM protective social service cases (n = 250) at a large community agency in New York City were collected and coded by multiple, independent raters. Multinomial and binary logistic regression were used to examine undifferentiated risk alleviation for the entire sample of EM cases as well as differentiated financial, emotional, and physical abuse sub-types. Undifferentiated EM risk alleviation was associated with male victim gender, older victim age, previous community help-seeking, and victim-perpetrator dyads characterized by a separate living arrangement and shorter term abuse longevity. Financial abuse cases with younger perpetrators were less likely to have risk reduction. Physical abuse risk reduction was less likely when the perpetrator was male and the victim-perpetrator dyad included different genders. Distinct findings across EM sub-types suggest a need to develop targeted practice strategies with clients experiencing different forms of EM. Findings highlight a need to develop EM protective service infrastructure around perpetrator rehabilitation.


Preparation, characterization and biocatalytic activity of a nanoconjugate of alpha amylase and silver nanoparticles.
The primary challenge in developing nanoparticle based enzymatic devices is to be able to chemically immobilize an enzyme, which will retain its activity or improve its function while being attached to the nanoparticle. This would be of even greater significance if the whole process could be performed under benign conditions without having to resort to functionalization of key molecules at various steps. In the present study the conjugates of amylase and silver nanoparticles were synthesized using neem leaf extract as the reducing and stabilizing agent. The silver nanoparticles were characterized using Surface Plasmon Resonance Spectra, Dynamic Light Spectroscopy (DLS), Fourier Transform Infrared Spectroscopy (FTIR), Circular Dichroism (CD) and Surface Tunneling Microscopy (STM). The silver nanoparticles retained 85% amylase activity. The nanobiocatalyst was further characterized in terms of kinetic parameters and thermal stability. It was thermally more stable as compared to the free alpha amylase enzyme.


C-reactive protein, procalcitonin, clinical pulmonary infection score, and pneumonia severity scores in nursing home acquired pneumonia.
Patients with nursing home acquired pneumonia (NHAP) present a distinct group of lower respiratory track infections with different risk factors, clinical presentation, and mortality rates. To evaluate the diagnostic value of clinical pulmonary infection score (CPIS), C-reactive protein, and procalcitonin and to compare the accuracy of pneumonia severity scores (confusion, urea nitrogen, breathing frequency, blood pressure, ≥ 65 y of age [CURB-65]; pneumonia severity index; NHAP index; systolic blood pressure, multilobar involvement, albumin, breathing frequency, tachycardia, confusion, oxygen, arterial pH [SMART-COP]; and systolic blood pressure, oxygen, age > 65 y, breathing frequency [SOAR]) in predicting in-patient mortality from NHAP. Nursing home residents admitted to the hospital with acute respiratory illness were enrolled in the study. Subjects were classified as having NHAP (Group A) or other pulmonary disorders (Group B). Clinical, imaging, and laboratory data were assessed to compute CPIS and severity scores. C-reactive protein and procalcitonin were measured by immunonephelometry and immunoassay, respectively. Fifty-eight subjects were diagnosed with NHAP (Group A) and 29 with other pulmonary disorders (Group B). The mean C-reactive protein ± SD was 16.38 ± 8.6 mg/dL in Group A and 5.2 ± 5.6 mg/dL in Group B (P < .001). The mean procalcitonin ± SD was 1.52 ± 2.75 ng/mL in Group A and 0.24 ± 0.21 ng/mL in Group B (P = .001). The mean CPIS ± SD was 5.4 ± 1.2 in Group A and 2.3 ± 1.5 in Group B (P < .001). At a cutoff value of 0.475 ng/mL, procalcitonin had a sensitivity of 83% and a specificity of 72%. At a cutoff value of 8.05 mg/dL, C-reactive protein had a sensitivity of 81% and a specificity of 79%. Procalcitonin and C-reactive protein levels were significantly higher in Gram-positive NHAP. The in-patient mortality was 17.2% in Group A. Procalcitonin levels were 4.67 ± 5.4 ng/mL in non-survivors and 0.86 ± 0.9 ng/mL in survivors (P < .001). The area under the curve for procalcitonin in predicting in-patient mortality was 0.84 (95% CI 0.70-0.98, P = .001). A procalcitonin level upon admission > 1.1 ng/mL was an independent predictor of in-patient mortality. Of the pneumonia severity scores, CURB-65 showed greater accuracy in predicting in-patient mortality (area under the curve of 0.68, 95% CI 0.53-0.84, P = .06). CPIS, procalcitonin, and C-reactive protein are reliable for the diagnosis of NHAP. Procalcitonin and CURB-65 are accurate in predicting in-patient mortality in NHAP.


[Tissue engineering: a multidisciplinary approach].
The prostheses have been around for thousands of years. Initially, it was substitute materials to replace members (leg, foot, hand) or for surgery (suture). The materials used have evolved, but they had never been created for medical applications. Recently, other strategies have emerged to construct or repair tissues. They are based on the use of biological components such as proteins or cells and provide a biological dimension to the term "biomaterial" and they often involve engineering. We illustrate the tissue engineering approaches using the examples of muscle and vessel regeneration strategies in the frame of restorative medicine.


Effect of verbal instructions on muscle activity and risk of injury to the anterior cruciate ligament during landing.
Minimising the likelihood of injury to the anterior cruciate ligament (ACL) during abrupt deceleration requires proper synchrony of the quadriceps and hamstring muscles. However, it is not known whether simple verbal instructions can alter landing muscle activity to protect the knee. To assess the efficacy of verbal instructions to alter landing muscle activity. Twenty four athletes landed abruptly in single limb stance. Sagittal plane motion was recorded with an optoelectric device, and ground reaction force and surface electromyographic data were recorded for the rectus femoris, vastus lateralis, biceps femoris, and semimembranosus muscles. Subjects performed 10 landings per condition: normal landing (N); repeat normal landing (R); landing after instruction to increase knee flexion (K); and landing after instruction to recruit hamstring muscles earlier (M). Muscle bursts immediately before landing were analysed relative to initial foot-ground contact (IC). The K condition resulted in significantly (p</=0.05) greater knee flexion at IC compared with the other conditions. The M condition did not result in earlier hamstring muscle activity, but instead caused significantly (p</=0.05) earlier rectus femoris onset relative to IC, with a similar trend for the vastus lateralis. As these muscles are ACL antagonists, earlier onset times would be detrimental to the ACL. Subjects successfully increased knee flexion during landing following the K condition instruction. However, further research is warranted to establish the efficacy of more extensive lower limb muscle retraining programmes to ensure landings that decrease susceptibility to ACL injury.


