Chronic hepatitis B virus in young adults: the need for new approaches to management.
One in four patients infected with hepatitis B virus (HBV) at birth or in early childhood will develop cirrhosis or hepatocellular carcinoma. Historically, guidelines have overlooked treatment in young people, as the immune tolerant disease phase is considered synonymous with chronic infection in the young. Current treatment aims to suppress HBV replication through long-term nucleos(t)ide therapy with little emphasis on virus eradication. To achieve HBsAg loss, it is accepted that effective immune control of virus is required, mimicking that seen in those who resolve acute HBV infection. We have recently challenged the accuracy of a generic immune tolerant state in young people, thus raising a potential role for earlier treatment. Here we report on our immunological analysis of HBV in young people and the role of a dedicated clinic; we make the case for earlier intervention to achieve effective immune control leading to better outcomes.


Bicycle helmet effectiveness is not overstated.
The objective of this study was to discuss the challenges in estimating bicycle helmet effectiveness from case-control studies of injured cyclists and to estimate helmet effectiveness from cases and available exposure data. Data were extracted from studies of cyclists in Seattle; Victoria and New South Wales, Australia; and The Netherlands. Estimates of helmet use were used as exposure to compute relative risks for Seattle and Victorian data. Cycling distance data are routinely collected in The Netherlands; however, these data cannot be disaggregated by helmet use, which makes it unsuitable for estimating helmet effectiveness. Alternative controls were identified from larger cohorts for the Seattle and New South Wales cases. Estimates of helmet effectiveness were similar from odds ratios (ORs) using hospital controls or from relative risks (RRs) using helmet use estimates (Seattle: OR = 0.339, RR = 0.444; Victoria: OR = 0.500, RR = 0.353). Additionally, the odds ratios using hospital controls were similar when controls were taken from a larger cohort for head injury of any severity (Seattle: OR = 0.250, alt OR = 0.257; NSW: OR = 0.446, alt OR = 0.411) and for serious head injury (Seattle: OR = 0.135, alt OR = 0.139; NSW: OR = 0.335, alt OR = 0.308). Although relevant exposure data were unavailable for The Netherlands, the odds ratio for helmet effectiveness of those using racing, mountain, or hybrid bikes was similar to other estimates (OR = 0.371). Despite potential weaknesses with case-control study designs, the best available evidence suggests that helmet use is an effective measure of reducing cycling head injury.


In vitro assessment of the accuracy of extraoral periapical radiography in root length determination.
To determine the accuracy of extra oral periapical radiography in obtaining root length by comparing it with the radiographs obtained from standard intraoral approach and extended distance intraoral approach. It was an in vitro, comparative study conducted at the dental clinics of Aga Khan University Hospital. ERC exemption was obtained for this work, ref number 3407Sur-ERC-14. We included premolars and molars of a standard phantom head mounted with metal and radiopaque teeth. Radiation was exposed using three radiographic approaches: Standard intraoral, extended length intraoral and extraoral. Since, the unit of analysis was individual root, thus, we had a total of 24 images. The images were stored in VixWin software. The length of the roots was determined using the scale function of the measuring tool inbuilt in the software. Data were analyzed using SPSS version 19.0 and GraphPad software. Pearson correlation coefficient and Bland-Altman test was applied to determine whether the tooth length readings obtained from three different approaches were correlated. P = 0.05 was taken as statistically significant. The correlation between standard intraoral and extended intraoral was 0.97; the correlation between standard intraoral and extraoral method was 0.82 while the correlation between extended intraoral and extraoral was 0.76. The results of Bland-Altman test showed that the average discrepancy between these methods is not large enough to be considered as significant. It appears that the extraoral radiographic method can be used in root length determination in subjects where intraoral radiography is not possible.


JK null alleles identified from Japanese individuals with Jk(a−b−) phenotype.
The Kidd blood group system consists of three common phenotypes: Jk(a+b−), Jk(a−b+) and Jk(a+b+), and one rare phenotype, Jk(a−b−). Jka/Jkb polymorphism is associated with c.838G>A (p.Asp280Asn) in exon 9 of the JK (SLC14A1) gene, and the corresponding alleles are named JK*01 and JK*02. The rare phenotype Jk(a−b−) was first found in a Filipina of Spanish and Chinese ancestry, and to date, several JK null alleles responsible for the Jk(a−b−) phenotype have been reported. We report seven novel JK null alleles, 4 with a JK*01 background and 3 with a JK*02 background, identified from Jk(a−b−) Japanese.


Selenium-induced inhibition of angiogenesis in mammary cancer at chemopreventive levels of intake.
The trace element nutrient selenium (Se) has been shown to possess cancer-preventive activity in both animal models and humans, but the mechanisms by which this occurs remain to be elucidated. Because angiogenesis is obligatory for the genesis and growth of solid cancers, we investigated, in the study presented here, the hypothesis that Se may exert its cancer-preventive activity, at least in part, by inhibiting cancer-associated angiogenesis. The effects of chemopreventive levels of Se on the intra-tumoral microvessel density and the expression of vascular endothelial growth factor in 1-methyl-1-nitrosourea-induced rat mammary carcinomas and on the proliferation and survival and matrix metalloproteinase activity of human umbilical vein endothelial cells in vitro were examined. Increased Se intake as Se-enriched garlic, sodium selenite, or Se-methylselenocysteine led to a significant reduction of intra-tumoral microvessel density in mammary carcinomas, irrespective of the manner by which Se was provided: continuous exposure (7-wk feeding) with a chemoprevention protocol or acute bolus exposure (3 d) after carcinomas had established. Compared with the untreated controls, significantly lower levels of vascular endothelial growth factor expression were observed in a sizeable proportion of the Se-treated carcinomas. In contrast to the mammary carcinomas, the microvessel density of the uninvolved mammary glands was not altered by Se treatment. In cell culture, direct exposure of human umbilical vein endothelial cells to Se induced cell death predominantly through apoptosis, decreased the gelatinolytic activities of matrix metalloproteinase-2, or both. These results indicate a potential for Se metabolites to inhibit key attributes (proliferation, survival, and matrix degradation) of endothelial cells critical for angiogenic sprouting. Therefore, inhibition of angiogenesis associated with cancer may be a novel mechanism for the anticancer activity of Se in vivo, and multiple mechanisms are probably involved in mediating the anti-angiogenic activity.


Patient profiles as organizing HIV clinicians' ART adherence management: a qualitative analysis.
The effectiveness of antiretroviral therapy (ART) depends on optimal clinical management and patient adherence. Little is known about patient characteristics that clinicians consider in the management of ART adherence. Exploring this issue, five focus groups were conducted with 31 HIV-clinicians from across France. A qualitative typological analysis suggests that clinician management of patient adherence is based on characteristics that coalesce into seven patient profiles. For the "passive" patient, described as taking ART exactly as prescribed without questioning their doctor's expertise, a directive and simple management style was preferred. The "misleading" patient is characterized as concerned with social desirability and as reporting no adherence difficulties for fear of displeasing their doctor. If clinical outcomes are suboptimal, the clinicians' strategy is to remind them of the importance of open patient-clinician communication. The "stoic" patient is described as requesting and adequately taking the most potent ART available. Here, clinicians emphasize assessment of side effects, which the patient may minimize. The "hedonistic" patient's festive lifestyle and sexual risk-taking are seen as compromising adherence; with them, clinicians stress the patient's responsibility for their own health and that of their sexual partners. The "obsessive" patient is portrayed as having an irrational fear of ART failure and an inability to distinguish illusory from genuine adherence barriers. With this patient, clinicians seek to identify the latter. The "overburdened" patient is recognized as coping with life priorities that interfere with adherence and, with them, a forgiving ART is favored. The "underprivileged" patient is presented as having limited education, income and housing. In this case, clinicians seek to improve the patient's living conditions and access to care. These results shed light on HIV clinicians' ART adherence management. The value of these profiles for HIV care and patients should be investigated.


[Barriers and facilitators aspects of adherence to antiretroviral therapy in Belo Horizonte-MG].
The aim of this study was to know the constraining and facilitating aspects of adherence to highly active antiretroviral therapy (HAART) among people with HIV/AIDS. This was a qualitative study, carried out with 26 individuals receiving HAART and assisted by a referral service in Belo Horizonte, Minas Gerais, Brazil. The analysis of the interviews regarding the constraints found by users, resulted in categories relating to Day-by-day life, HIV representations, and the complexity of the treatment. As for the facilitating aspects, the categories found were absence of side effects, remembering the symptoms of the disease, improved survival, and influences from the social networks. Results have shown the importance of an effective follow-up so that health care professionals can build strategies to improve adherence to HAART together with the individuals.


Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes.
Genome-wide association studies (gwas) are invaluable in revealing the common variants predisposing to complex human diseases. Yet, until now, the large volumes of data generated from such analyses have not been explored extensively enough to identify the molecular and functional framework hosting the susceptibility genes. We investigated the relationships among five neurodegenerative and/or autoimmune complex human diseases (Parkinson's disease--Park, Alzheimer's disease--Alz, multiple sclerosis--MS, rheumatoid arthritis--RA and Type 1 diabetes--T1D) by characterising the interactomes linked to their gwas-genes. An initial study on the MS interactome indicated that several genes predisposing to the other autoimmune or neurodegenerative disorders may come into contact with it, suggesting that susceptibility to distinct diseases may converge towards common molecular and biological networks. In order to test this hypothesis, we performed pathway enrichment analyses on each disease interactome independently. Several issues related to immune function and growth factor signalling pathways appeared in all autoimmune diseases, and, surprisingly, in Alzheimer's disease. Furthermore, the paired analyses of disease interactomes revealed significant molecular and functional relatedness among autoimmune diseases, and, unexpectedly, between T1D and Alz. The systems biology approach highlighted several known pathogenic processes, indicating that changes in these functions might be driven or sustained by the framework linked to genetic susceptibility. Moreover, the comparative analyses among the five genetic interactomes revealed unexpected genetic relationships, which await further biological validation. Overall, this study outlines the potential of systems biology to uncover links between genetics and pathogenesis of complex human disorders.


