Medicolegal Investigation for Cremation Clearance: How and Why?
This study on cremation clearance examines whether physical inspections detect more unnatural unreported deaths than medicolegal investigations without inspections. We reviewed all deaths reported to the medical examiner for cremation clearance during 2 distinct years and compared subsequent amendments of death certificates after 2 different investigative methodologies (1 with and 1 without physical inspection). Of 10,367 deaths in 2012, there were 86 deaths (0.83%) in which the investigation with physical inspection resulted in amendments to the death certificate. Of 11,906 deaths in 2016 without physical inspection, there were 153 that resulted in amendments (1.3%) including 2 homicides. For the detection of accidents, there was no statistically significant difference (χ = 0.8119, P = 0.367552). For cremation investigations, the work effort and costs of performing physical inspections do not appear justified given the similar detection rates (approximately 1%) for unnatural deaths among the 2 groups. Both methods, however, do detect unreported unnatural deaths.


Btk-dependent epithelial cell rearrangements contribute to the invagination of nearby tubular structures in the posterior spiracles of Drosophila.
The Drosophila respiratory system consists of two connected organs, the tracheae and the spiracles. Together they ensure the efficient delivery of air-borne oxygen to all tissues. The posterior spiracles consist internally of the spiracular chamber, an invaginated tube with filtering properties that connects the main tracheal branch to the environment, and externally of the stigmatophore, an extensible epidermal structure that covers the spiracular chamber. The primordia of both components are first specified in the plane of the epidermis and subsequently the spiracular chamber is internalized through the process of invagination accompanied by apical cell constriction. It has become clear that invagination processes do not always or only rely on apical constriction. We show here that in mutants for the src-like kinase Btk29A spiracle cells constrict apically but do not complete invagination, giving rise to shorter spiracular chambers. This defect can be rescued by using different GAL4 drivers to express Btk29A throughout the ectoderm, in cells of posterior segments only, or in the stigmatophore pointing to a non cell-autonomous role for Btk29A. Our analysis suggests that complete invagination of the spiracular chamber requires Btk29A-dependent planar cell rearrangements of adjacent non-invaginating cells of the stigmatophore. These results highlight the complex physical interactions that take place among organ components during morphogenesis, which contribute to their final form and function.


A glutathione peroxidase, intracellular peptidases and the TOR complexes regulate peptide transporter PEPT-1 in C. elegans.
The intestinal peptide transporter PEPT-1 in Caenorhabditis elegans is a rheogenic H(+)-dependent carrier responsible for the absorption of di- and tripeptides. Transporter-deficient pept-1(lg601) worms are characterized by impairments in growth, development and reproduction and develop a severe obesity like phenotype. The transport function of PEPT-1 as well as the influx of free fatty acids was shown to be dependent on the membrane potential and on the intracellular pH homeostasis, both of which are regulated by the sodium-proton exchanger NHX-2. Since many membrane proteins commonly function as complexes, there could be proteins that possibly modulate PEPT-1 expression and function. A systematic RNAi screening of 162 genes that are exclusively expressed in the intestine combined with a functional transport assay revealed four genes with homologues existing in mammals as predicted PEPT-1 modulators. While silencing of a glutathione peroxidase surprisingly caused an increase in PEPT-1 transport function, silencing of the ER to Golgi cargo transport protein and of two cytosolic peptidases reduced PEPT-1 transport activity and this even corresponded with lower PEPT-1 protein levels. These modifications of PEPT-1 function by gene silencing of homologous genes were also found to be conserved in the human epithelial cell line Caco-2/TC7 cells. Peptidase inhibition, amino acid supplementation and RNAi silencing of targets of rapamycin (TOR) components in C. elegans supports evidence that intracellular peptide hydrolysis and amino acid concentration are a part of a sensing system that controls PEPT-1 expression and function and that involves the TOR complexes TORC1 and TORC2.


Photoswitched DNA-binding of a photochromic spiropyran.
The dramatically different DNA-binding properties of the two isomeric forms of a photochromic spiropyran have been demonstrated, enabling photoswitched DNA binding. The closed, UV-absorbing form shows no signs of interaction with DNA. Upon UV exposure the spiropyran is isomerized to the open form that binds to DNA by intercalation. The process is fully reversible as the corresponding dissociation process is induced by visible light.


Motion transduction in nanoelectromechanical systems (NEMS) arrays using near-field optomechanical coupling.
Development of efficient and sensitive motion transducers for arrays of nanoelectromechanical systems (NEMS) is important for fundamental research as well as for technological applications. Here, we report a single-wire nanomechanical transducer interface, which relies upon near-field optomechanical interactions. This multiplexed transducer interface comes in the form of a single-mode fiber taper on a fiber-optic cable. When the fiber taper is positioned sufficiently close to the NEMS array such that it can attain evanescent optical coupling with the array, individual NEMS resonances can be actuated using optical dipole forces. In addition, sensitive detection of nanomechanical motion can be realized when the evanescent waves confined around the taper are scattered by the motion. We have measured resonances from an array of 63 NEMS resonators with a displacement sensitivity of 2-8 pm·Hz(-1/2) at a detection power of ~100 μW (incident on the entire array).