Imaging glioma cell invasion in vivo reveals mechanisms of dissemination and peritumoral angiogenesis.
Infiltration of cancer cells into normal tissue is a hallmark of malignant gliomas and compromises treatment options. A lack of appropriate models limits the study of this invasion in vivo, which makes it difficult to fully understand its anatomy and the role of dynamic interactions with structures of the normal brain. We developed a novel methodology by utilizing multiphoton laser scanning microscopy (MPLSM) to image the movement of glioma cells deep within the normal brain of live mice in real time. This allowed us to track the invasion of individual RFP-expressing GL261 cells in relation to perfused vasculature or GFP-labeled endothelial cells repetitively over days, up to a depth of 0.5 mm. Glioma cells moved faster and more efficiently when the abluminal site of a blood vessel was utilized for invasion. Cells that invaded perivascularly were frequently found next to (a) multiple capillary structures where microvessels run parallel to each other, (b) capillary loops or glomeruloid-like bodies, and (c) dilated capillaries. Dynamic MPLSM for more than 48 h revealed that single invasive glioma cells induced intussusceptive microvascular growth and capillary loop formation, specifically at the microvascular site with which they had contact. As the main tumor grew by cooption of existing brain vessels, these peritumoral vascular changes may create a beneficial environment for glioma growth. In conclusion, our study revealed new mechanisms of peritumoral angiogenesis and invasion in gliomas, providing an explanation for their interdependence.


The second and fourth cluster of class A cysteine-rich repeats of the low density lipoprotein receptor-related protein share ligand-binding properties.
The low density lipoprotein receptor-related protein (LRP) is a multifunctional endocytic cell-surface receptor that binds and internalizes a diverse array of ligands. The receptor contains four putative ligand-binding domains, generally referred to as clusters I, II, III, and IV. In this study, soluble recombinant receptor fragments, representing each of the four individual clusters, were used to map the binding sites of a set of structurally and functionally distinct ligands. Using surface plasmon resonance, we studied the binding of these fragments to methylamine-activated alpha(2)-macroglobulin, pro-urokinase-type plasminogen activator, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1, t-PA.plasminogen activator inhibitor-1 complexes, lipoprotein lipase, apolipoprotein E, tissue factor pathway inhibitor, lactoferrin, the light chain of blood coagulation factor VIII, and the intracellular chaperone receptor-associated protein (RAP). No binding of the cluster I fragment to any of the tested ligands was observed. The cluster III fragment only bound to the anti-LRP monoclonal antibody alpha(2)MRalpha3 and weakly to RAP. Except for t-PA, we found that each of the ligands tested binds both to cluster II and to cluster IV. The affinity rate constants of ligand binding to clusters II and IV and to LRP were measured, showing that clusters II and IV display only minor differences in ligand-binding kinetics. Furthermore, we demonstrate that the subdomains C3-C7 of cluster II are essential for binding of ligands and that this segment partially overlaps with a RAP-binding site on cluster II. Finally, we show that one RAP molecule can bind to different clusters simultaneously, supporting a model in which RAP binding to LRP induces a conformational change in the receptor that is incompatible with ligand binding.


Entangled double-helix phase.
We present a novel phase with an entangled double-helix structure. Beams with this phase have the same transverse patterns as those of interference between two doughnut beams. This proposed method allows a complete set of the superpositions of the doughnut modes or the orbital angular momentum states with different topological orders to be obtained. Furthermore, it introduces a simple continuous and controlled rotation of the transverse patterns by use of a spatial light modulator. It can be used to form a three-dimensional structure by three-dimensional trapping in an optical tweezers setup or to study the quantum characteristics of an optical vortex.


CX3CL1 and CX3CR1 expression in tertiary lymphoid structures in salivary gland infiltrates: fractalkine contribution to lymphoid neogenesis in Sjogren's syndrome.
Primary SS is an autoimmune disease characterized by chronic lymphocytic inflammation and ectopic germinal centre (GC) formation within salivary glands. Fractalkine (CX3CL1), associated with the pathogenesis of RA, is the sole member of the CX3C chemokine (CK) family and acts as an adhesion and chemotactic molecule. The objectives of this work are to determine to what extent CX3CL1 and its receptor CX3CR1 expression might be altered in salivary glands obtained from patients and to establish whether these CKs might be involved in SS ectopic lymphoneogenesis. We assessed the presence of CX3CL1 protein in sera by ELISA in 21 patients with primary SS, 11 patients with Sicca syndrome (Sicca), 20 RA patients and 10 blood donors. Histological evaluation was performed on sequential sections of salivary gland tissue. Using TaqMan RT-PCR we studied CX3CL1 and CX3CR1 mRNA expression in salivary gland tissues from a molecular point of view. Increased serum levels of CX3CL1 protein were observed in SS patients compared with controls (P < 0.0001) and in RA patients compared with controls (P < 0.0001), but no difference was found between Sicca patients and controls (P = 0.22). We identified histologically the cells expressing CX3CL1 and CX3CR1 in salivary glands of SS patients and we localized the molecule within tertiary lymphoid structures. Finally, the mRNA levels of the CK and its receptor were up-regulated in SS salivary glands. We believe that our findings point to the need for future studies on CX3CL1 and CX3CR1 proteins as contributors to the formation of ectopic GCs and possibly as a new tool in the evaluation and diagnosis of SS.