Nuclei accumbens phase synchrony predicts decision-making reversals following negative feedback.
The nucleus accumbens plays a key role in reinforcement-guided behaviors. Here, we report that electrophysiological oscillatory phase synchrony between the two nuclei accumbens may play a crucial role in using negative feedback to guide decision making. We recorded local field potentials from the human nucleus accumbens and the medial frontal cortex (via surface EEG) from patients who had deep brain stimulation electrodes implanted. Patients performed a reversal learning task in which they decided whether to alter their decision strategy following monetary losses. Strategy switches following losses were preceded by enhanced theta (4-8 Hz) phase synchrony between the nuclei accumbens, and a break-down of gamma (20-80 Hz)-alpha (8-12 Hz) coupling. Furthermore, the strength of the intersite phase synchrony predicted response time adjustments in the subsequent trial. These findings suggest that a neural network including the nucleus accumbens bilaterally becomes functionally connected via theta phase synchrony to signal the need to adjust behavior.


[Criteria for admission of drug dependent criminals for withdrawal treatment according to section 64 StGB with reference to the newest legal guidelines].
Due to a sentence of the German Federal Court of constitution from March 16th, 1994 requirements on the contents of expert opinions on drug or alcohol dependent delinquents considered for being sentenced to withdrawal treatment have changed. Up to that date it has to be stated that the prognosis of withdrawal does not seem to be useless at all. Later experiences with these dependent patients are often disappointing, mostly due to a lack of any therapeutical motivation. Requirements on prognostical criteria have now profoundly changed. The psychiatric expert must positively point out now that predictors of a positive outcome of withdrawal therapy really does exist. A marked decrease in frequency of these legal sentences to withdrawal therapy must be expected as a consequence of altered prognostical criteria.


Functions of the lethal leaf-spot 1 gene in wheat cell death and disease tolerance to Puccinia striiformis.
Pheophorbide a oxygenase (PaO) is a key enzyme in chlorophyll catabolism that is known to suppress cell death in maize and Arabidopsis. The catalytic activity of PaO in chlorophyll degradation has been clearly demonstrated, but the function of PaO in the regulation of cell death and plant-microbe interactions is largely unknown. In this study, we characterized a PaO homologue in wheat of the lethal leaf-spot 1 gene, TaLls1, that was induced in leaves infected by Puccinia striiformis f.sp. tritici (Pst) and wounding treatment. The TaLls1 protein contains a conserved Rieske [2Fe-2S] motif and a mononuclear iron-binding site typical of PaOs. Silencing of TaLls1 by virus-induced gene silencing in wheat led to leaf cell death without pathogen attacks, possibly due to the accumulation of pheophorbide a (upstream substrate of PaO), indicating a suppressor role of TaLls1, while overexpression of TaLls1 also triggered cell death in both tobacco and wheat leaves, probably owing to the accumulation of the red chlorophyll catabolite (downstream product of PaO). Further deletion mutant analysis showed that the conserved Rieske domain, but not the iron-binding site, was essential for cell death induction. These results thus suggest a threshold for TaLls1 in maintaining cell homeostasis to adapt in various stresses, and shed new light on the role of TaLls1 in cell death regulation. Furthermore, silencing of TaLls1 in wheat did not change the disease symptoms but enhanced tolerance to Pst via an significant increase in H2O2 generation, elevated cell death occurrence, and upregulation of pathogenesis-related genes.


Hardware implementation of fuzzy Petri net as a controller.
The paper presents a new approach to fuzzy Petri net (FPN) and its hardware implementation. The authors' motivation is as follows. Complex industrial processes can be often decomposed into many parallelly working subprocesses, which can, in turn, be modeled using Petri nets. If all the process variables (or events) are assumed to be two-valued signals, then it is possible to obtain a hardware or software control device, which works according to the algorithm described by conventional Petri net. However, the values of real signals are contained in some bounded interval and can be interpreted as events which are not only true or false, but rather true in some degree from the interval [0, 1]. Such a natural interpretation from multivalued logic (fuzzy logic) point of view, concerns sensor outputs, control signals, time expiration, etc. It leads to the idea of FPN as a controller, which one can rather simply obtain, and which would be able to process both analog, and binary signals. In the paper both graphical, and algebraic representations of the proposed FPN are given. The conditions under which transitions can be fired are described. The algebraic description of the net and a theorem which enables computation of new marking in the net, based on current marking, are formulated. Hardware implementation of the FPN, which uses fuzzy JK flip-flops and fuzzy gates, are proposed. An example illustrating usefulness of the proposed FPN for control algorithm description and its synthesis as a controller device for the concrete production process are presented.


Endovascular coil embolization of parent artery for giant intracranial basilar artery dissection: a case report.
Isolated dissection of the basilar artery (BA) is rare and still a big challenge regarding treatment. The suitable therapeutic strategies for dissection of the BA remain controversial. We report the case of a young patient with a giant unruptured dissection of the BA successfully treated by endovascular coil embolization. A 14-year-old male who underwent computed tomography (CT) scan following a minor head trauma was incidentally found to have a lesion located anterior to brain stem. Further imaging with magnetic resonance imaging (MRI), computed tomography angiography (CTA) and digital subtraction angiography (DSA) were consistent with a diagnosis of giant unruptured dissection of the BA. The patient was initially observed conservatively. The follow-up DSA obtained 3 months later revealed extension of the dissection inferiorly to involve the left VA. The dissection expanded at the conjunction of VAs in the shape of ball. Therefore, coil embolization to occlude BA at the bottom of aneurysm was performed as a further treatment. Follow-up DSA 6 months later demonstrated complete obliteration of the dissection and good compensative perfusion from extensively collateral circulation. For young patients with isolated dissection of the BA, coil embolization to occlude BA at the bottom of aneurysm might be tolerable and effective.


Subroutines in the programme of Chlamydomonas gene expression induced by flagellar regeneration.
The unicellular green alga Chlamydomonas reinhardtii possesses two anterior flagella that are rapidly replaced if they are lost. A cytoplasmic pool of flagellar precursors supports regeneration of partial length flagella, but complete regeneration requires de novo synthesis of flagellar proteins. This increase in protein synthesis is transient and is programmed by changes in the physical abundance of a set of RNAs. These changes were measured using cloned cDNAs. The curves that were generated with probes for a number of different RNAs were variations-on-the-theme of a rapid accumulation following deflagellation of the cells, followed by similarly rapid degradation. Differences in the characteristics of the accumulation curves suggest that several 'subroutines' for RNA metabolism appear to run concurrently during flagellar regeneration. A significant portion of the mRNA abundance regulation occurs at the transcriptional level. A group of cDNAs that encode mRNAs whose abundance remains at constant levels during regeneration provides an important internal control for the abundance and transcription measurements. Flagella contain over 200 different proteins, so the possibility exists that the cells coordinately and rapidly alter the transcription of the same number of genes. Chlamydomonas flagellar regeneration thus provides an opportunity to study cellular mechanisms for coordinating the expression of a large set of genes, and correlating these changes with an easily monitored morphogenetic process.


Short Course in the Microbiome.
Over the past decade, it has become evident that the microbiome is an important environmental factor that affects many physiological processes, such as cell proliferation and differentiation, behaviour, immune function and metabolism. More importantly, it may contribute to a wide variety of diseases, including cancer, inflammatory diseases, metabolic diseases and responses to pathogens. We expect that international, integrative and interdisciplinary translational research teams, along with the emergence of FDA-approved platforms, will set the framework for microbiome-based therapeutics and diagnostics. We recognize that the microbiome ecosystem offers new promise for personalized/precision medicine and targeted treatment for a variety of diseases. The short course was held as a four-session webinar series in April 2015, taught by pioneers and experts in the microbiome ecosystem, covering a broad range of topics from the healthy microbiome to the effects of an altered microbiome from neonates to adults and the long term effects as it is related to disease, from asthma to cancer. We have learned to appreciate how beneficial our microbes are in breaking down our food, fighting off infections and nurturing our immune system, and this information provides us with ideas as to how we can manipulate our microbiome to prevent certain diseases. However, given the variety of applications, there are scientific challenges, though there are very promising areas in reference to the clinical benefits of understanding more about our microbiome, whether in our gut or on our skin: the outlook is bright. A summary of the short course is presented as a meeting dispatch.


Hypertension complicating diabetic pregnancies: pathophysiology, management, and controversies.
Hypertensive disorders of pregnancy (HDP), including pre-existing hypertension, gestational hypertension, and preeclampsia, further complicate already high-risk pregnancies in women with diabetes mellitus (DM). Women with both pre-existing and gestational diabetes are at increased risk for HDP, leading to higher maternal and fetal morbidity. Further, particularly in diabetic women and women with a history of gestational diabetes, HDP significantly increases the risk for future cardiovascular events. For clinicians, women with hypertension and diabetes during pregnancy pose a management challenge. Specifically, preconception management should stress strict control of glycemia, blood pressure, and prevention of diabetic complications, specifically nephropathy, which specifically increases the risk for preeclampsia. During gestation, clinicians must be aware of potential maternal and fetal complications associated with various anti-hypertensive therapies, including known fetotoxicity of ACE inhibitors and ARBs when given in the 2nd or 3rd trimester, and the risks and benefits of expectant management versus delivery in cases of severe gestational hypertension or preeclampsia. Indeed, diabetic women must be followed closely prior to conception and throughout gestation to minimize the risk of HDP and its associated complications.


Reconstruction of Positron Emission Tomography Images Using Gaussian Curvature.
Positron emission tomography (PET) provides images of metabolic activity in the body, and it is used in the research, monitoring, and diagnosis of several diseases. However, the raw data produced by the scanner are severely corrupted by noise, causing a degraded quality in the reconstructed images. In this paper, we proposed a reconstruction algorithm to improve the image reconstruction process, addressing the problem from a variational geometric perspective. We proposed using the weighted Gaussian curvature (WGC) as a regularization term to better deal with noise and preserve the original geometry of the image, such as the lesion structure. In other contexts, the WGC term has been found to have excellent capabilities for preserving borders and structures of low gradient magnitude, such as ramp-like structures; at the same time, it effectively removes noise in the image. We presented several experiments aimed at evaluating contrast and lesion detectability in the reconstructed images. The results for simulated images and real data showed that our proposed algorithm effectively preserves lesions and removes noise.