V2CTX catalyzes polysulfide conversion to enhance the redox kinetics of Li-S batteries.
Lithium-sulfur (Li-S) batteries have the potential to become the future energy storage system, yet they are plagued by sluggish redox kinetics. Therefore, enhancing the redox kinetics of polysulfides is key for the development of high-energy density and long-life Li-S batteries. Herein, a Ketjen Black (KB)/V2CTX modified separator (KB/V2CTX-PP) based on the catalytic effect in continuous solid-to-liquid-to-solid reactions is proposed to accelerate the conversion of sulfur species during the charge/discharge process in which the V2CTX can enhance the redox kinetics and inhibit polysulfide shuttling. The cells assembled with KB/V2CTX-PP achieve a gratifying first discharge capacity of 1236.1 mA h g-1 at 0.2C and the average capacity decay per cycle reaches 0.049% within 1000 cycles at 1C. The work provides an efficient idea to accelerate redox conversion and suppress shuttle effects by designing a multifunctional catalytic separator.


Characterization and metal-induced gene transcription of two new copper zinc superoxide dismutases in the solitary ascidian Ciona intestinalis.
Antioxidant enzymes are known to protect living organisms against the oxidative stress risk, also induced by metals. In the present study, we describe the purification and molecular characterization of two Cu,Zn superoxide dismutases (SODs), referred to as Ci-SODa and Ci-SODb, from Ciona intestinalis, a basal chordate widely distributed in temperate shallow seawater. The putative amino acid sequences were compared with Cu,Zn SODs from other metazoans and phylogenetic analyses indicate that the two putative Ci-SODs are more related to invertebrate SODs than vertebrate ones. Both phylogenetic and preliminary homology modeling analyses suggest that Ci-SODa and Ci-SODb are extracellular and intracellular isoform, respectively. The mRNA of the two Cu,Zn SODs was localized in hemocytes and in ovarian follicular cells, as revealed by in situ hybridization. The time course of SOD mRNA levels in the presence of three different metals showed upregulation of ci-soda and inhibition of ci-sodb. Spectrophotometric analysis confirms the presence of SOD activity in Ciona tissues. Our in silico analyses of the ci-soda promoter region revealed putative consensus sequences similar to mammalian metal-responsive elements (MRE), suggesting that the transcription of these genes directly depends on metals. These data emphasize the importance of complex metal regulation of ci-soda and ci-sodb transcription, as components of an efficient detoxification pathway allowing the survival of C. intestinalis in continued, elevated presence of metals in the environment.


Value of three-dimensional reconstructions in pancreatic carcinoma using multidetector CT: initial results.
To evaluate the use of three-dimensional imaging of pancreatic carcinoma using multidetector computed tomography (CT) in a prospective study. Ten patients with suspected pancreatic tumors were examined prospectively using multidetector CT (Somatom Sensation 16, Siemens, Erlangen, Germany). The images were evaluated for the presence of a pancreatic carcinoma and invasion of the peripancreatic vessels and surrounding organs. Using the isotropic CT data sets, a three-dimensional image was created with automatic vascular analysis and semi-automatic segmentation of the organs and pancreatic tumor by a radiologist. The CT examinations and the three-dimensional images were presented to the surgeon directly before and during the patient's operation using the Medical Imaging Interaction Toolkit-based software "ReLiver". Immediately after surgery, the value of the two images was judged by the surgeon. The operation and the histological results served as the gold standard. Nine patients had a pancreatic carcinoma (all pT3), and one patient had a serous cystadenoma. One tumor infiltrated the superior mesenteric vein. The infiltration was correctly evaluated. All carcinomas were resectable. In comparison to the CT image with axial and coronal reconstructions, the three-dimensional image was judged by the surgeons as better for operation planning and consistently described as useful. A 3D-image of the pancreas represents an invaluable aid to the surgeon. However, the 3D-software must be further developed in order to be integrated into daily clinical routine.


The genetic control of chemically and radiation-induced skin tumorigenesis: a study with carcinogenesis-susceptible and carcinogenesis-resistant mice.
Outbred carcinogenesis-resistant (Car-R) and carcinogenesis-susceptible (Car-S) mouse lines were generated by phenotypic selection for resistance or susceptibility to two-stage skin carcinogenesis. These two Car mouse lines differ by >100-fold in susceptibility. In the present study, we tested the hypothesis that a subset of genetic loci responsible for susceptibility or resistance to chemical skin tumorigenesis may also be involved in radiation-induced skin tumorigenesis. Skin tumorigenesis was tested in groups of Car-S/R mice after X-ray initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. We found that ionizing radiation can initiate skin tumors in Car-S mice but not in Car-R mice. In Car-S mice, the most effective radiation doses (6 and 10 Gy given in four fractions) gave a threefold increase in tumor multiplicity and a twofold increase in tumor incidence compared to a TPA-only control group. We performed a molecular analysis of Hras gene mutations in skin tumors of Car-S mice induced by X-ray initiation/TPA promotion or by TPA promotion alone. The most notable difference emerging from the comparison of these mutation patterns is the high incidence ( approximately 50%) of papillomas lacking Hras gene mutations in X-ray-initiated/TPA-promoted papillomas compared to 13% in papillomas induced by TPA alone, suggesting that lack of Hras gene mutations is a consistent feature of radiation-induced papillomas.