Ventilatory responses to specific CNS hypoxia in sleeping dogs.
Our study was concerned with the effect of brain hypoxia on cardiorespiratory control in the sleeping dog. Eleven unanesthetized dogs were studied; seven were prepared for vascular isolation and extracorporeal perfusion of the carotid body to assess the effects of systemic [and, therefore, central nervous system (CNS)] hypoxia (arterial PO(2) = 52, 45, and 38 Torr) in the presence of a normocapnic, normoxic, and normohydric carotid body during non-rapid eye movement sleep. A lack of ventilatory response to systemic boluses of sodium cyanide during carotid body perfusion demonstrated isolation of the perfused carotid body and lack of other significant peripheral chemosensitivity. Four additional dogs were carotid body denervated and exposed to whole body hypoxia for comparison. In the sleeping dog with an intact and perfused carotid body exposed to specific CNS hypoxia, we found the following. 1) CNS hypoxia for 5-25 min resulted in modest but significant hyperventilation and hypocapnia (minute ventilation increased 29 +/- 7% at arterial PO(2) = 38 Torr); carotid body-denervated dogs showed no ventilatory response to hypoxia. 2) The hyperventilation was caused by increased breathing frequency. 3) The hyperventilatory response developed rapidly (<30 s). 4) Most dogs maintained hyperventilation for up to 25 min of hypoxic exposure. 5) There were no significant changes in blood pressure or heart rate. We conclude that specific CNS hypoxia, in the presence of an intact carotid body maintained normoxic and normocapnic, does not depress and usually stimulates breathing during non-rapid eye movement sleep. The rapidity of the response suggests a chemoreflex meditated by hypoxia-sensitive respiratory-related neurons in the CNS.


Simultaneous determination of a novel c-Met/AXL dual-target small-molecule inhibitor BPI-9016M and its metabolites in human plasma by liquid chromatography-tandem mass spectrometry: Application in a pharmacokinetic study in Chinese advanced solid tumor patients.
BPI-9016M is a novel dual-target small-molecule inhibitor targeting c-Met and AXL, which was developed by Betta Pharmaceuticals Co., Ltd (Hangzhou, China). It has great potential in the treatment of advanced cancer. A high throughput quantitation method, based on liquid chromatography-tandem mass spectrometry, was developed and validated for the simultaneous determination of BPI-9016M and its main metabolite, M1 and M2-2, in human plasma with a sample preparation method of precipitation of protein. Liquid chromatographic separation was performed with a gradient elution of formic acid-10mM ammonium acetate aqueous solution (1:1000, v/v) and acetonitrile at a flow rate of 0.4mL/min within 2.2min. A Waters ACQUITY UPLC BEH C18 column (1.7μm, 2.1×50mm) was chosen, of which the temperature was set to be 40°C. Mass spectrometric detection, which were achieved in positive mode, were performed by multiple reaction monitoring with SCIEX API 5500 Qtrap equipped with an ESI ion source. This method showed good linearity, accuracy and precision in the range of 0.4-200ng/mL for BPI-9016M and 0.8-800ng/mL for M1 and M2-2, with high recovery and slight matrix effect for all analytes. And under the conditions same as stability assessments in method validation, the three analytes stayed stable during the entire destiny of a clinical sample from the collection of whole blood to the analysis of plasma by this method. The validated method was successfully applied to a first-in-human, dose-escalation phase I clinical trial in Chinese advanced solid tumor patients for the pharmacokinetic research of BPI-9016M tablet after oral administration. The concentration-time curves of BPI-9016M, M1, M2-2 were detailly captured with good veracity. And according to the results of hemolysis assessment, plasma concentrations of analytes in hemolyzed plasma samples could be reported normally without label.


Active Video Gaming for Children with Cerebral Palsy: Does a Clinic-Based Virtual Reality Component Offer an Additive Benefit? A Pilot Study.
To compare changes in gross motor skills and functional mobility between ambulatory children with cerebral palsy who underwent a 1-week clinic-based virtual reality intervention (VR) followed by a 6-week, therapist-monitored home active video gaming (AVG) program and children who completed only the 6-week home AVG program. Pilot non-randomized controlled trial. Five children received 1 hour of VR training for 5 days followed by a 6-week home AVG program, supervised online by a physical therapist. Six children completed only the 6-week home AVG program. The Gross Motor Function Measure Challenge Module (GMFM-CM) and Six Minute Walk Test (6MWT) evaluated change. There were no significant differences between groups. The home AVG-only group demonstrated a statistically and clinically significant improvement in GMFM-CM scores following the 6-week AVG intervention (median difference 4.5 points, interquartile range [IQR] 4.75, p = 0.042). The VR + AVG group demonstrated a statistically and clinically significant decrease in 6MWT distance following the intervention (median decrease 68.2 m, IQR 39.7 m, p = 0.043). All 6MWT scores returned to baseline at 2 months post-intervention. Neither intervention improved outcomes in this small sample. Online mechanisms to support therapist-child communication for exercise progression were insufficient to individualize exercise challenge.