A cytological study of mammary disease.
An analysis is presented of 887 cytological biopsies performed on 610 patients with mammary disease, including 510 fine needle aspirations. Technical details of fine needle biopsy, imprints, and scrape-smears are provided, together with both histological and cytological descriptions. The case material has been classified into 6 series, the most important being a clinicocytological study in which fine needle biopsy achieved a 96.2% accuracy rate in respect of breast cancer. The status of cytology in the clinical management of mammary disease is evaluated.


Predicting Listeria monocytogenes virulence potential using whole genome sequencing and machine learning.
Contamination with food-borne pathogens, such as Listeria monocytogenes, remains a big concern for food safety. Hence, rigorous and continuous microbial surveillance is a standard procedure. At this point, however, the food industry and authorities only focus on detection of Listeria monocytogenes without characterization of individual strains into groups of more or less concern. As whole genome sequencing (WGS) gains increasing interest in the industry, this methodology presents an opportunity to obtain finer resolution of microbial traits such as virulence. Within this study, we therefore aimed to explore the use of WGS in combination with Machine Learning (ML) to predict L. monocytogenes virulence potential on a sub-species level. The WGS datasets used in this study for ML model training consisted of i) national surveillance isolates (n = 169, covering 38 MLST types) and ii) publicly available isolates acquired through the GenomeTrakr network (n = 2880, spanning 80 MLST types). We used the clinical frequency, i.e., ratio of the number of clinical isolates to total amount of isolates, as estimate for virulence potential. The predictive performance of input features from three different genomic levels (i.e., virulence genes, pan-genome genes, and single nucleotide polymorphisms (SNPs)) and six machine learning algorithms (i.e., Support Vector Machine with a linear kernel, Support Vector Machine with a radial kernel, Random Forrest, Neural Networks, LogitBoost, and Majority Voting) were compared. Our machine learning models predicted sub-species virulence potential with nested cross-validation F1-scores up to 0.88 for the majority voting classifier trained on national surveillance data and using pan-genome genes as input features. The validation of the pre-trained ML models based on 101 previously in vivo studied isolates resulted in F1-scores up to 0.76. Furthermore, we found that the more rapid and less computationally intensive raw read alignment yields comparably accurate models as de novo assembly. The results of our study suggest that a majority voting classifier trained on pan-genome genes is the best and most robust choice for the prediction of clinical frequency. Our study contributes to more rapid and precise characterization of L. monocytogenes virulence and its variation on a sub-species level. We further demonstrated a possible application of WGS data in the context of microbial hazard characterization for food safety. In the future, predictive models may assist case-specific microbial risk management in the food industry. The python code, pre-trained models, and prediction pipeline are deposited at (https://github.com/agmei/LmonoVirulenceML).


[History of the split between medicine and surgery].
This paper summarizes historical and philosophical aspects, from Ancient Greece to the Middle Ages, concerning the split between physicians and surgeons that began to take place in Alexandria. When exploring the changes in classical medical thought and its influence on philosophy, we conclude that this historical moment was marked by a dual distinction between an essential being and a body subjected to becoming. From a unified mind in Hippocrates, in which medicine is based in knowledge of the relations, subjected to laws, of the organism exposed to natural forces Φνσις (physis among the Jonics), a rift amongst body and soul is conceived, specifically in Platonic thought, from which the surgical intervention of the body is considered improper of the medical art.


Differential involvement of ezrin/radixin/moesin proteins in sphingosine 1-phosphate-induced human pulmonary endothelial cell barrier enhancement.
Endothelial cell (EC) barrier dysfunction induced by inflammatory agonists is a frequent pathophysiologic event in multiple diseases. The platelet-derived phospholipid sphingosine-1 phosphate (S1P) reverses this dysfunction by potently enhancing the EC barrier through a process involving Rac GTPase-dependent cortical actin rearrangement as an integral step. In this study we explored the role of the ezrin, radixin, and moesin (ERM) family of actin-binding linker protein in modulating S1P-induced human pulmonary EC barrier enhancement. S1P induces ERM translocation to the EC periphery and promotes ERM phosphorylation on a critical threonine residue (Ezrin-567, Radixin-564, Moesin-558). This phosphorylation is dependent on activation of PKC isoforms and Rac1. The majority of ERM phosphorylation on these critical threonine residues after S1P occurs in moesin and ezrin. Baseline radixin phosphorylation is higher than in the other two ERM proteins but does not increase after S1P. S1P-induced moesin and ezrin threonine phosphorylation is not mediated by the barrier enhancing receptor S1PR1 because siRNA downregulation of S1PR1 fails to inhibit these phosphorylation events, while stimulation of EC with the S1PR1-specific agonist SEW2871 fails to induce these phosphorylation events. Silencing of either all ERM proteins or radixin alone (but not moesin alone) reduced S1P-induced Rac1 activation and phosphorylation of the downstream Rac1 effector PAK1. Radixin siRNA alone, or combined siRNA for all three ERM proteins, dramatically attenuates S1P-induced EC barrier enhancement (measured by transendothelial electrical resistance (TER), peripheral accumulation of di-phospho-MLC, and cortical cytoskeletal rearrangement. In contrast, moesin depletion has the opposite effects on these parameters. Ezrin silencing partially attenuates S1P-induced EC barrier enhancement and cytoskeletal changes. Thus, despite structural similarities and reported functional redundancy, the ERM proteins differentially modulate S1P-induced alterations in lung EC cytoskeleton and permeability. These results suggest that ERM activation is an important regulatory event in EC barrier responses to S1P.


A subvertebrate system for rapid determination of potential teratogenic hazards.
The multiplicity of potential teratogenic mechanisms requires that a practical screening system for developmental hazards simultaneously assess effects on as wide a variety of developmental phenomena as possible. The system also must provide the relevant dose level based on adult toxicity. A fresh water coelenterate fashioned into an artificial "embryo" may provide the former, while exposure of adult polyps may provide the latter. The system appears to separate the two dose levels as adequately as standard laboratory rodents but as significantly lower cost in time and effort.


[Modified method of isolating thymopoietin and its effect on neuromuscular transmission].
A modified method for isolation of the calf thymus hormone thymopoetin has been developed. For hormone purification high-speed multi-stage centrifugation and gel-filtration on sefadexes were used instead of filtration. The thymus hormonal factor was identified on the basis of its ability to block neuromuscular transmission.


Corticosteroids for blastomycosis-induced ARDS: a report of two patients and review of the literature.
ARDS secondary to blastomycosis is associated with a high mortality rate despite appropriate antifungal therapy. Corticosteroids are of proven benefit in the treatment of severe Pneumocystis jiroveci pneumonia and are recommended for the treatment of severe pulmonary infections with Histoplasma capsulatum. However, their role in the treatment of severe pulmonary infections with Blastomyces dermatitidis has not been established. We report the cases of two previously healthy men who presented with severe ARDS secondary to blastomycosis. Refractory hypoxemia developed in both patients despite adequate antifungal coverage with amphotericin B. Dramatic improvement was seen in each patient after initiation of corticosteroids in addition to amphotericin B. Both patients survived and did well on follow-up. We suggest that treatment with corticosteroids may be of benefit in patients with blastomycosis-induced ARDS. This may be due to a decrease in the severity of the inflammatory response.


1,2,4-thiadiazol-5(4H)-ones: a new class of selective inhibitors of Trypanosoma cruzi triosephosphate isomerase. Study of the mechanism of inhibition.
Triosephosphate isomerase (TIM) is a ubiquitous enzyme that has been targeted for the discovery of small molecular weight compounds with potential use against Trypanosoma cruzi, the causative agent of Chagas disease. We have identified a new selective inhibitor chemotype of TIM from T. cruzi (TcTIM), 1,2,4-thiadiazol-5(4H)-one. Study the mechanism of TcTIM inhibition by a 1,2,4-thiadiazol derivative. We performed the biochemical characterization of the interaction of the 1,2,4-thiadiazol derivative with the wild-type and mutant TcTIMs, using DOSY-NMR and MS experiments. Studies of T. cruzi growth inhibition were additionally carried out. At low micromolar concentrations, the compound induces highly selective irreversible inactivation of TcTIM through non-covalent binding. Our studies indicate that it interferes with the association of the two monomers of the dimeric enzyme. We also show that it inhibits T. cruzi growth in culture.


[Drug stimulation of the peripheral nerve regeneration].
A comparative study of the effects of xymedone, riboxin, and piracetam upon the regeneration of myelinated axons and the number of surviving sensory neurons in spinal ganglia L4-L5 was studied on the model of sciatic nerve transection in rats. The three drugs decrease the number of neurons entering the posttraumatic apoptosis. Riboxin and xymedone stimulate the regeneration of myelinated axons, the latter drug being more effective and producing a 21.3 and 14.7% increase in the number of regenerated myelinated axons and a 29.3 and 37.7% increase in the relative number of sensory neurons (the transected/contralateral side ratio) in spinal ganglia L4-L5 relative to control by the 60th and 90th day upon transection, respectively.


Fully Printed Halide Perovskite Light-Emitting Diodes with Silver Nanowire Electrodes.
Printed organometal halide perovskite light-emitting diodes (LEDs) are reported that have indium tin oxide (ITO) or carbon nanotubes (CNTs) as the transparent anode, a printed composite film consisting of methylammonium lead tribromide (Br-Pero) and poly(ethylene oxide) (PEO) as the emissive layer, and printed silver nanowires as the cathode. The fabrication can be carried out in ambient air without humidity control. The devices on ITO/glass have a low turn-on voltage of 2.6 V, a maximum luminance intensity of 21014 cd m(-2), and a maximum external quantum efficiency (EQE) of 1.1%, surpassing previous reported perovskite LEDs. The devices on CNTs/polymer were able to be strained to 5 mm radius of curvature without affecting device properties.


Kerr-induced synchronization of a cavity soliton to an optical reference.
The phase-coherent frequency division of a stabilized optical reference laser to the microwave domain is made possible by optical-frequency combs (OFCs)1,2. OFC-based clockworks3-6 lock one comb tooth to a reference laser, which probes a stable atomic transition, usually through an active servo that increases the complexity of the OFC photonic and electronic integration for fieldable clock applications. Here, we demonstrate that the Kerr nonlinearity enables passive, electronics-free synchronization of a microresonator-based dissipative Kerr soliton (DKS) OFC7 to an externally injected reference laser. We present a theoretical model explaining this Kerr-induced synchronization (KIS), which closely matches experimental results based on a chip-integrated, silicon nitride, micro-ring resonator. Once synchronized, the reference laser captures an OFC tooth, so that tuning its frequency provides direct external control of the OFC repetition rate. We also show that the stability of the repetition rate is linked to that of the reference laser through the expected frequency division factor. Finally, KIS of an octave-spanning DKS exhibits enhancement of the opposite dispersive wave, consistent with the theoretical model, and enables improved self-referencing and access to the OFC carrier-envelope offset frequency. The KIS-mediated enhancements we demonstrate can be directly implemented in integrated optical clocks and chip-scale low-noise microwave generators.