Antiangiogenetic effects of 4 varieties of grapes in vitro.
The purpose of this study was to investigate the inhibitory effects of grapes on the human umbilical vein endothelial (HUVE) cells' capillary tube formation and matrix metalloproteinase-2 (MMP-2) expression secreted into the medium. Four different grape varieties (Concord, Niagara, Chardonnay, and Pinot Noir) were extracted using 80% acetone and the extracts were stored at -80 degrees C. The total amount of phenolics and flavonoids for each of the 4 grape varieties were determined by spectrophotometry. Grape extracts were co-cultured with HUVE cells on Matrigel and inhibitory effects on tube formation were observed under a microscope. The inhibitory effects of grape extracts on MMP-2 expression were examined by zymogram. All 4 grape varieties inhibited the tube formation of HUVE cells in a dose-dependent manner on Matrigel. Except for Chardonnay, the other 3 grape varieties completely inhibited secretion of MMP-2 at 20 mg/mL. There was a significant positive relationship between the total phenolics and flavonoids and antiangiogenetic activities. The grapes tested have the potential to inhibit angiogenesis mainly by their phenolics and flavonoids contents, which partly contribute to their cancer chemopreventive efficacy.


Aspiring to Unintended Consequences of Natural Language Processing: A Review of Recent Developments in Clinical and Consumer-Generated Text Processing.
This paper reviews work over the past two years in Natural Language Processing (NLP) applied to clinical and consumer-generated texts. We included any application or methodological publication that leverages text to facilitate healthcare and address the health-related needs of consumers and populations. Many important developments in clinical text processing, both foundational and task-oriented, were addressed in community- wide evaluations and discussed in corresponding special issues that are referenced in this review. These focused issues and in-depth reviews of several other active research areas, such as pharmacovigilance and summarization, allowed us to discuss in greater depth disease modeling and predictive analytics using clinical texts, and text analysis in social media for healthcare quality assessment, trends towards online interventions based on rapid analysis of health-related posts, and consumer health question answering, among other issues. Our analysis shows that although clinical NLP continues to advance towards practical applications and more NLP methods are used in large-scale live health information applications, more needs to be done to make NLP use in clinical applications a routine widespread reality. Progress in clinical NLP is mirrored by developments in social media text analysis: the research is moving from capturing trends to addressing individual health-related posts, thus showing potential to become a tool for precision medicine and a valuable addition to the standard healthcare quality evaluation tools.


Sphingosine Kinase 1 and Sphingosine-1-Phosphate Signaling in Colorectal Cancer.
Sphingosine kinase 1 (Sphk1) is a highly conserved lipid kinase that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). Growing studies have demonstrated that Sphk1 is overexpressed in various types of solid cancers and can be induced by growth factors, cytokines, and carcinogens, leading to the increase of S1P production. Subsequently, the increased Sphk1/S1P facilitates cancer cell proliferation, mobility, angiogenesis, invasion, and metastasis. Therefore, Sphk1/S1P signaling plays oncogenic roles. This review summarizes the features of Sphk1/S1P signaling and their functions in colorectal cancer cell growth, tumorigenesis, and metastasis, as well as the possible underlying mechanisms.


Psychosocial aspects of prolonged ventilator dependency.
Placement of the ventilator-dependent patient must take into consideration the psychosocial aspects of the situation. These include the patient's age, level of emotional and cognitive function, financial status, insurance benefits, cultural and personal-experience influences regarding life-threatening illness and institutionalization, and the availability of suitable caregivers. The hospital provides the greatest physical security but is expensive and allows minimal patient autonomy and family involvement. A nursing home is homier and less expensive, but it must have a staff well trained in the complex care of these patients and someone to oversee execution of the care plan, and its cost may not be adequately reimbursed by private insurance. Home care usually provides the best conditions for the patient, but it requires trained and available health professionals; a committed physician; education of the patient, family, and attendants; a suitable residence; a system for delivery and maintenance of supplies and equipment; and dependable financing; and it must allow the patient increased independence, socialization, and activities of daily living. Ventilator-dependent patients commonly experience fear, feelings of total dependency, and even degradation. Caregivers can relieve these feelings by reassuring the patient about safety measures, by keeping him informed about medical procedures, and by establishing communication.