Short-read reading-frame predictors are not created equal: sequence error causes loss of signal.
Gene prediction algorithms (or gene callers) are an essential tool for analyzing shotgun nucleic acid sequence data. Gene prediction is a ubiquitous step in sequence analysis pipelines; it reduces the volume of data by identifying the most likely reading frame for a fragment, permitting the out-of-frame translations to be ignored. In this study we evaluate five widely used ab initio gene-calling algorithms-FragGeneScan, MetaGeneAnnotator, MetaGeneMark, Orphelia, and Prodigal-for accuracy on short (75-1000 bp) fragments containing sequence error from previously published artificial data and "real" metagenomic datasets. While gene prediction tools have similar accuracies predicting genes on error-free fragments, in the presence of sequencing errors considerable differences between tools become evident. For error-containing short reads, FragGeneScan finds more prokaryotic coding regions than does MetaGeneAnnotator, MetaGeneMark, Orphelia, or Prodigal. This improved detection of genes in error-containing fragments, however, comes at the cost of much lower (50%) specificity and overprediction of genes in noncoding regions. Ab initio gene callers offer a significant reduction in the computational burden of annotating individual nucleic acid reads and are used in many metagenomic annotation systems. For predicting reading frames on raw reads, we find the hidden Markov model approach in FragGeneScan is more sensitive than other gene prediction tools, while Prodigal, MGA, and MGM are better suited for higher-quality sequences such as assembled contigs.


A multiple circular path convolution neural network system for detection of mammographic masses.
A multiple circular path convolution neural network (MCPCNN) architecture specifically designed for the analysis of tumor and tumor-like structures has been constructed. We first divided each suspected tumor area into sectors and computed the defined mass features for each sector independently. These sector features were used on the input layer and were coordinated by convolution kernels of different sizes that propagated signals to the second layer in the neural network system. The convolution kernels were trained, as required, by presenting the training cases to the neural network. In this study, randomly selected mammograms were processed by a dual morphological enhancement technique. Radiodense areas were isolated and were delineated using a region growing algorithm. The boundary of each region of interest was then divided into 36 sectors using 36 equi-angular dividers radiated from the center of the region. A total of 144 Breast Imaging-Reporting and Data System-based features (i.e., four features per sector for 36 sectors) were computed as input values for the evaluation of this newly invented neural network system. The overall performance was 0.78-0.80 for the areas (Az) under the receiver operating characteristic curves using the conventional feed-forward neural network in the detection of mammographic masses. The performance was markedly improved with Az values ranging from 0.84 to 0.89 using the MCPCNN. This paper does not intend to claim the best mass detection system. Instead it reports a potentially better neural network structure for analyzing a set of the mass features defined by an investigator.


Edge location in SAR images: performance of the likelihood ratio filter and accuracy improvement with an active contour approach.
The likelihood ratio edge detector is an efficient filter for the segmentation of synthetic aperture radar (SAR) images. We show that this filter provides biased location of the edge, when the window does not have the same orientation as the edge. A phenomenological model is proposed to characterize this bias. We then introduce an efficient technique to refine edge location: the statistical active contour. The combination of these two methods permits to achieve accurate and regularized edge location.


Effect of cations on the structure of bilayers formed by lipopolysaccharides isolated from Pseudomonas aeruginosa PAO1.
The asymmetric outer membrane of Gram-negative bacteria contains lipopolysaccharides (LPSs) which contribute significantly to the bacterium's surface properties and play a crucial role in regulating membrane permeability. We report on neutron diffraction studies performed on aligned, self-assembled bilayers of Na-, Ca-, and Mg-salt forms of LPS isolated from Pseudomonas aeruginosa PAO1. From the one-dimensional neutron scattering length density profiles we find that water penetrates Ca2+-LPS bilayers to a lesser extent than either Na+- or Mg2+-LPS bilayers. This differential water penetration could have implications as to how small molecules permeate the outer membrane of Gram-negative bacteria and, possibly, how nonlamellar phases are formed.


Cytological analysis of the distension fluid used during diagnostic office hysteroscopies in patients with suspected endometrial pathology.
Evaluation of the feasibility and usefulness of cytological analysis of the distension fluid used during diagnostic office hysteroscopy in patients with suspected endometrial pathology. In 243 consecutive patients undergoing diagnostic hysteroscopy for suspected endometrial pathology a few milliliters of the distension medium used for uterine visualization were collected and sent for cytological analysis. Findings of these "endometrial washings" were compared to visual hysteroscopic impression, endometrial biopsy and uterine histology--when available. Endometrial washings were considered adequate in 227 patients (93.4%). In 12 cases (5.3%) atypical cells were detected: all of these presented either atypical complex hyperplasia or endometrial cancer at the final histological evaluation of the uterus. Four of the 16 (25%) patients diagnosed with endometrial cancer or atypical complex hyperplasia at the final histopathological analysis of the uterus had inadequate washings. No patient with cancer or atypical hyperplasia had negative cytology. Collection and analysis of the distension fluid is feasible and, when positive, has a remarkable value in the diagnosis of endometrial cancer and its precursors.


Five EMT-Related Gene Signatures Predict Acute Myeloid Leukemia Patient Outcome.
The epithelial mesenchymal transition (EMT) gene has been shown to be significantly associated with the prognosis of solid tumors; however, there is a lack of models for the EMT gene to predict the prognosis of AML patients. First, we downloaded clinical data and raw transcriptome sequencing data from the TCGA database of acute myeloid leukemia (AML) patients. All currently confirmed EMT-related genes were obtained from the dbEMT 2.0 database, and 30% of the TCGA data were randomly selected as the test set. Univariate Cox regression analysis, random forest, and lasso regression were used to optimize the number of genes for model construction, and multivariate Cox regression was used for model construction. Area under the ROC curve was used to assess the efficacy of the model application, and the internal validation set was used to assess the stability of the model. A total of 173 AML samples were downloaded, and a total of 1184 EMT-related genes were downloaded. The results of univariate batch Cox regression analysis suggested that 212 genes were associated with patient prognosis, random forest and lasso regression yielded 18 and 8 prognosis-related EMT genes, respectively, and the results of multifactorial COX regression model suggested that 5 genes, CBR1, HS3ST3B1, LIMA1, MIR573, and PTP4A3, were considered as independent risk factors affecting patient prognosis. The model ROC results suggested that the area under the curve was 0.868 and the internal validation results showed that the area under the curve was 0.815. During this study, we constructed a signature model of five EMT-related genes to predict overall survival in patients with AML; it will provide a useful tool for clinical decision making.