Measurements, models and drivers of incoming longwave radiation in the Himalaya.
Melting snow and glacier ice in the Himalaya forms an important source of water for people downstream. Incoming longwave radiation (LWin) is an important energy source for melt, but there are only few measurements of LWin at high elevation. For the modelling of snow and glacier melt, the LWin is therefore often represented by parameterizations that were originally developed for lower elevation environments. With LWin measurements at eight stations in three catchments in the Himalaya, with elevations between 3,980 and 6,352 m.a.s.l., we test existing LWin parameterizations. We find that these parameterizations generally underestimate the LWin, especially in wet (monsoon) conditions, where clouds are abundant and locally formed. We present a new parameterization based only on near-surface temperature and relative humidity, both of which are easy and inexpensive to measure accurately. The new parameterization performs better than the parameterizations available in literature, in some cases halving the root-mean-squared error. The new parameterization is especially improving existing parameterizations in cloudy conditions. We also show that the choice of longwave parameterization strongly affects melt calculations of snow and ice.


Neuropsychiatric Disorder Subtyping Via Clustered Deep Learning Classifier Explanations.
Identifying subtypes of neuropsychiatric disorders based on characteristics of their brain activity has tremendous potential to contribute to a better understanding of those disorders and to the development of new diagnostic and personalized treatment approaches. Many studies focused on neuropsychiatric disorders examine the interaction of brain networks over time using dynamic functional network connectivity (dFNC) extracted from resting-state functional magnetic resonance imaging data. Some of these studies involve the use of either deep learning classifiers or traditional clustering approaches, but usually not both. In this study, we present a novel approach for subtyping individuals with neuropsychiatric disorders within the context of schizophrenia (SZ). We trained an explainable deep learning classifier to differentiate between dFNC data from individuals with SZ and controls, obtaining a test accuracy of 79%. We next used cross-validation to obtain robust average explanations for SZ training participants across folds, identifying 5 SZ subtypes that each differed from controls in a distinct manner and that had different degrees of symptom severity. These subtypes specifically differed from one another in their interactions between the visual network and the subcortical, sensorimotor, and auditory networks and between the cerebellar network and the cognitive control and subcortical networks. Additionally, we uncovered statistically significant differences in negative symptom scores between the subtypes. It is our hope that the proposed novel subtyping approach will contribute to the improved understanding and characterization of SZ and other neuropsychiatric disorders.


General Green's functions for SAW device analysis.
The traditional Green's function has been widely used to analyze surface acoustic wave (SAW) devices for many years because of its physical basis and its ability to model many propagating modes. Simplifications are, however, introduced in the derivation of the traditional Green's function that cause it to ignore some important effects, such as mass loading caused by surface electrodes. Recently, a generalized Green's function was introduced that is able to include mechanical loading effects. Based on previous work by E.L. Adler (1994) and R.C. Peach (1995), we use concise matrix notation to deduce the generalized Green's functions that describe the effects of surface stresses and electrical displacement on the three mechanical displacement components and on the electrical potential. Effective permittivities of 15 materials/cuts and the 16-element Green's functions for two materials are presented.


Music therapy in palliative setting.
The expectations on the care of humans with an incurable disease are to console, to relieve pain and to take away somebody's fears. Therefore, palliative care tries to support terminally ill persons during the last stage of life and to ameliorate the living conditions. The question is how far music therapy can increase the quality of life. Until now, there is only small evidence for that, because there are too few applicable studies.


[The genesis of experimental granulosa cell tumors of the ovaries].
Ovaries and their tumors were investigated in virgin female mice (78 control and 252 experimental) of line A and CC57W (aged-from 1 to 1 1/2 months) in the experiments with intravaginal application of polyurethan, 7,12-dimethylbenz (a) anthracene, 8-oxychinoline, synoestrol. It was demonstrated that only granulosa elements of atresic follicles are involved in the process of blastomogenesis. Theca-tissue showed no appreciable participation in proliferative processes. Totally, pretumor changes were noted in 56 cases, folliculomas or pathological changes morphologically identical to microfolliculomas- in 26 cases.


Apnoeic Oxygenation during Simulated Difficult Intubation in Obese Patients: Comparison of Buccal Ring, Adair and Elwyn Tube Versus Nasal Cannula: A Prospective Randomized Controlled Trial.
Apnoeic oxygenation is an established method of increasing safe apnoea times during intubation and this is of more importance in obese patients. The usefulness of buccal Ring, Adair and Elwyn (RAE) oxygenation has been established in previous studies, however a head-to-head comparison with nasal cannula (NC) is lacking. The aim of this study was to compare apnoea time with buccal RAE (BR) versus NC in obese patients. This was a prospective, nonblinded randomized controlled trial conducted in a tertiary hospital where fifty American Society of Anaesthesiologists Physical Status Class I and II, obese patients with body mass index ≥30, posted for elective surgery were included. Following adequate preoxygenation and standard induction of anaesthesia, a prolonged simulated difficult laryngoscopy was performed during which oxygen was provided via either BR or NC. The primary outcome was time to desaturation to <95% or 10 min, which ever occurred first. Other outcomes recorded were lowest saturation, time to resaturation and highest end tidal carbon di oxide. Mean with standard deviation (SD) or median with inter quartile range were used for continuous variables and absolute number with percentage were used for categorical variables. The primary outcome was analyzed using Kaplan-Meier survival curves, and log-rank tests were applied. Patient characteristics were similar in both arms. The mean apnoea time in seconds (SD) in the BR group, 375.3 (116.6) was higher than the NC group 316.1 (94.1), P = 0.054. From the Kapan Meier curves the probability of desaturating to <95% was earlier in the NC group than the BR group (P = 0.092). The other outcomes were similar in both groups. This is the first study that demonstrates that oxygenation via a BR is better than NC in providing apnoeic oxygenation in obese patients and can safely be used when NC are contraindicated.


Fast Purcell-enhanced single photon source in 1,550-nm telecom band from a resonant quantum dot-cavity coupling.
High-bit-rate nanocavity-based single photon sources in the 1,550-nm telecom band are challenges facing the development of fibre-based long-haul quantum communication networks. Here we report a very fast single photon source in the 1,550-nm telecom band, which is achieved by a large Purcell enhancement that results from the coupling of a single InAs quantum dot and an InP photonic crystal nanocavity. At a resonance, the spontaneous emission rate was enhanced by a factor of 5 resulting a record fast emission lifetime of 0.2 ns at 1,550 nm. We also demonstrate that this emission exhibits an enhanced anti-bunching dip. This is the first realization of nanocavity-enhanced single photon emitters in the 1,550-nm telecom band. This coupled quantum dot cavity system in the telecom band thus provides a bright high-bit-rate non-classical single photon source that offers appealing novel opportunities for the development of a long-haul quantum telecommunication system via optical fibres.


Palmitoylation of claudins is required for efficient tight-junction localization.
Palmitoylation of integral membrane proteins can affect intracellular trafficking, protein-protein interactions and protein stability. The goal of the present study was to determine whether claudins, transmembrane-barrier-forming proteins of the tight junction, are palmitoylated and whether this modification has functional implications for the tight-junction barrier. Claudin-14, like other members of the claudin family, contains membrane-proximal cysteines following both the second and the fourth transmembrane domains, which we speculated could be modified by S-acylation with palmitic acid. We observed that [(3)H]-palmitic acid was incorporated into claudin-14 expressed by transfection in both cultured epithelial cells and fibroblasts. Mutation of cysteines to serines following either the second or the fourth transmembrane segments decreased the incorporation of [(3)H]-palmitic acid, and mutation of all four cysteines eliminated palmitoylation. We previously reported that expression of claudin-14 in epithelial monolayers results in a fivefold increase in electrical resistance. By contrast, expression of the mutant claudin-14 resulted in smaller increases in resistance. The mutants localized less well to tight junctions and were also found in lysosomes, suggesting an alteration in trafficking or stability. However, we observed no change in protein half-life and only a small shift in fractionation out of caveolin-enriched detergent-resistant membranes. Although less well localized to the tight junction, palmitoylation-deficient claudin-14 was still concentrated at sites of cell-cell contact and was competent to assemble into freeze-fracture strands when expressed in fibroblasts. These results demonstrate that palmitoylation of claudin-14 is required for efficient localization into tight junctions but not stability or strand assembly. Decreased ability of the mutants to alter resistance is probably the result of their less efficient localization into the barrier.


School age outcome of hospitalisation with respiratory syncytial virus infection of prematurely born infants.
Hospitalisation due to respiratory syncytial virus (RSV) infection in the first 2 years after birth has been associated with increased healthcare utilisation and associated costs up to 5 years of age in children born prematurely at less than 32 weeks of gestation who developed bronchopulmonary dysplasia (BPD). A study was undertaken to determine whether hospitalisation due to RSV infection in the first 2 years was associated with increased morbidity and lung function abnormalities in such children at school age, and if any effects were influenced by age. Healthcare utilisation and cost of care in years 5-7 were reviewed in 147 children and changes in healthcare utilisation between 0 and 8 years were assessed also using results from two previous studies. At age 8-10 years, 77 children had their lung function assessed and bronchial hyper-responsiveness determined. Children hospitalised with RSV infection (n = 25) in the first 2 years had a greater cost of care related to outpatient attendance than those with a non-respiratory or no admission (n = 72) when aged 5-7 years (p = 0.008). At 8-10 years of age, children hospitalised with RSV infection (n = 14) had lower forced expiratory volume in 0.75 s (FEV(0.75)) (p = 0.015), FEV(0.75)/forced vital capacity (p = 0.027) and flows at 50% (p = 0.034) and 75% (p = 0.006) of vital capacity than children hospitalised for non-RSV causes (n = 63). Healthcare utilisation decreased with increasing age regardless of RSV hospitalisation status. In prematurely born children who had BPD, hospitalisation due to RSV infection in the first 2 years is associated with reduced airway calibre at school age.