Thermoneutral immersion exercise accelerates heart rate recovery: A potential novel training modality.
This study compared heart rate recovery (HRR) after incremental maximal exercise performed at the same external power output (Pext) on dry land ergocycle (DE) vs. immersible ergocycle (IE). Fifteen young healthy participants (30 ± 7 years, 13 men and 2 women) performed incremental maximal exercise tests on DE and on IE. The initial Pext on DE was 25 W and was increased by 25 W/min at a pedalling cadence between 60 and 80 rpm, while during IE immersion at chest level in thermoneutral water (30°C), the initial Pext deployment was at a cadence of 40 rpm which was increased by 10 rpm until 70 rpm and thereafter by 5 rpm until exhaustion. Gas exchange and heart rate (HR) were measured continuously during exercise and recovery for 5 min. Maximal HR (DE: 176 ± 15 vs. IE 169 ± 12 bpm) reached by the subjects in the two conditions did not differ (P > .05). Parasympathetic reactivation parameters (ΔHR from 10 to 300 s) were compared during the DE and IE HR recovery recordings. During the IE recovery, parasympathetic reactivation in the early phase was more predominant (HRR at Δ10-Δ60 s, P < .05), but similar in the late phase (HRR at Δ120-Δ300 s, P > .05) when compared to the DE condition. In conclusion, incremental maximal IE exercise at chest level immersion in thermoneutral water accelerates the early phase parasympathetic reactivation compared to DE in healthy young participants.


Diet and alcohol in liver cirrhosis: a case-control study.
A retrospective case-control study on alcohol and dietary habits was conducted over 3 years in a Gastroenterology Department on 152 male patients with liver cirrhosis. The study also included 304 hospital controls, selected within the same age range (32-83 years). Alcohol consumption and dietary habits were assessed from a standardized questionnaire by a highly trained dietician. The variations of the relative risk (RR) of liver cirrhosis as a function of the estimated mean daily intakes of alcohol, fats, carbohydrates and proteins were studied using stratified conditional logistic regression models. Obviously the relative risk of liver cirrhosis was found to be strongly and positively correlated with alcohol consumption but, in addition, this study has been able to show a significant and positive association with the mean daily fat intake and negative associations with the mean daily carbohydrate and protein intakes. Whereas in the control group, the calorie percentage from fats was 33.8 (87.11 g/d), it was 39.6 in the cirrhotic group (102.1 g/d). These findings indicate that in addition to alcohol consumption, dietary habits and in particular, high mean daily fat intake, should be considered.


Computer literacy for life sciences: helping the digital-era biology undergraduates face today's research.
Computer literacy plays a critical role in today's life sciences research. Without the ability to use computers to efficiently manipulate and analyze large amounts of data resulting from biological experiments and simulations, many of the pressing questions in the life sciences could not be answered. Today's undergraduates, despite the ubiquity of computers in their lives, seem to be largely unfamiliar with how computers are being used to pursue and answer such questions. This article describes an innovative undergraduate-level course, titled Computer Literacy for Life Sciences, that aims to teach students the basics of a computerized scientific research pursuit. The purpose of the course is for students to develop a hands-on working experience in using standard computer software tools as well as computer techniques and methodologies used in life sciences research. This paper provides a detailed description of the didactical tools and assessment methods used in and outside of the classroom as well as a discussion of the lessons learned during the first installment of the course taught at Emory University in fall semester 2009.


Community nurses working in piloted primary care teams: Irish Republic.
Primary care health services in the Irish Republic have undergone fundamental transformation with the establishment of multidisciplinary primary care teams nationwide. Primary care teams provide a community-based health service delivered through a range of health professionals in an integrated way. As part of this initiative ten pilot teams were established in 2003. This research was undertaken in order to gain an understanding of nurse's experiences of working in a piloted primary care team. The methodology used was a focus group approach. The findings from this study illustrated how community nurse's roles and responsibilities have expanded within the team. The findings also highlighted the benefits and challenges of working as a team with various other community-based health-care disciplines.


Endosomal localization of phospholipase D 1a and 1b is defined by the C-termini of the proteins, and is independent of activity.
The factors regulating the activity of cellular phospholipase D (PLD) have been well characterized; however, the cellular distribution of specific PLD isoforms and the factors defining localization are less clear. Two specific PLD1 isoforms, PLD1a and PLD1b, are shown in the present study to be localized in endosomal compartments with early endosomal autoantigen 1, internalizing epidermal growth factor receptor (ErbB1) and lysobisphosphatidic acid. Novel C-terminal splice variants of PLD1, PLD1a2 and PLD1b2, do not exhibit this endosomal localization. Studies using catalytically inactive and C-terminal deletion mutants of the four PLD1 isoforms led to the conclusion that the C-terminus plays an important part in the catalytic activity of PLD1, but that the endosomal localization of PLD1a and PLD1b is defined by the C-terminus and not catalytic activity.


Network Pharmacology and Molecular Docking Validation to Reveal the Pharmacological Mechanisms of Kangai Injection against Colorectal Cancer.
Kangai injection is a traditional Chinese medicine (TCM) mixed by extracts from astragalus, ginseng, and kurorinone with modern technology. It is a commonly used antitumor injection in China, but the mechanism of Kangai injection in the treatment of colorectal cancer (CRC) is still unclear. The purpose of this study is to explore the mechanism of Kangai injection against CRC using network pharmacology and molecular docking technology. Targets of Kangai injection in CRC were predicted by SwissTargetPrediction and DisGeNET databases. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed by using the DAVID database. A component-disease-target gene-pathway network was constructed by Cytoscape 3.8.0 software. 114 overlapping targets of Kangai injection and CRC were used to construct a PPI network, and the top 10 hub targets of Kangai injection were rated from high to low as TP53, VEGFA, EGFR, TNF, ESR1, STAT3, HSP90AA1, HDAC1, AR, and MMP9. The ingredient-target-disease interactive network was constructed, which included 22 compounds and 114 overlapping targets with 161 nodes and 707 edges. Entries of enrichment analysis were obtained based on P value (<0.05), which included 19 of GO-MF, 217 of GO-BP, 8 of GO-CC, and 13 KEGG. Molecular docking analysis showed that Kangai injection strongly interacted with top 10 hub target proteins. Network pharmacology intuitively showed the multicomponent, multiple targets, and multiple pathways of Kangai injection in the treatment of CRC. The molecular docking experiment verified that compounds of Kangai injection had good binding ability with top 10 hub target proteins as well.