Black raspberry restores the expression of the tumor suppressor p120ctn in the oral cavity of mice treated with the carcinogen dibenzo[a,l]pyrene diol epoxide.
One of the major risk factors for head and neck squamous cell carcinoma (HNSCC) is tobacco smoke exposure, but the mechanisms that can account for disease development remain to be fully defined. Utilizing our HNSCC mouse model, we analyzed oral squamous cell carcinomas (OSCC) induced by the active metabolite of a common smoke constituent, dibenzo[a,l]pyrene diol-epoxide (DBPDE). Analyzing protein expression by either immunofluorescence or immunohistochemistry, we identified biologic processes that are dysregulated in premalignant and invasive cancer lesions induced by DBPDE. Interestingly, p120ctn expression is downregulated in both stages of the disease. In addition to decreased p120ctn expression, there was also increased proliferation (as measured by Ki67), inflammation (as measured by NFkB (p65) expression), neovascularization (as measured by CD31) and recruitment of Ly6G-positive immune cells as well as strong EGFR expression. We also examined the effect of the chemopreventive agent black raspberry (BRB) on p120ctn and EGFR protein expression in DBPDE treated mice. p120ctn, but not EGFR, protein expression increased in mice treated with BRB. Our results suggest that modulation of p120ctn may, in part, account for the mechanism by which BRB inhibits DBPDE induced OSCC in mice.


Fever of unknown origin: revisit of 142 cases in a tertiary Chinese hospital.
To investigate the causes of fever of unknown origin (FUO), we analyzed the clinical data on 142 patients with FUO admitted to our department from January 2002 to December 2003. After various examinations and specific treatment, a definitive diagnosis was reached in 122 cases. Of them, 51 cases (35.9%) were caused by infections, 46 (32.4%) were due to autoimmune diseases, 18 (12.7%) were due to tumors, 7 (4.9%) were due to other diseases, and in 20 (14.1%) the cause was still unknown after hospitalization. In conclusion, infection is the main cause of FUO. Autoimmune diseases and malignant tumors are both significant causes. Most patients with an FUO were ultimately diagnosed with various examinations and careful analysis.


Urinary glycosaminoglycans excretion and the effect of dimethyl sulfoxide in an experimental model of non-bacterial cystitis.
We reproduced a non-bacterial experimental model to assess bladder inflammation and urinary glycosaminoglycans (GAG) excretion and examined the effect of dimethyl sulfoxide (DMSO). Female rats were instilled with either protamine sulfate (PS groups) or sterile saline (control groups). At different days after the procedure, 24 h urine and bladder samples were obtained. Urinary levels of hyaluronic acid (HA) and sulfated glycosaminoglycans (S-GAG) were determined. Also to evaluate the effect of DMSO animals were instilled with either 50% DMSO or saline 6 hours after PS instillation. To evaluate the effect of DMSO in healthy bladders, rats were instilled with 50% DMSO and controls with saline. In the PS groups, bladder inflammation was observed, with polymorphonuclear cells during the first days and lymphomononuclear in the last days. HA and S-GAG had 2 peaks of urinary excretion, at the 1st and 7th day after PS injection. DMSO significantly reduced bladder inflammation. In contrast, in healthy bladders, DMSO produced mild inflammation and an increase in urinary HA levels after 1 and 7 days and an increase of S-GAG level in 7 days. Animals instilled with PS and treated with DMSO had significantly reduced levels of urinary HA only at the 1st day. Urinary S-GAG/Cr levels were similar in all groups. Increased urinary levels of GAG were associated with bladder inflammation in a PS-induced cystitis model. DMSO significantly reduced the inflammatory process after urothelial injury. Conversely, this drug provoked mild inflammation in normal mucosa. DMSO treatment was shown to influence urinary HA excretion.


[Improving ambulatory services for children in the foci of tuberculosis with special reference to the factors of increased risk of infection].
The paper deals with the results of the examination of certain factors that increase the risk of children's contamination in tuberculosis infection foci. It has been established that primary infection takes place more frequently in children under 6 years of age (1.3-fold), in children who do not attend preschool establishments (2-fold), in those having inappropriate BCG vaccination and revaccination (2.4-fold) and in the foci where patients abuse alcohol (2.2-fold). These children comprise a group of especially high contamination risk. It is expedient to check up them 3 times a year, performing a tuberculin test in children showing an uncertain response, to conduct clinical and X-ray examinations in accordance with the indications and to strictly controlled chemoprophylaxis. The proposed scheme of children's medical examination is one of the pattern to make better therapeutic and preventive measures in tuberculosis infection foci.


Employment retention after moderate-severe traumatic brain injury (TBI) in the British Army 1989-98.
To examine retention in employment of subjects with moderate-severe traumatic brain injury (TBI) in the British Army. Comparative groups study of retention in Army employment after TBI using 564 TBI, 368 lower limb fracture, and 25 575 healthy subjects. Kaplan-Meier survival analysis was used to examine, stratifying for age, continuation in Army employment for six years after TBI. Subjects in the younger groups (mean ages 23 years and 27 years respectively) with either TBI or lower limb fracture remained in employment longer than healthy peers (median time for TBI, 3.91 years, lower limb fracture, 4.39 years, and healthy, 1.74 years). This trend changed through age stratification and for older subjects the reverse pattern was seen. In group 4 (mean age 41 years), median retention time for TBI was 3.33 years, for lower limb fracture, 3.75 years, healthy 5.55 years. Older subjects also showed a marked drop out rate at one year after injury; 32.7% of those with TBI in group 3 (mean age 31 years) had left Army employment at the end of year one compared with 19% in age group 1 (mean age 23 years). Younger soldiers with either TBI or lower limb fracture are retained in Army employment longer than their healthy peers. This may be due to sheltered employment, the availability of ongoing support, or transience of the healthy population. Since these results were drawn from incidence data on moderate and severe TBI it may be that those who serve on after TBI will do so with some degree of disability which affects occupational performance. There may be a significant unmet rehabilitation need for this group which is the focus of ongoing research.