TASOM: a new time adaptive self-organizing map.
The time adaptive self-organizing map (TASOM) network is a modified self-organizing map (SOM) network with adaptive learning rates and neighborhood sizes as its learning parameters. Every neuron in the TASOM has its own learning rate and neighborhood size. For each new input vector, the neighborhood size and learning rate of the winning neuron and the learning rates of its neighboring neurons are updated. A scaling vector is also employed in the TASOM algorithm for compensation against scaling transformations. Analysis of the updating rules of the algorithm reveals that the learning parameters may increase or decrease for adaptation to a changing environment, such that the minimum increase or decrease is achieved according to a specific measure. Several versions of the TASOM-based networks are proposed in this paper for different applications, including bilevel thresholding of grey level images, tracking of moving objects and their boundaries, and adaptive clustering. Simulation results show satisfactory performance of the proposed methods in the implemented applications.


Paraoxon hydrolysis vs. covalent binding in the elimination of paraoxon in the rabbit.
Hydrolysis and covalent binding to nonessential esterases are two biochemical processes which can prevent paraoxon from reacting with the essential enzyme, acetylcholinesterase. Both processes have been proposed as the primary route of paraoxon detoxification in vivo. These experiments were designed to assess the relative contribution of each pathway to the disappearance of paraoxon in the rabbit. In vitro, paraoxon disappeared from whole rabbit blood with a t 1/2 of 17.7 sec. Hydrolysis by paraoxonase (EC 22.214.171.124) accounted entirely for this disappearance and covalent binding contributed essentially nothing. In vivo, following an iv injection of 0.15 mg/kg paraoxon, serum paraoxonase hydrolyzed as much as 41% of the injected dose within the first 30 sec. Pretreatment of rabbits with an ip injection of tri-o-tolyl phosphate eliminated more than 95% of the paraoxon binding sites. However, pretreatment with tri-o-tolyl phosphate had no significant effect on the t 1/2 or volume of distribution of paraoxon, indicating that covalent binding sites did not contribute significantly to the clearance of paraoxon from whole rabbits under these conditions. Hydrolysis of paraoxon by tissue paraoxonases, in addition to that catalyzed by paraoxonase in the blood, could account for its rapid metabolism. These findings demonstrate that paraoxonase has a major role in the disappearance of paraoxon in the rabbit. This suggests that susceptibility of people to chronic paraoxon poisoning may vary, according to their inherited level and type of serum paraoxonase.


Prevalence and risk factors of urinary incontinence in women residing in a tribal area in Maharashtra, India.
To study the prevalence and risk factors of urinary incontinence in tribal women and to assess the treatment seeking behavior of affected women. A cross-sectional descriptive study was conducted in Khardi, a tribal village, selected by random sampling, in Thane district, Maharashtra, India during the period October 2010 to January 2011. All women aged 20 years and above were selected for the study except pregnant and lactating women and those with neurological disorders affecting bladder continence. A semi-structured questionnaire assessing socio-demographic factors of women, severity, type of incontinence, obstetric and other risk factors of incontinence was administered to the study participants. The participants who suffered from incontinence were inquired regarding their treatment seeking behavior for the same. Logistic regression analysis was used to determine the independent association between these factors and primary outcome of incontinence. Of 353 women participated in the study, 90 (25.5%) reported urinary incontinence. Prevalence of urinary incontinence showed significant association with increasing age (P<0.010). Associated obstetric factors included high parity (P<0.001), early post-partum resumption of heavy work (P<0.050) and prolonged labor (P<0.010). Other risk factors like hypertension, diabetes, chronic cough and constipation were predictors of incontinence in regression analysis (R2=0.47). Healthcare seeking rate was only 14.4% since they either accepted incontinence as a normal ageing process or were embarrassed to seek medical advice. Urinary incontinence is a neglected problem in tribal women predicted by obstetric and other risk factors.


Benchmarking joint multi-omics dimensionality reduction approaches for the study of cancer.
High-dimensional multi-omics data are now standard in biology. They can greatly enhance our understanding of biological systems when effectively integrated. To achieve proper integration, joint Dimensionality Reduction (jDR) methods are among the most efficient approaches. However, several jDR methods are available, urging the need for a comprehensive benchmark with practical guidelines. We perform a systematic evaluation of nine representative jDR methods using three complementary benchmarks. First, we evaluate their performances in retrieving ground-truth sample clustering from simulated multi-omics datasets. Second, we use TCGA cancer data to assess their strengths in predicting survival, clinical annotations and known pathways/biological processes. Finally, we assess their classification of multi-omics single-cell data. From these in-depth comparisons, we observe that intNMF performs best in clustering, while MCIA offers an effective behavior across many contexts. The code developed for this benchmark study is implemented in a Jupyter notebook-multi-omics mix (momix)-to foster reproducibility, and support users and future developers.


Tissue kallikrein synthesis and its modification by testosterone or low dietary sodium.
A method has been developed to measure the relative rate of rat tissue kallikrein synthesis which employs a specific antiserum raised against a purified rat urinary kallikrein. Incorporation of [35S]methionine into kallikrein and protein 20 min after intraperitoneal injection was measured in submaxillary gland, pancreas, kidney and descending colon. Kallikrein content was measured with a direct radioimmunoassay, and kallikrein-specific incorporation of [35S]methionine measured after immunoprecipitation. Kallikrein specific radioactivity (c.p.m./mg of enzyme) was about 100-fold greater than that in total protein in both kidney and colon. In contrast, in pancreas the incorporation into the enzyme was only 5-fold higher than into protein, and in submaxillary gland the incorporation was equivalent. Measured as kallikrein-specific radioactivity relative to total protein radioactivity incorporated in 20 min, kallikrein represents 0.18% of total protein synthesis in the kidney, 0.34% in the pancreas, 0.41% in the colon, but 7.29% in the submaxillary gland. Dietary Na+ restriction increased the relative rate of kallikrein synthesis 1.8-fold in the kidney without a comparable effect in submaxillary gland. In contrast, testosterone increased the relative rate of synthesis 2.3-fold in submaxillary gland, but decreased it in kidney. The data show that endogenous kallikrein synthesis differs markedly in various tissues, and that interventions which are known to change kallikrein content or excretion also change the relative rate of enzyme synthesis.


Deep Learning Enabled Diagnosis of Children's ADHD Based on the Big Data of Video Screen Long-Range EEG.
Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children. At the same time, ADHD is prone to coexist with other mental disorders, so the diagnosis of ADHD in children is very important. Electroencephalogram (EEG) is the sum of the electrical activity of local neurons recorded from the extracranial scalp or intracranial. At present, there are two main methods of long-range EEG monitoring commonly used in clinical practice: one is ambulatory EEG monitoring, and the other is long-range video EEG monitoring. The purpose of this study is to summarize the brain electrical activity and clinical characteristics of children with ADHD through the video long-range computer graphics data of children with ADHD and to explore the clinical significance of video long-range EEG in the diagnosis of children with ADHD. For a more effective analysis, this study further processed the video data of long-range computer graphics of children with ADHD and constructed several neural network algorithm models based on deep learning, mainly including fully connected neural network models and two-dimensional convolutional neural networks. Model and long- and short-term memory neural network model. By comparing the recognition effects of these several algorithms, find the appropriate recognition algorithm to improve the accuracy and then establish a recognition method for the diagnosis of children's ADHD based on deep learning long-range EEG big data. Finally, it is concluded that long-term video EEG can analyze the EEG relationship of children with ADHD and provide a diagnostic basis for the diagnosis of ADHD.


The microbial colonization profile of respiratory devices and the significance of the role of disinfection: a blinded study.
Approximately 10-40% of all the nosocomial infections are pulmonary, which lead to grave complications. Elderly, debilitated, or critically ill patients are at a high risk. The respiratory care equipments which include ventilators, humidifiers, nebulizers may have been identified as the potential vehicles which cause major nosocomial infections if they are colonized by fungi or bacteria. To determine the rate of colonization by bacteria and fungi of the oxygen humidifier chambers of the portable cylinders and central lines at our hospital. The Hudson's chambers of nebulizers were also studied for the same. Swab samples were obtained from the equipments by using sterile cotton swabs on a tuesday, as these chambers were usually cleaned on every Saturday. Spot samples were taken from the ICUs, wards, the casualty and OPDs on a single day. Air samples were also obtained on the same day to determine whether the fungal spore load in the inhaled room air was normal or high. We performed a disinfection with 70% ethanol after cleaning these devices. 53/70 (75.71%) samples showed fungal growth; out of which, 23/33 (69.70%) were from the ICU, 24/30(80%) were from the wards and 6/7 (85.71%) were from the OPDs. 23/30 (76.66%) swabs from the central line humidifiers, 18/23(78.26%) swabs from the O2 cylinder humidifiers and 8/17 (47.5%) swabs from the nebulizers grew bacteria. Of the total 61(87.14%) bacterial isolates, 42(68.85%) were gram negative bacteria and 19(31.14%) were gram positive cocci. Out of the 42 gram negative bacteria, 17 were multi-drug resistant like ESBL producers ie. Pseudomonas spp. (6) Acinetobacter spp.(4), Klebseilla pneumoniae (4), E.coli (2) and Stenotrophomonas maltophila (1). Our findings (before disinfection) showed that the colonization rate for fungi was 75% and that for bacteria, it was 87%. After the 70% ethanol disinfection and strict compliance with the hand hygiene, the colonization rates reduced significantly. The fungal colonization rate was reduced and only 15% fungi grew after the disinfection, while only 12% bacterial colonization rate was found. This study indicates a potential in-hospital source of allergens and infections. The oxygen and nebulizer chambers need to be cleaned more frequently with disinfectants, to control the possible nosocomial infections.