Kill the Real with the Fake: Eliminate Intracellular Staphylococcus aureus Using Nanoparticle Coated with Its Extracellular Vesicle Membrane as Active-Targeting Drug Carrier.
Staphylococcus aureus bacteremia is one of the most serious bacterial infections worldwide. Most complications of S. aureus bacteremia arise because the pathogen can survive inside host phagocytes, especially macrophages, which makes elimination of intracellular S. aureus key to clinical success. Unfortunately, most antibiotics have poor cellular penetration capacity, which necessitates intracellular delivery of antibiotics. We herein use nanoparticle coated with membrane of extracellular vesicle secreted by S. aureus (i.e., NP@EV) as active-targeting antibiotic carrier, with counterparts coated with PEGylated lipid bilayer (i.e., NP@Lipo; PEG = poly(ethylene glycol)) or with membrane of outer membrane vesicle secreted by Escherichia coli (i.e., NP@OMV) included as controls. NP@EV is internalized at higher efficiency by S. aureus-infected macrophage than by naïve counterpart, whereas NP@Lipo and NP@OMV are not; instead, NP@OMV, but neither NP@EV nor NP@Lipo, is internalized at higher efficiency by E. coli-infected macrophage than by naïve counterpart. Moreover, when injected intravenously into mouse models, NP@EV, but neither NP@OMV nor NP@Lipo, exhibits significantly higher accumulations within four major organs (kidney, lung, spleen, and heart) bearing metastatic S. aureus infections than within healthy counterparts. These observations suggest that EV membrane coating of NP@EV endows the particle with active targeting capacity both in vitro and in vivo. As a result, when preloaded with antibiotics and intravenously administered to alleviate metastatic infection in S. aureus bacteremia-bearing mouse model, NP@EV confers its cargoes with strikingly improved efficacy; in doing so, NP@EV is significantly more efficient than both NP@Lipo and NP@OMV in kidney and lung-which bear the highest metastatic bacterial burden and represent most common sites for S. aureus infection, respectively. Such an active-targeting delivery platform may have implications in promoting clinical success on intracellular pathogen-associated complications.


[Experimental study of tensile strength at arterioprosthetic anastomosis].
An experimental study was conducted to investigate the possible role of the suture materials in occurrence of false aneurysms at the suture line. Mature mongrel dogs were used in the experiment. A segment of abdominal aorta was replaced by woven Teflon graft. Braided silk was used as the suture material on one side, and polyglycolic acid suture on the other. The dogs were sacrificed one to 16 weeks after the operation, and the implanted prostheses were excised along with the abdominal aorta. The tensile strengths of the anastomosis on both ends of the graft were calculated. The tensile strength of the braided silk consisted about 8% of the total tensile strength at 16 weeks after surgery. The degree of sliding of the synthetic graft at the anastomotic site and the outer layer of the graft were analyzed at each measurement of tensile strength. In the 1st Department of Surgery, Yokohama City University Hospital 125 arterial synthetic prostheses have been implanted in patients during 1964 to 1982. False aneurysms occurred in 9 cases. The incidence was 19.2% in the cases where silk suture material was used but was 4.0% when synthetic suture material was used. It was concluded that the use of synthetic grafts was preferable, since it conjoined well with the outer layer. Furthermore, the plastic suture material did not degenerate and seemed to prevent the occurrence of false aneurysm.


Imaging and pathological discordance amongst the plethora of breast lesions in breast biopsies.
Imaging-guided breast tissue biopsy has become an acceptable alternative to open surgical biopsy for nonpalpable breast lesions. Discussion of abnormal results of the correlation between imaging and pathological findings can be very challenging as it can assist in decision-making with regard to the further treatment options by arriving at a comprehensive diagnosis. This was a retrospective study. Radiological data from imaging-guided breast biopsies of 500 patients during a 6-year period was collected and classified by a specialist radiologist as per the BI-RADS format. Histopathology reports were studied and discordance analyzed. A total of 500 cases were reviewed. Approximately 33% (168) cases fell into the BI-RADS 3 category, 24.4% (122) into the BI-RADS 4, and 37% (187) into BI-RADS 5 categories. Approximately 50% (n = 250) cases were benign, 2.6% (13) belonged to the high-risk category, and 47.4% (237) were malignant. The number of discordant cases was 12 (2.4%), mostly due to technical factors. Sensitivity of biopsies to detect malignancy was 85%, specificity was 96%, and accuracy of biopsy in diagnosing cancer was 90%. The "triple assessment" is the most sensitive method for detecting early breast cancer. An effective communication pathway must be established between a clinician, radiologist, and pathologist for surgical excision in discordance as it carries a high prevalence of carcinoma in these lesions. In discordant cases, either due to abnormal results of imaging or of abnormal pathological findings, the final decision is based on two concordant findings, out of the three parameters. This involves a multidisciplinary breast conference and an active participation by the pathologist.