The role of aspirin in the primary prevention of accelerated atherosclerosis in systemic autoimmune rheumatic diseases.
Aspirin is the most commonly used medication worldwide. Beside its well-known anti-inflammatory effects, a role has emerged in the prevention of cardiovascular events. However, a significant benefit has been demonstrated in secondary cardiovascular prevention only, while there is limited evidence supporting a role in primary prevention. This discrepancy might depend on the that so far, the high-risk populations that will achieve the greatest benefits yet experiencing minimal harmful side effects have not been identified. Patients with autoimmune systemic rheumatic diseases have an increased risk of cardiovascular complications compared with the general population, which makes aspirin of potential value in these subjects. Moving from general aspects of aspirin pharmacology and specific issues in general population, the aim of this study is to review the evidence about the role of low-dose aspirin in primary cardiovascular prevention in autoimmune systemic rheumatic diseases.


Nonwillingness to Return to the Emergency Department and Nonattendance of Follow-Up Care Arrangements Following an Initial Suicide-Related Presentation.
Background: For people experiencing a suicidal crisis the emergency department (ED) is often the only option to find help. Aims: The aims of this study were (a) to identify predictors of patients' nonwillingness to return to the ED for help with a future suicidal crisis, and (b) whether nonwillingness to return was associated with follow-up appointment nonattendance. Method: This study utilized baseline data from the RESTORE online survey, and included 911 participants who had presented to an ED for suicidal crisis in the past 18 months, across participating local health districts in the Australian Capital Territory and New South Wales. Results: Patients who reported a more negative ED experience and longer triage wait times were less willing to return. Those who were less willing to return were also less likely to attend their follow-up appointment. Limitations: Due to the cross-sectional study design, causal inferences are not possible. Additionally, the self-report measures used are susceptible to recall bias. Conclusion: Patients' experience of service at EDs is a key indicator to drive improvement of patient outcomes for individuals experiencing a suicidal crisis.


Characterization of Rabbit Antibodies Against the Immunogenic JC Polyomavirus Peptide JCPyV_VP2_167-15mer.
JC Polyomavirus (JCPyV) is a widespread polyomavirus that usually resides latently in its host. As reactivation of the virus upon immune-modulating conditions holds serious risk, it is of importance to properly determine who is infected with this virus. Assessment of infection with JCPyV currently is based on the detection of antibodies against the major capsid protein VP1. However, specific antibodies against the peptide JCPyV_VP2_167-15mer have been shown to hold potential as a novel serological marker for infection with JCPyV. We have immunized rabbits with this peptide and the resulting hyperimmune serum was further characterized by detailed epitope mapping. The results demonstrated that the rabbit immune response is polyclonal in nature, recognizing two different epitopes in the 15-mer peptide. The strongest epitope consisted of L173PALTSQEI181, while a second moderate epitope consisted of D171DLPALT177. While some of the essential amino acid residues are the same as the ones for human plasma samples (P174, L176), some others are different. L173, T177, and I181 are essential for the rabbit hyperimmune serum, but not for human plasma samples, while E180 was essential for the human plasma samples and not for the rabbit hyperimmune serum. In conclusion, we generated polyclonal rabbit antibodies with strong reactivity against JCPyV_VP2_167-15mer recognizing at least two different epitopes in this peptide.


Avoiding in hospital delays and eliminating the three-hour effect in thrombolysis for stroke.
Intravenous thrombolysis for acute stroke is more efficient the earlier the treatment is initiated. In-hospital delays account for a significant proportion of avoidable time loss before treatment is initiated. Paradoxically, studies have reported longer door-to-needle times the earlier the patients arrive ('three-hour effect'). Hypothesis We hypothesized that a standardized thrombolysis procedure carried out in a specialized neurological emergency room can minimize in-hospital delays and erase the 'three-hour effect'. Onset-to-door and door-to-needle times of 246 consecutive thrombolysis patients were analyzed. A standardized protocol designed to minimize in-hospital delays was tested using a resident-based stroke team within a neurological emergency room. Correlation of onset-to-door and door-to-needle times was measured as well as differences in treatment times for daytime versus night hours and weekend vs. weekday. Outcome, rate of symptomatic intracranial hemorrhage and mortality were compared with the results of SITS-MOST. Median door-to-needle time was 25 min compared with a mean of 68 min in SITS-MOST. door-to-needle time did not correlate with onset-to-door time (Pearson's r = -0 · 097; P = 0 · 13) and patients arriving within 90 min from symptom onset showed comparable door-to-needle times with patients arriving within 90-180 min. Neither treatment on weekends nor during night hours led to significant in-hospital treatment delays. Outcome and safety parameters were comparable with those observed in SITS-MOST. By applying a standardized and diligently monitored thrombolysis protocol, carried out by a specialized stroke team within a neurological emergency room, in-hospital delays can be minimized. This allows improvement of door-to-needle times irrespective of the time to arrival and treatment during off-hours.


Update on the safety of linezolid.
Linezolid is still the only representative of the oxazolidinones antibiotic class. Because of its novel mechanism of action and excellent tissue penetration, it is used in a variety of approved and off-label clinical conditions. To review the literature (including latest publications) about the adverse events of linezolid and its overall safety. The range of adverse events of linezolid is growing; new ones, such as nephro-toxicity and Bell's palsy, have been reported. Toxicity of linezolid is mostly related with the prolonged duration of treatment and the presence of predisposing factors. Physicians must be alerted when using linezolid for indications and duration different from the approved ones, and must be aware of the possible adverse events. In case of toxicity, the main option is the discontinuation of the drug; although, not all adverse events are fully reversible. Linezolid represents an important advance in therapeutics and is still considered safe enough, but anticipated benefits must always be counterbalanced by the possible toxicity.