Evolution of group 14 rhodamines as platforms for near-infrared fluorescence probes utilizing photoinduced electron transfer.
The absorption and emission wavelengths of group 14 pyronines and rhodamines, which contain silicon, germanium, or tin at the 10 position of the xanthene chromophore, showed large bathochromic shifts compared to the original rhodamines, owing to stabilization of the LUMO energy levels by σ*-π* conjugation between group 14 atom-C (methyl) σ* orbitals and a π* orbital of the fluorophore. These group 14 pyronines and rhodamines retain the advantages of the original rhodamines, including high quantum efficiency in aqueous media (Φ(fl) = 0.3-0.45), tolerance to photobleaching, and high water solubility. Group 14 rhodamines have higher values of reduction potential than other NIR light-emitting original rhodamines, and therefore, we speculated their NIR fluorescence could be controlled through the photoinduced electron transfer (PeT) mechanism. Indeed, we found that the fluorescence quantum yield (Φ(fl)) of Si-rhodamine (SiR) and Ge-rhodamine (GeR) could be made nearly equal to zero, and the threshold level for fluorescence on/off switching lies at around 1.3-1.5 V for the SiRs. This is about 0.1 V lower than in the case of TokyoGreens, in which the fluorophore is well established to be effective for PeT-based probes. That is to say, the fluorescence of SiR and GeR can be drastically activated by more than 100-fold through a PeT strategy. To confirm the validity of this strategy for developing NIR fluorescence probes, we employed this approach to design two kinds of novel fluorescence probes emitting in the far-red to NIR region, i.e., a series of pH-sensors for use in acidic environments and a Zn(2+) sensor. We synthesized these probes and confirmed that they work well.


Electronic cigarette use is not associated with quitting of conventional cigarettes in youth smokers.
BackgroundTo investigate the association between electronic cigarette (e-cig) use and smoking cessation among smokers who called the Youth Quitline in Hong Kong.MethodsThis longitudinal study collected data on youth smokers' (N=189) use and perception of e-cigs, conventional cigarette smoking behavior, and sociodemographic characteristics at baseline. Self-reported past 7-day point prevalence of abstinence (PPA) was assessed in the 6-month telephone follow-up. Linear and logistic regressions were used to estimate the association of e-cig use with quitting cigarette smoking and other cessation-related outcomes.ResultsE-cig users were younger, more addicted to nicotine, and less ready to quit (all P<0.05) at baseline. The PPA rate was lower in e-cig users (13.4% vs. 20.8%) at follow-up. E-cig use was not associated with PPA at the 6-month follow-up (odds ratio (OR): 0.56, 95% CI: 0.24 to 1.35), but it was nonsignificantly related to more cessation attempts (raw coefficient (b): 1.26, 95% CI: -0.13 to 2.66). Among those who still smoked, e-cig use was nonsignificantly associated with intention to quit smoking (OR: 0.55, 95% CI: 0.15 to 2.05), nicotine dependence (Fagerström score, b: 0.75, 95% CI: -0.39 to 1.90), and perceptions on quitting cigarette smoking.ConclusionE-cig use was not associated with successful smoking cessation among Youth Quitline smokers.


Extent and sources of occupational stress in university staff.
Canadian higher education sector has undergone numerous changes during the past decades. Increased student enrolments, massive cuts in human resources and constant restructuring are changes likely to have had a considerable impact on all employees (e.g., administrative, trades, and faculty). While many studies conducted in different countries have shown that stress in universities is a problem of alarming proportions, to date, no study of the entire staff of a university has been carried out in Canada. This research uses an approach based on the prevention and management of the sources of occupational stress to study 1086 employees of a Quebec university. Data were collected by means of questionnaires and semi-structured interviews. It was found that the proportion of individuals who reported a high level of psychological distress was twice as high (40%) than that reported for a Quebec-wide sample (20%). Work overload, the relationship with one's superior and participation in decision making were systematically reported as high risks to employees' health. It was found that human resources management practices have not followed the rapid organizational changes which affected the university in the past years. The results are discussed in light of the risk management approach.


From higher order thinking to higher order behavior: exploring the relationship between early cognitive skills and social competence in black boys.
This study examines the relations of higher order (i.e., abstract) thinking (HOT) skills to specific domains of social competence in Black boys (n = 108) attending publicly sponsored prekindergarten (pre-K) programs. Data for the study were collected as part of the National Center for Early Development and Learning (NCEDL) Multi-State Study, a national, longitudinal study examining the quality and outcomes in a representative sample of publicly sponsored pre-K programs in six states (N = 240). Pre-K and kindergarten teachers rated randomly selected children on measures of abstract thinking, self-regulation, and social functioning at the beginning and end of each school year. Applying structural equation modeling, compared with earlier time points, HOT measured in the fall of kindergarten significantly predicted each of the domains of social competence in the spring of kindergarten, with the exception of peer social skills, while controlling for general cognitive ability. Results suggest that early intervention to improve HOT may be an effective and more focused approach to address concerns about Black boys' early social competencies in specific domains and potentially reduce the risk of later social difficulties.


Bluetongue virus serotype 8 (BTV-8) infection reduces fertility of Dutch dairy cattle and is vertically transmitted to offspring.
In 2007, BTV-8 re-emerged for the second year in the Netherlands and caused morbidity and increased mortality in cattle herds. In addition, cattle farmers reported reduced fertility in their cows. For this study, fifteen herds that were not vaccinated were selected. These were matched to 10 vaccinated herds by geographic region. At the start of the study, in July 2008, all cattle in the non-vaccinated herds >1 year old were sampled. All seronegative cows entered the study program and blood samples from these cows were tested for antibodies against BTV-8 in an ELISA. Cows were sampled at intervals of three weeks and sampling was stopped once a cow tested seropositive. Sampling ceased in all remaining cows in December 2008. Newborn calves originating from infected dams or from vaccinated dams were tested by PCR for BTV-8. Fertility data were obtained from the Royal Dutch Cattle Syndicate (CRV). Multi-level generalized latent and linear models were used for analyses. In 2008, 185 (17.2%) out of 1,074 initially seronegative non-vaccinated cattle seroconverted and were assumed to be infected with BTV-8. Infected cows were 5 (95% CI: 1.9-14.3) times more likely to return for insemination within 56 days after first insemination. In addition, these cows needed 1.7 (95% CI: 1.4-2.0) times more inseminations for an assumed pregnancy, and needed 2.5 (95% CI: 2.4-2.6) times more days between first and last insemination compared to the period prior to seroconversion and compared to cows not infected by BTV-8 in 2008. No association between BTV-8 infection and the chance to abort between 100 and 260 days after last insemination was found. In total, 48 calves originating from infected cows were tested by PCR for the presence of BTV-8. Ten (20.8%) out of these 48 calves were born PCR-positive. None of 256 calves from vaccinated dams tested PCR-positive. Further, cows infected during the second half of gestation had a 15.5 times (95% CI: 1.3-190.4) higher chance of a PCR-positive newborn calf compared to cows infected in the first half of gestation. This study showed that BTV-8 has a negative effect on fertility of dairy cattle.


Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness.
The recent identification of "side population" (SP) cells in a number of unrelated human cancers and their normal tissue sources has renewed interest in the hypothesis that cancers may arise from somatic stem/progenitor cells. The high incidence of recurrence attributable to multidrug resistance and the multiple histologic phenotypes indicative of multipotency suggests a stem cell-like etiology of ovarian cancer. Here we identify and characterize SP cells from two distinct genetically engineered mouse ovarian cancer cell lines. Differential efflux of the DNA-binding dye Hoechst 33342 from these cell lines defined a human breast cancer-resistance protein 1-expressing, verapamil-sensitive SP of candidate cancer stem cells. In vivo, mouse SP cells formed measurable tumors sooner than non-SP (NSP) cells when equal numbers were injected into the dorsal fat pad of nude mice. The presence of Mullerian Inhibiting Substance (MIS) signaling pathway transduction molecules in both SP and NSP mouse cells led us to investigate the efficacy of MIS against these populations in comparison with traditional chemotherapies. MIS inhibited the proliferation of both SP and NSP cells, whereas the lipophilic chemotherapeutic agent doxorubicin more significantly inhibited the NSP cells. Finally, we identified breast cancer-resistance protein 1-expressing verapamil-sensitive SPs in three of four human ovarian cancer cell lines and four of six patient primary ascites cells. In the future, individualized therapy must incorporate analysis of the stem cell-like subpopulation of ovarian cancer cells when designing therapeutic strategies for ovarian cancer patients.


Effect of monensin sodium on histological lesions of naturally occurring bovine paratuberculosis.
Of 19 adult cows naturally infected with paratuberculosis, 13 were treated with monensin sodium and six remained untreated. At the beginning of the study, the severity of the histological lesions was assessed from biopsy samples of ileum, liver, mesenteric lymph node and rectal mucosa. From the data acquired it was possible to assign the animals so that the lesions in the two groups were similar (P=0. 8323). Monensin was administered in the feed, which contained 147.5 mg/kg, and each treated cow received 450 mg of monensin daily for 120 days. At the end of this period all cows were killed and histopathological findings in the ileum, liver, mesenteric lymph node and rectal mucosa were compared with the initial findings. A scoring system showed that monensin had a beneficial effect in the ileum (P=0.077), liver (P=0.0322) and rectal mucosa (P=0.0578), but under the conditions of the experiment no such effect could be demonstrated in mesenteric lymph node (P=0.3599). There appeared to be an overall effect on all tissues taken together (P=0.1335). The effect of monensin may have been due to both a halting and a reversal of the pathological process. In all but one of the six untreated cows, the lesions worsened during the course of the experiment.


Catalytic mechanism of a family 3 beta-glucosidase and mutagenesis study on residue Asp-247.
A family 3 beta-glucosidase (EC 22.214.171.124) from Flavobacterium meningosepticum has been cloned and overexpressed. The mechanistic action of the enzyme was probed by NMR spectroscopy and kinetic investigations, including substrate reactivity, secondary kinetic isotope effects and inhibition studies. The stereochemistry of enzymic hydrolysis was identified as occurring with the retention of an anomeric configuration, indicating a double-displacement reaction. Based on the k(cat) values with a series of aryl glucosides, a Bronsted plot with a concave-downward shape was constructed. This biphasic behaviour is consistent with a two-step mechanism involving the formation and breakdown of a glucosyl-enzyme intermediate. The large Bronsted constant (beta=-0.85) for the leaving-group-dependent portion (pK(a) of leaving phenols >7) indicates substantial bond cleavage at the transition state. Secondary deuterium kinetic isotope effects with 2,4-dinitrophenyl beta-D-glucopyanoside, o-nitrophenyl beta-D-glucopyanoside and p-cyanophenyl beta-D-glucopyanoside as substrates were 1.17+/-0.02, 1.19+/-0.02 and 1.04+/-0.02 respectively. These results support an S(N)1-like mechanism for the deglucosylation step and an S(N)2-like mechanism for the glucosylation step. Site-directed mutagenesis was also performed to study essential amino acid residues. The activities (k(cat)/K(m)) of the D247G and D247N mutants were 30000- and 200000-fold lower respectively than that of the wild-type enzyme, whereas the D247E mutant retained 20% of wild-type activity. These results indicate that Asp-247 is an essential amino acid. It is likely that this residue functions as a nucleophile in the reaction. This conclusion is supported by the kinetics of the irreversible inactivation of the wild-type enzyme by conduritol-B-epoxide, compared with the much slower inhibition of the D247E mutant and the lack of irreversible inhibition of the D247G mutant.