Contactin-Associated Protein 1 (CNTNAP1) Mutations Induce Characteristic Lesions of the Paranodal Region.
Congenital hypomyelinating neuropathy is a rare neonatal syndrome responsible for hypotonia and weakness. Nerve microscopic examination shows amyelination or hypomyelination. Recently, mutations in CNTNAP1 have been described in a few patients. CNTNAP1 encodes contactin-associated protein 1 (caspr-1), which is an essential component of the paranodal junctions of the peripheral and central nervous systems, and is necessary for the establishment of transverse bands that stabilize paranodal axo-glial junctions. We present the results of nerve biopsy studies of three patients from two unrelated, non-consanguineous families with compound heterozygous CNTNAP1 mutations. The lesions were identical, characterized by a hypomyelinating process; on electron microscopy, we detected, in all nodes of Ranvier, subtle lesions that have never been previously described in human nerves. Transverse bands of the myelin loops were absent, with a loss of attachment between myelin and the axolemma; elongated Schwann cell processes sometimes dissociated the Schwann cell and axon membranes that bound the space between them. These lesions were observed in the area where caspr-1 is located and are reminiscent of the lesions reported in sciatic nerves of caspr-1 null mice. CNTNAP1 mutations appear to induce characteristic ultrastructural lesions of the paranodal region.


A Prediction Model on Viscoelastic Fatigue Damage of Asphalt Mixture.
Fatigue damage affects both durability and safety, and it has been the most important distress in asphalt concrete. Fatigue damage occurs as a result of repeated traffic loading. An asphalt mixture is a typical viscoelastic material, and its fatigue damage is related to its viscoelastic properties. Under repeated traffic loading, the combined effects of creep damage and fatigue damage will shorten its fatigue life. Currently, the evaluation of the fatigue damage of asphalt mixtures rarely considers the combined effects of creep damage and fatigue damage. To solve this problem, a viscoelastic fatigue damage prediction model of an asphalt mixture considering the combined effects of creep damage and fatigue damage is put forward by introducing parameter β and a displacement factor based on theoretical derivations and testing. The results show that the model can embody the viscoelastic fatigue damage essence of asphalt mixtures, and it can also consider the effects of aging degree, temperature, load frequency and stress on fatigue damage of asphalt mixtures. The maximum relative error of the testing and prediction results of fatigue life is 0.15, and it is a reasonable prediction model.


Association of macular corneal dystrophy with excessive cell senescence and apoptosis induced by the novel mutant CHST6.
Macular corneal dystrophy (MCD) is a rare form of hereditary corneal dystrophy caused by CHST6 mutations. Owing to the genetic heterogeneity and population differences among patients with MCD, the genetic cause of MCD has not been fully elucidated, and the pathogenesis underlying the genetic mutation is still unclear. In this study, Chinese families and sporadic patients were included as subjects, and clinical and genetic analyses were performed to detect novel CHST6 mutations. In addition, the underlying pathogenic mechanisms of MCD were investigated by in vitro cell experiments. Two consanguineously married families and 10 sporadic patients with MCD were enrolled. Direct sequencing of the CHST6 gene was performed in all the patients to identify novel mutations. Wild-type and mutant overexpression cell lines were constructed to study the effects of the mutation in vitro. The expressions of endoplasmic reticulum (ER) stress markers and apoptotic factors, cell senescence, and migration levels tests were performed in different overexpression cell lines. As a result, four novel mutations (R155Afs*66, S84Cfs*17, E71G, and E71Q) and 10 previously reported mutations in the CHST6 gene were identified. Among the reported mutations, the most frequent mutations detected in the patients were L21Rfs*88 (4/14) and L21H (4/14). All the novel mutations were absent in the 50 healthy controls and were predicted to alter highly conserved amino acids across the different species and considered to be "disease causing" by function prediction. The results of the in vitro cell experiment further demonstrated that the novel homozygous frameshift mutations (S84Cfs*17 and R155Afs*66) of CHST6 detected in the consanguineously married families could lead to truncated proteins with defect functions, higher ER stress and apoptotic levels, decreased cell migration, and excessive cell senescence in corneal stromal cells, thereby affecting the normal functions of corneal stromal cells. These changes might play important roles in corneal opacity, which is characteristic of corneas with MCD. Our study extended the existing spectrum of disease-causing mutations and further elucidated the underlying pathogenic mechanisms of MCD.