Current Status and Future Directions for Electronic Point-of-Care Clinical Decision Support to Improve Diabetes Management in Primary Care.
In the past decade there have been major improvements in the design, use, and effectiveness of point-of-care clinical decision support (CDS) systems to improve quality of care for patients with diabetes and related conditions. Advances in data exchange, data security, and human factors research have driven these improvements. Current diabetes CDS systems have high use rates, high clinician/user satisfaction rates, and have measurably improved glucose control, blood pressure control, and cardiovascular risk trajectories in adults with diabetes. As diabetes care increasingly relies on complex biomarker-driven risk prediction methods to optimize care goals and prioritize treatment options based on potential benefit to an individual patient, CDS systems will become indispensable tools to guide clinician and patient decision-making. In this study we describe specific challenges that must be addressed further to improve the design, implementation, and effectiveness of primary care diabetes CDS systems in coming years.


Knowledge and anticipated behaviour of health-care workers in response to an outbreak of pandemic influenza in Georgia.
Avian influenza has been documented in over 331 humans since 2003 with 203 associated deaths. Health Care Workers (HCWs) have been shown to be at personal risk during other highly virulent outbreaks with a high attack rate. This study aimed to determine the magnitude and factors associated with absenteeism of hospital based health care workers (HCWs) in Georgia associated with a potential highly virulent influenza pandemic. This was a cross-sectional study of how HCWs responded to a potentially highly virulent influenza pandemic in two urban hospitals in Georgia. Hospital-based physicians and nurses were studied. Data was collected utilizing a survey instrument. The survey was either self-administered or interviewer administered based upon the preference of the respondent. There were 288 HCWs surveyed. The study suggested a 23% rate of worker absenteeism, predominately among women and nurses. The majority of the respondents (58.1%), mostly HCWs less than age 35, were opposed to forced isolation or quarantine of staff during a highly virulent influenza pandemic. Seventy-six percent of respondents correctly reported that the strain of virus that was responsible for the outbreaks in the neighboring countries was H5N1. Only 15.5% of respondents, however, correctly identified influenza as the culprit virus. The rate of work absenteeism suggested by this study represents a significant workforce reduction. There are specific groups who would choose not to attend work in the face of a flu pandemic. This information may allow planners to target these specific groups for education and social support services to encourage greater inclination to attend to clinical duties.


[Evidence-based and promising interventions to prevent infectious diseases among youth as a result of poor hand hygiene in schools: a literature review].
Infectious diseases remain a major cause of death among young people throughout the world. This paper reviews the current knowledge of empirically validated and promising interventions aimed at preventing infectious diseases among children caused by poor hand hygiene in schools. The study used a standard protocol to identify and review the literature and to classify the selected interventions. Approximately ten interventions were found to have a beneficial effect by promoting hand washing and hand hygiene in schools. The study also found that most of the interventions were implemented at elementary school. However, some interventions were also implemented at kindergarten or in child care centers, while others were aimed at university students. Most of the interventions were implemented by teachers, peers and/or external professionals. The study found that hand hygiene is effective regardless of the type of cleaning product used (i.e. antibacterial or plain soap, alcohol-based or alcohol-free hand sanitizer). This study aims to contribute to the understanding of empirically validated and promising interventions and to promote reflection on professional practice in France.


Structural differences between subtype A and B strains of respiratory syncytial virus.
Differences in the properties of homologous intracellular structural components of eight strains of subtype A and eight strains of subtype B of human respiratory syncytial (RS) virus were examined. The size of the fusion (F) protein cleavage products and the phosphoprotein (P) showed systematic differences between virus strains representing the two subtypes. The apparent mol. wt. in SDS-polyacrylamide gels under reducing conditions was 48,000 (48K) and 46K to 47K for the cleavage product F1 in subtype A and B strains, respectively. The size of the F2 protein was 18K to 20K. The subtype B strains showed a slightly higher mol. wt. of this protein compared to the subtype A strains. The size of the P protein was 36K in subtype A strains, but only 34K in subtype B strains. Variations also occurred in the size of the glycoprotein (G) and the 22K to 24K structural protein. These variations did not correlate with the virus subtypes, but were strain-specific. The size of non-glycosylated forms of the F protein cleavage products was determined by use of material from tunicamycin-treated cells. A 44K to 45K non-glycosylated form of the F1 protein was detected with subtype A virus strains, but the corresponding protein of subtype B strains was not reproducibly identified, presumably due to instability in the absence of glycosylation or altered antigenicity. Monoclonal antibody immunosorbent-bound viral glycoproteins were partially digested with proteases. The pattern of breakdown products of the F1 protein was distinctly different between subtype A and B strains, but it was similar among strains of the same subtype. No subtype-specific pattern was seen in proteolytic digests of monoclonal antibody-bound G protein.


Multidimensional compressed sensing to advance 23 Na multi-quantum coherences MRI.
Sodium (23 Na) multi-quantum coherences (MQC) MRI was accelerated using three-dimensional (3D) and a dedicated five-dimensional (5D) compressed sensing (CS) framework for simultaneous Cartesian single (SQ) and triple quantum (TQ) sodium imaging of in vivo human brain at 3.0 and 7.0 T. 3D 23 Na MQC MRI requires multi-echo paired with phase-cycling and exhibits thus a multidimensional space. A joint reconstruction framework to exploit the sparsity in all imaging dimensions by extending the conventional 3D CS framework to 5D was developed. 3D MQC images of simulated brain, phantom and healthy brain volunteers obtained from 3.0 T and 7.0 T were retrospectively and prospectively undersampled. Performance of the CS models were analyzed by means of structural similarity index (SSIM), root mean squared error (RMSE), signal-to-noise ratio (SNR) and signal quantification of tissue sodium concentration and TQ/SQ ratio. It was shown that an acceleration of three-fold, leading to less than 2 × 10 $$ 2\times 10 $$ min of scan time with a resolution of 8 × 8 × 20 mm 3 $$ 8\times 8\times 20\;{\mathrm{mm}}^3 $$ at 3.0 T, are possible. 5D CS improved SSIM by 3%, 5%, 1% and reduced RMSE by 50%, 30%, 8% for in vivo SQ, TQ, and TQ/SQ ratio maps, respectively. Furthermore, for the first time prospective undersampling enabled unprecedented high resolution from 8 × 8 × 20 mm 3 $$ 8\times 8\times 20\;{\mathrm{mm}}^3 $$ to 6 × 6 × 10 mm 3 $$ 6\times 6\times 10\;{\mathrm{mm}}^3 $$ MQC images of in vivo human brain at 7.0 T without extending acquisition time. 5D CS proved to allow up to three-fold acceleration retrospectively on 3.0 T data. 2-fold acceleration was demonstrated prospectively at 7.0 T to reach higher spatial resolution of 23 Na MQC MRI.