Psychiatric hospitalization and managed care in conflict.
The managed-care concurrent review process often results in denied or limited coverage of psychiatric inpatient care due to reviewers' misconceptions about psychiatric hospitalization and in an effort to achieve savings. For employers, such decisions may cost more in the long run.


Constant-distance mode scanning potentiometry. 1. Visualization of calcium carbonate dissolution in aqueous solution.
Constant-distance mode scanning potentiometry was established by integrating potentiometric microsensors as ion-selective scanning probes into a SECM setup that was equipped with a piezoelectric shear force-based tip-to-sample distance control. The combination of specially designed micrometer-sized potentiometric tips with an advanced system for tip positioning allowed simultaneous acquisition of both topographic and potentiometric information at solid/liquid interfaces with high spatial resolution. The performance of the approach was evaluated by applying Ca(2+)-selective constant-distance mode potentiometry to monitor the dissolution of calcium carbonate occurring either at the (104) surface of calcite crystals or in proximity to the more complex surface of cross sections of a calcium carbonate shell of Mya arenaria exposed to slightly acidic aqueous solutions. Micrometer-scale heterogeneities in the apparent calcium activity profiles have successfully been resolved for both samples.


Characterization of a haemolysin from Mycobacterium tuberculosis with homology to a virulence factor of Serpulina hyodysenteriae.
Scrutiny of sequence data from the Mycobacterium leprae genome sequencing project identified the presence of a gene encoding a 268-amino-acid polypeptide which is highly similar to a pore-forming haemolysin/cytotoxin virulence determinant, TlyA, from the swine pathogen Serpulina hyodysenteriae. Using degenerate oligonucleotide primers based on the TlyA sequences, the Mycobacterium tuberculosis homologue was amplified and this product was used to obtain the clone and sequence a 2.5 kb fragment containing the whole M. tuberculosis tlyA gene. tlyA encodes a 267-amino-acid protein with a predicted molecular mass of 28 kDa. TlyA homologues were identified by PCR in M. leprae, Mycobacterium avium and Mycobacterium bovis BCG, but appeared absent in Mycobacterium smegmatis, Mycobacterium vaccae, Mycobacterium kansasii, Mycobacterium chelonae and Mycobacterium phlei. The M. tuberculosis gene appeared to be the first gene in an operon containing at least two other genes. Introduction of the M. tuberculosis tlyA gene into M. smegmatis using a mycobacterial shuttle expression plasmid converted non-haemolytic cells into those exhibiting significant haemolytic activity. Similarly, inducible haemolytic activity was observed in sonicated bacteria when tlyA was expressed as a His6-tagged fusion protein in Escherichia coli. tlyA mRNA was detected in both M. tuberculosis and M. bovis BCG using RT-PCR, confirming that this gene is expressed in organisms cultured in vitro.


Comparison of different methods of classifying patients with systemic lupus erythematosus.
The sensitivity and percent agreement of 3 methods of classifying patients with systemic lupus erythematosus (SLE), the 1982 American Rheumatism Association (ARA) revised criteria and a simple and full classification tree, were compared using data from The Johns Hopkins Lupus Cohort, a prospective study of 198 patients with SLE. The 1982 revised criteria were significantly more sensitive than the simple classification tree, correctly identifying 184 (93%) cases compared to 168 (85%) (p = 0.016). Agreement between these 2 classification schema was noted in 174 (87%) cases with 164 classified correctly and 10 failing to satisfy either criteria set. The full classification tree correctly identified 186 (94%) cases. There was no difference in the sensitivity of either the 1982 revised criteria or the full classification tree by racial group; however, the simple classification tree was significantly less sensitive among black than Caucasian patients (80 vs 91.5% p = 0.038). Our data support the continued use of the 1982 revised ARA criteria for the classification of patients with SLE for clinical and epidemiologic research studies.


Phase transformations in carbon fullerenes at high shock pressures.
C(60) powders were shock-compressed quasi-isentropically and quenched from pressures in the range 10 to 110 GPa (0.1 to 1.1 Mbar). Recovered specimens were analyzed by Raman spectroscopy and optical microscopy. C(60) fullerenes are stable into the 13- to 17-GPa pressure range. The onset of a fast ( approximately 0.5 micros) reconstructive transformation to graphite occurs near 17 GPa. The graphite recovered from 27 GPa and about 600 degrees C is relatively well ordered with crystal planar domain size of about 100 A. Above 50 GPa a continuous transformation to an amorphous state is observed in recovered specimens. The fast transformation to graphite is proposed to occur by pi-electron rehybridization which initiates breakup of the ball structure and formation of the graphite structure at high density.


MutY is down-regulated by oxidative stress in E. coli.
In Escherichia coli, MutM (8-oxoG DNA glycosylase/lyase or Fpg protein), MutY (adenine DNA glycosylase) and MutT (8-oxodGTPase) function cooperatively to prevent mutation due to 7, 8-dihydro-8-oxoguanine (8-oxoG), a highly mutagenic oxidative DNA adduct. MutM activity has been demonstrated to be induced by oxidative stress. Its regulation is under the negative control of the global regulatory genes, fur, fnr and arcA. However, interestingly the presence of MutY increases the mutation frequency in mutT- background because of MutY removes adenine (A) from 8-oxoG:A which arises from the misincorporation of 8-oxoG against A during DNA replication. Accordingly we hypothesized that the response of MutY to oxidative stress is opposite to that of MutM and compared the regulation of MutY activity with MutM under various oxidative stimuli. Unlike MutM, MutY activity was reduced by oxidative stress. Its activity was reduced to 30% of that of the control when E. coli was treated with paraquat (0.5mM) or H2O2 (0.1 mM) and induced under anaerobic conditions to more than twice that observed under aerobic conditions. The reduced mRNA level of MutY coincided with its reduced activity by paraquat treatment. Also, the increased activity of MutY in anaerobic conditions was reduced further in E. coli strains with mutations in fur, fnr and arcA and the maximum reduction in activity was when all mutations were present in combination, indicating that MutY is under the positive control of these regulatory genes. Therefore, the down-regulation of MutY suggests that there has been complementary mechanism for its mutagenic activity under special conditions. Moreover, the efficacy of anti-mutagenic action should be enhanced by the reciprocal co-regulation of MutM.


[Criminal claims about medical professional liability in the Instituto de Medicina Legal of Lima, Peru].
To determine the characteristics of the criminal complaints claining medical professional liability, based on the expert reports issued by the Forensic Examination Division of Lima, Peru. A cross-sectional study was carried out, which included all the expert reports issued between 2005 and 2010 at the Forensic Examination Division of Lima, Peru. A descriptive analysis of each of the variables was performed. 60.3% (495/821) of the criminal complaints for medical professional liability were valued as being in accordance with the lex artis while 16.8% (138/821) were not in accordance with the lex artis. In 13% (107/821) of the cases, conclusions could not be drawn;in 9.9% (81/821) of the cases, the conclusions in the expert report did not include an valuations of the medical act.The cases in which the injury was attributed to the process of the disease itself accounted for 80.9% (502/620), and those in which in the injury was considered a result of the health care received were 19.0% (118/620). The distribution of the cause of the injury based on accordance with the lex artis showed significant differences. In our country, the number of claims for claimed medical liability is increasing, predominantly in relation to surgical specialties, where a medical act is more likely to be considered not in accordance with the lex artis. In addition, in a significant percentage of cases, no conclusions are drawn about the medical act.


Molecular divergence of the sia locus in different serogroups of Neisseria meningitidis expressing polysialic acid capsules.
The serogroups B, C, W135 and Y of Neisseria meningitidis express chemically and immunologically distinct capsular polysaccharides containing sialic acid. In the case of serogroup B meningococci sialic acid is synthesized by the gene products of a locus termed sia and forms the homopolymers of the capsule. The organization of the genes required for sialic acid synthesis in serogroups B, C, W135 and Y was elucidated by PCR technology. Cloning, sequencing and the functional expression of the polysialyltransferase (PST) genes of serogroups B and C demonstrated that the difference in capsule composition derives from the presence of related, but distinct siaD genes coding for PSTs. Analysis of meningococci of serogroups W135 and Y expressing sialic acid heteropolymers revealed that the DNA sequences of the corresponding genetic loci in these serogroups were highly homologous, but differed completely from the siaD genes of serogroups B and C. This finding suggests that enzymes unrelated to those of serogroups B and C are required for the formation of sialic acid heteropolymers characteristic of the capsules of serogroups W135 and Y.


Resonant activation in polymer translocation: new insights into the escape dynamics of molecules driven by an oscillating field.
The translocation of molecules across cellular membranes or through synthetic nanopores is strongly affected by thermal fluctuations. In this work we study how the dynamics of a polymer in a noisy environment changes when the translocation process is driven by an oscillating electric field. An improved version of the Rouse model for a flexible polymer has been adopted to mimic the molecular dynamics, by taking into account the harmonic interactions between adjacent monomers and the excluded-volume effect by introducing a Lennard-Jones potential between all beads. A bending recoil torque has also been included in our model. The polymer dynamics is simulated in a two-dimensional domain by numerically solving the Langevin equations of motion. Thermal fluctuations are taken into account by introducing a Gaussian uncorrelated noise. The mean first translocation time of the polymer centre of inertia shows a minimum as a function of the frequency of the oscillating forcing field. This finding represents the first evidence of the resonant activation behaviour in the dynamics of polymer translocation.