High tibial osteotomy: an operation based on a spurious mechanical concept. A theoretic treatise.
The biomechanical basis for high tibial osteotomy (HTO) is erroneously conceived, in that to unload the medial side of the knee, an osteotomy would have to be performed of sufficient magnitude to shift the lateral side of the knee joint far enough medially to intersect the dynamic axis, not the mechanical axis. The resulting angular deformity would be functionally and cosmetically unacceptable in the eyes of most patients and surgeons. To corroborate these theoretic considerations, and to define the angular deformity necessary to unload the medial side of the knee joint during the midstance phase of gait, a cadaver osteotomy model was used with compartmental loading defined by direct observation, as well as by load-sensitive film. As predicted, medial compartment unloading did not occur until the lateral side of the joint crossed the dynamic axis. In both cadavers tested, the extremity alignment necessary to unload the medial side was approximately 25 degrees valgus. The efficacy of HTO should be re-examined, as its biomechanical basis is fundamentally flawed.


Detection of Aspergillus species in bone marrow transplant patients.
Invasive aspergillosis is a severe complication of cytotoxic chemotherapies and bone marrow transplantation (BMT). The aim of this study was to assess the utility of a real-time PCR assay for the early diagnosis of Aspergillus species in blood samples from BMT patients. Blood specimens (n = 993) from patients (n = 82) scheduled for BMT were collected prior to transplant and for 100 days post transplantation. The specimens were later tested using an Aspergillus-specific real-time PCR assay. Cultures of clinical samples, along with sonography and computerized tomographic scans, were performed as standard of care. Aspergillus DNA was positive in 94 sequential blood samples from 13 patients with clinical and radiological signs of infection. Samples from three of these patients were PCR-positive for Aspergillus in the first week of admission, prior to transplantation. Four patients with aspergillosis were cured with antifungal agents and nine died. An additional 12 patients without clinical signs of infection were PCR-positive on one occasion each, while two patients with clinical signs of infection were PCR-negative. Compared to routine methods of aspergillosis diagnosis, the respective sensitivity, specificity, negative, and positive predictive values of the PCR method by patient were 86.6%, 82%, 96.5% and 52%. The results show that Aspergillus infections in the blood of bone marrow transplant patients can be dectected by PCR methods. Early detection of Aspergillus infections by PCR has the potential to positively impact patient mortality rate and provide cost savings to hospitals.


Chilean Men Exposed to the Major Earthquake in 2010.
The article presents the results of a study involving 18 men, 4 years after one of South America's most powerful natural disasters: An earthquake occurring off the coast of Chile in February 2010. Participants reported having developed new psychological health problems in the months following the catastrophe. The manifestations most frequently reported by participants were the presence of depressive and stress symptoms, as well as sleep disorders. The majority of participants registered scores of 33 and above on the Impact of Event Scale-Revised, indicating that they were suffering from posttraumatic stress. Furthermore, although the majority of interviewed men reported having suffered psychological or physical health problems following the disaster, only a small minority had sought help from professional health services. The article develops insights into the men's social interactions and underlines the importance of supporting further research on red health topics, in particular the help-seeking behavior of men following exposure to natural disasters.


Metabolites and DNA-binding of carbamazepine and oxcarbazepine in vitro by rat liver microsomes.
DNA-binding of carbamazepine (CBZ) and oxcarbazepine (OCBZ) catalysed by non-induced, phenobarbital-induced or methylcholanthrene-induced rat liver microsomes in vitro was studied. 14C-CBZ 200 nmol incubated with DNA, liver microsomes and cofactors led to the formation of a significant amount of CBZ-epoxide, which has been suspected as the cause of teratogenesis and other side-effects of CBZ, 1,2 but has not been reactive in any test systems for genotoxicity, including the Ames test.3 No enzyme-dependent DNA-binding of CBZ was found. Using the same conditions, however, OCBZ was bound to DNA. This binding was dependent on the presence of NADPH. 10-hydroxy-10, 11-dihydro-carbamazepine, which is known to be the major metabolite of OCBZ, and an unknown peak were demonstrated by HPLC. These results are the first indication of a higher level of covalent DNA binding of OCBZ than of CBZ. The nature of the unknown metabolite and the pathway leading to covalent binding remain to be studied.


Conservation of chicken male germline by orthotopic transplantation of primordial germ cells from genetically distant donors†.
Successful derivation and cultivation of primordial germ cells (PGCs) opened the way to efficient transgenesis and genome editing in the chicken. Furthermore, implantation of male PGCs from non-chicken galliform species into the chicken embryos resulted in cross-species germline chimeras and viable offspring. We have recently improved the PGC technology by demonstrating that chicken male PGCs transplanted into the testes of adult cockerel recipients mature into functional sperms. However, the availability of this orthotopic transplantation for cross-species transfer remains to be explored. Here we tested the capacity of genetically distant male PGCs to mature in the microenvironment of adult testes. We derived PGCs from the Chinese black-bone Silkie and transplanted them into infertile White Leghorn cockerels. Within 15-18 weeks after transplantation, we observed restoration of spermatogenesis in recipient cockerels and production of healthy progeny derived from the transplanted PGCs. Our findings also indicate the possibility of cross-species orthotopic transplantation of PGCs. Thus, our results might contribute to the preservation of endangered avian species and maintaining the genetic variability of the domestic chicken.