Intraspecific diversity of Yersinia pestis.
Increased interest in the pathogenic potential of Yersinia pestis has emerged because of the potential threats from bioterrorism. Pathogenic potential is based on genetic factors present in a population of microbes, yet most studies evaluating the role of specific genes in virulence have used a limited number of strains. For Y. pestis this issue is complicated by the fact that most strains available for study in the Americas are clonally derived and thus genetically restricted, emanating from a strain of Y. pestis introduced into the United States in 1902 via marine shipping and subsequent spread of this strain throughout North and South America. In countries from the former Soviet Union (FSU), Mongolia, and China there are large areas of enzootic foci of Y. pestis infection containing genetically diverse strains that have been intensely studied by scientists in these countries. However, the results of these investigations are not generally known outside of these countries. Here we describe the variety of methods used in the FSU to classify Y. pestis strains based on genetic and phenotypic variation and show that there is a high level of diversity in these strains not reflected by ones obtained from sylvatic areas and patients in the Americas.


[Mesangial kidney cells: structure and function under normal and pathological conditions].
A review of the data on the structure and functions of mesangial cells (MC) and mesangial matrix of the kidneys in normal subjects under experimental conditions and in human pathology is presented. An important role of MC in purification of the glomerular filter is emphasized, their participation in regulation of the glomerular blood flow, the possibility of renin production by them and other functions are considered. Most frequent lesions of MC and their importance in the development of glomerular pathology of the kidneys are described. The nature of MC is discussed.


Noninvasive indices of arterial stiffness in hemodialysis patients.
The purpose of this study was to evaluate the validity of brachial-ankle pulse wave velocity (baPWV) and the cardio-ankle vascular index (CAVI) as measures of arterial stiffness in hemodialysis (HD) patients. We studied 160 consecutively enrolled HD patients (mean age: 59+/-13 years; 91 male patients). We measured baPWV and CAVI using a VaSera VS-1000, maximum intima-media thickness (max IMT) of the carotid artery by ultrasonography and blood renal and lipid parameters. As a control, baPWV and CAVI were also measured in age- and gender-matched healthy volunteers. Both baPWV and CAVI were significantly higher in HD patients than in controls (baPWV: 1698+/-355 vs. 1454+/-263 cm s(-1), P<0.0001; CAVI: 9.3+/-1.4 vs. 8.9+/-1.2, P<0.01). BaPWV correlated positively with age (r=0.549, P<0.0001), systolic blood pressure (SBP) (r=0.510, P<0.0001), diastolic blood pressure (r=0.203, P<0.0001), pulse pressure (PP) (r=0.499, P<0.0001), Kt V(-1) (r=0.221, P<0.01), Brinkman index (r=0.186, P<0.05) and max IMT (r=0.285, P<0.001). CAVI also correlated positively with age (r=0.562, P<0.0001), SBP (r=0.395, P<0.0001), PP (r=0.490, P<0.0001), Kt V(-1) (r=0.216, P<0.01), Brinkman index (r=0.238, P<0.01) and max IMT (r=0.280, P<0.001). Multiple regression analysis demonstrated baPWV and CAVI correlated independently with age and SBP. Receiver operating characteristics (ROC) curve analysis demonstrated that baPWV and CAVI had similar power to predict increases in max IMT. We also measured baPWV and CAVI immediately before and after HD, and showed CAVI was influenced by changes in water volume. Both baPWV and CAVI are therefore useful indices of arterial stiffness in HD patients.


[specifics of professional stress of medical workers in the post-COVID period].
The purpose of the study is to determine the specifics of occupational stress among medical workers in the post-COVID period. Material and methods. The study involved 620 medical workers who worked and are working in the red zone. Questionnaires for susceptibility to stress at work, assessments of occupational maladaptation, occupational stress, occupational stress test, occupational stress scale, K. Pearson's correlation criterion and the Chaddok-Snedekor scale were used. Results. The study has identified the following specific features of occupational stress among medical workers in the post-COVID period: above the average level of sings of somatovegetative disorders (26.05); average level of the general indicator for assessing professional maladaptation (67.66), signs of sleep and wakefulness cycle disturbance (8.36), signs of feeling tired (5.96), signs of decreased motivation for activity (4.25), signs of decreased general activity (5.87), signs of deteriorated well-being (22.18), signs of emotional shifts (7.31), stress at work (9.25), stressful impact of professional activity on a specialist (995), stressful conditions and neuroses (24.91); below the average level of occupational stress (2.37), signs of characteristics of social interaction (6.82), signs of characteristics of individual mental processes (3.04). A noticeable relationship was established between the sign of somatovegetative disorders and the stressful impact of professional activity on a specialist (0.636), and the general indicator of assessing professional maladaptation (0.598), and stress conditions and neuroses (0.582), and the sign of deteriorated well-being (0.573), and stress at work (0.569), signs of disturbed sleep and wakefulness cycle (0.555), emotional shifts (0.542), feelings of fatigue (0.531), decreased overall activity (0.525) and motivation for activity (0.519).