Phosphorus-31 MRI of hard and soft solids using quadratic echo line-narrowing.
Magnetic resonance imaging (MRI) of solids is rarely attempted. One of the main reasons is that the broader MR linewidths, compared to the narrow resonance of the hydrogen ((1)H) in free water, limit both the attainable spatial resolution and the signal-to-noise ratio. Basic physics research, stimulated by the quest to build a quantum computer, gave rise to a unique MR pulse sequence that offers a solution to this long-standing problem. The "quadratic echo" significantly narrows the broad MR spectrum of solids. Applying field gradients in sync with this line-narrowing sequence offers a fresh approach to carry out MRI of hard and soft solids with high spatial resolution and with a wide range of potential uses. Here we demonstrate that this method can be used to carry out three-dimensional MRI of the phosphorus ((31)P) in ex vivo bone and soft tissue samples.


Overexpressing plant ferredoxin-like protein enhances photosynthetic efficiency and carbohydrates accumulation in Phalaenopsis.
Crassulacean acid metabolism (CAM) is one of three major models of carbon dioxide assimilation pathway with better water-use efficiency and slower photosynthetic efficiency in photosynthesis. Previous studies indicated that the gene of sweet pepper plant ferredoxin-like protein (PFLP) shows high homology to the ferredoxin-1(Fd-1) family that belongs to photosynthetic type Fd and involves in photosystem I. It is speculated that overexpressing pflp in the transgenic plant may enhance photosynthetic efficiency through the electron transport chain (ETC). To reveal the function of PFLP in photosynthetic efficiency, pflp transgenic Phalaenopsis, a CAM plant, was generated to analyze photosynthetic markers. Transgenic plants exhibited 1.2-folds of electron transport rate than that of wild type (WT), and higher CO2 assimilation rates up to 1.6 and 1.5-folds samples at 4 pm and 10 pm respectively. Enzyme activity of phosphoenolpyruvate carboxylase (PEPC) was increased to 5.9-folds in Phase III, and NAD+-linked malic enzyme (NAD+-ME) activity increased 1.4-folds in Phase IV in transgenic plants. The photosynthesis products were analyzed between transgenic plants and WT. Soluble sugars contents such as glucose, fructose, and sucrose were found to significantly increase to 1.2, 1.8, and 1.3-folds higher in transgenic plants. The starch grains were also accumulated up to 1.4-folds in transgenic plants than that of WT. These results indicated that overexpressing pflp in transgenic plants increases carbohydrates accumulation by enhancing electron transport flow during photosynthesis. This is the first evidence for the PFLP function in CAM plants. Taken altogether, we suggest that pflp is an applicable gene for agriculture application that enhances electron transport chain efficiency during photosynthesis.


Common variants of apolipoprotein E and cholesteryl ester transport protein genes in male patients with coronary heart disease and variable body mass index.
Plasma lipids are major risk factors for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) and apolipoprotein (apo) E genes are involved in lipoprotein metabolism, thus affecting plasma lipid and lipoproteins levels. Furthermore, such polymorphisms have been associated with susceptibility to CHD and obesity. We evaluated the influence of the gene polymorphisms of CETP TaqIB (B1, B2) and I405V (V, I) and apo E (∊2,∊3,∊4) on lipid levels, according to body mass index (BMI) in Greek men with CHD. The TaqIB (B1, B2) polymorphism affected plasma low-density lipoprotein cholesterol levels in overweight men with CHD, whereas the I405V (V, I) polymorphism affected triglyceride concentrations in normal weight men. No correlation was found between BMI and apo E polymorphisms. Large prospective studies are required to investigate the relationships of CETP and apo E polymorphisms with lipids, BMI, and CHD susceptibility.


Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation.
Mucoadhesive particles (MAP) have been widely explored for pulmonary drug delivery because of their perceived benefits in improving particle residence in the lungs. However, retention of particles adhesively trapped in airway mucus may be limited by physiologic mucus clearance mechanisms. In contrast, particles that avoid mucoadhesion and have diameters smaller than mucus mesh spacings rapidly penetrate mucus layers [mucus-penetrating particles (MPP)], which we hypothesized would provide prolonged lung retention compared to MAP. We compared in vivo behaviors of variously sized, polystyrene-based MAP and MPP in the lungs following inhalation. MAP, regardless of particle size, were aggregated and poorly distributed throughout the airways, leading to rapid clearance from the lungs. Conversely, MPP as large as 300 nm exhibited uniform distribution and markedly enhanced retention compared to size-matched MAP. On the basis of these findings, we formulated biodegradable MPP (b-MPP) with an average diameter of <300 nm and examined their behavior following inhalation relative to similarly sized biodegradable MAP (b-MAP). Although b-MPP diffused rapidly through human airway mucus ex vivo, b-MAP did not. Rapid b-MPP movements in mucus ex vivo correlated to a more uniform distribution within the airways and enhanced lung retention time as compared to b-MAP. Furthermore, inhalation of b-MPP loaded with dexamethasone sodium phosphate (DP) significantly reduced inflammation in a mouse model of acute lung inflammation compared to both carrier-free DP and DP-loaded MAP. These studies provide a careful head-to-head comparison of MAP versus MPP following inhalation and challenge a long-standing dogma that favored the use of MAP for pulmonary drug delivery.


A metabolomics approach to the identification of biomarkers of sugar-sweetened beverage intake.
The association between sugar-sweetened beverages (SSBs) and health risks remains controversial. To clarify proposed links, reliable and accurate dietary assessment methods of food intakes are essential. The aim of this present work was to use a metabolomics approach to identify a panel of urinary biomarkers indicative of SSB consumption from a national food consumption survey and subsequently validate this panel in an acute intervention study. Heat map analysis was performed to identify correlations between ¹H nuclear magnetic resonance (NMR) spectral regions and SSB intakes in participants of the National Adult Nutrition Survey (n = 565). Metabolites were identified and receiver operating characteristic (ROC) analysis was performed to assess sensitivity and specificity of biomarkers. The panel of biomarkers was validated in an acute study (n = 10). A fasting first-void urine sample and postprandial samples (2, 4, 6 h) were collected after SSB consumption. After NMR spectroscopic profiling of the urine samples, multivariate data analysis was applied. A panel of 4 biomarkers-formate, citrulline, taurine, and isocitrate-were identified as markers of SSB intake. This panel of biomarkers had an area under the curve of 0.8 for ROC analysis and a sensitivity and specificity of 0.7 and 0.8, respectively. All 4 biomarkers were identified in the SSB sample. After acute consumption of an SSB drink, all 4 metabolites increased in the urine. The present metabolomics-based strategy proved to be successful in the identification of SSB biomarkers. Future work will ascertain how to translate this panel of markers for use in nutrition epidemiology.


Evaluating quality of life and pulmonary function of long-term survivors of non-small cell lung cancer treated with radical or postoperative radiotherapy.
Our aim in the present study was to describe the quality of life (QOL), evaluate pulmonary function, and compare demographic and clinical characteristics with QOL in long-term survivors of non-small cell lung cancer treated with radical or postoperative radiotherapy. Twenty-eight patients were recruited in the study. QOL was evaluated using The European Organization for Research and Treatment of Cancer, Quality of Life Core Questionnaire (EORTC QLQ-C30, v.3). Statistical analysis was performed by SPSS 14. Patients' files were reviewed in October 2006. Median duration of follow-up was 46 months (range: 25-125 months). Seven of 9 scales were found to meet the minimal reliability limit (Cronbach's alpha >0.70). The lowest and highest reliability coefficients were 0.56 and 0.93 for social and role functioning, respectively. All interscale correlations were statistically significant (P < 0.01). The strongest positive correlation was found between physical functioning and, role and cognitive functioning (r = 0.59, r = 0.37 or P = 0.01, P = 0.05, respectively). The highest correlation of EORTC QLQ-C30 and the Karnofsky performance scale (KPS) during the questionnaire was found to be with physical functioning and constipation (r = 0.41, r = 0.44 or P = 0.02, P = 0.01, respectively). When the effect of various demographic and clinical parameters on QOL was evaluated; initial KPS, age, educational level, health insurance status, stage, chemotherapy, comorbid disease, and passive smoking were determined as significant factors influencing QOL. Physical, role, cognitive, and emotional functions were found to be significantly lower in the presence of dyspnea (r = 0.42, r = 0.58, r = 0.50, r = 0.63 or P = 0.02, P < 0.01, P < 0.01, P < 0.05, respectively). Regarding the symptom scales, dyspnea was found to be correlated with increasing of fatigue, pain, insomnia, and appetite loss (r = 0.52, r = 0.40, r = 0.64, r = 0.38 or P < 0.01, P = 0.03, P < 0.05, P = 0.04, respectively). The parameters of pulmonary function tests (FEV1, FVC, and FEV1/FVC) did not show any significant relation with any scale of QOL. Overall, we found that QOL of our patients who survived at least 2 years after radiotherapy, was good. The Turkish version of the EORTC QLQ-C30, v.3 is a valid and reliable instrument for Turkish lung cancer patients and can be used in clinical studies. We believe further studies are needed to have a better understanding of patients' pretreatment and posttreatment QOLs.


The relationship between rotator cuff tear and four acromion types: cross-sectional study based on shoulder magnetic resonance imaging in 227 patients.
Rotator cuff tear (RCT) has been believed to be related to specific types of the acromion. However, most of the studies were performed on a small number of patients with surgical findings not considering the severity of RCT. To analyze the relationship between age, gender, the side of the shoulder, the acromion type, and the severity of RCT using shoulder magnetic resonance arthrography (MRA). A total of 277 shoulder MRA findings were analyzed by a radiologist specializing in the musculoskeletal system. The relationship between variables (age, gender, side of the shoulder, and acromion type) and the injury of the supraspinatus (no rupture, partial rupture, full rupture, complete rupture) was confirmed. The partial tear of the supraspinatus tendon was divided into bursal and articular side tear in order to investigate the damage caused by the anatomical difference of the acromion. We also confirmed the differences between single supraspinatus injury and multiple RCTs. The severity of supraspinatus tear and multiple RCTs were statistically significant with the old age and the right side of the shoulder, but not with a specific acromion type. In supraspinatus partial tear, there was no statistical difference between bursal and articular side tears. Our study revealed that the age at which degeneration could occur also was associated with multiple RCTs and is considered to be the most important factor in RCT, not anatomical structures such as acromion type.