Site-specific polysialylation of an antitumor single-chain Fv fragment.
Protein pharmacokinetic modulation is becoming an important tool in the development of biotherapeutics. Proteins can be chemically or recombinantly modified to alter their half-lives and bioavailability to suit particular applications as well as improve side effect profiles. The most successful and clinically used approach to date is chemical conjugation with poly(ethylene glycol) polymers (PEGylation). Here, therapeutic protein half-life can be increased significantly while retaining biological function, reducing immunogenicity and cross-reaction. Naturally occurring alternatives to such synthetic polymers could have major advantages such as lower side effects due to biodegradability and metabolism. Polysialic acid (PSA) has been investigated as a pharmacokinetic modulatory biopolymer with many successful examples in preclinical and clinical development. Single-chain Fvs (scFvs) are a choice antibody format for human therapeutic antibody discovery. Because of their small size, they are rapidly eliminated from the circulation and often are rebuilt into larger proteins for drug development and a longer half-life. Here we show that chemical polysialylation can increase the half-life of an antiplacental alkaline (PLAP) and anticarcinoembryonic antigen (CEA) scFv (F1 and MFE-23, respectively) 3.4-4.9-fold, resulting in a 10.6-15.2-fold increase in blood exposure. Amine-directed coupling of the MFE-23 scFv reduced its immunoreactivity 20-fold which was resolved by site-specific polysialylation through an engineered C-terminal thiol residue. The site-specifically polysialylated MFE-23 scFv demonstrated up to 30-fold improved tumor uptake while displaying favorable tumor:normal tissue specificity. This suggests that engineering antibody fragments for site-specific polysialylation could be a useful approach to increase the half-life for a variety of therapeutic applications.


Pregnancy is special.
"Pregnancy is special--let's make it safe" is the slogan of the 1998 World Health Day. This worldwide focus on safe motherhood comes as the Safe Motherhood Initiative, launched in 1987, starts into its second decade. Pregnancy is a normal physiological process, but it is associated with certain risks to the life and health of both mother and baby. There has been much progress in making motherhood safer in the past 11 years, but much more needs to be done. A consultation that marked the Safe Motherhood Initiative's 10th birthday last year developed 10 messages that are key to future efforts to improve maternal and infant health. The special feature in this issue of Safe Motherhood examines these 10 messages in some detail and looks at their implications for health services, national policies, and community attitudes in the next century.


High CD34 surface expression in BCP-ALL predicts poor induction therapy response and is associated with altered expression of genes related to cell migration and adhesion.
Minimal residual disease (MRD) constitutes the most important prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Flow cytometry is widely used in MRD assessment, yet little is known regarding the effect of different immunophenotypic subsets on outcome. In this study of 200 BCP-ALL patients, we found that a CD34-positive, CD38 dim-positive, nTdT dim-positive immunophenotype on the leukemic blasts was associated with poor induction therapy response and predicted an MRD level at the end of induction therapy (EOI) of ≥ 0.001. CD34 expression was strongly and positively associated with EOI MRD, whereas CD34-negative patients had a low relapse risk. Further, CD34 expression increased from diagnosis to relapse. CD34 is a stemness-associated cell-surface molecule, possibly involved in cell adhesion/migration or survival. Accordingly, genes associated with stemness were overrepresented among the most upregulated genes in CD34-positive leukemias, and protein-protein interaction networks showed an overrepresentation of genes associated with cell migration, cell adhesion, and negative regulation of apoptosis. The present work is the first to demonstrate a CD34-negative immunophenotype as a good prognostic factor in ALL, whereas high CD34 expression is associated with poor therapy response and an altered gene expression profile reminiscent of migrating cancer stem-like cells.


Crystallization-Induced Deracemization: Experiments and Modeling.
Inspired by deracemization via temperature cycles, which enables the collection of crystals of the desired enantiomer from an initially racemic mixture, we focus in this work on an alternative batch process, namely crystallization-induced deracemization. This process starts with a suspension of enantiomerically pure crystals, which undergoes a simple cooling crystallization, coupled with liquid-phase racemization. The experimental and model-based analysis of such a process, carried out here, revealed that: (i) deracemization via temperature cycles is a safe choice to operate with high enantiomeric purity, although its throughput is limited by the suspension density; (ii) if the distomer is less prone to nucleation, crystallization-induced deracemization is a simple process; however, its performance is strongly limited by the solubility; (iii) the purity achieved with crystallization-induced deracemization can be increased by utilizing large seed mass and by optimizing the cooling profile or catalyst concentration. Alternatively, the purity increases via partial dissolution of the seeds, which resembles the heating part of the deracemization process via temperature cycles.


A model for group research by master's degree RNs in advanced roles.
Master's prepared RNs in advanced roles are ideally prepared to do clinical nursing research. Yet lack of time, resources, and a paucity of confidence have limited such scholarly pursuits among nurses in specialty roles. The article describes a group process by which five Master's prepared nurses (three clinical specialists, two Nursing Educators) successfully investigated and implemented a Nurse Research Interest Group (NRIG). The facilitators and obstacles are described as well as the past, present, and future activities of this group.


Informed decision making on PSA testing for the detection of prostate cancer: an evaluation of a leaflet with risk indicator.
Population-based screening for prostate cancer (PCa) remains controversial. To help men making informed decisions about prostate specific antigen (PSA) screening a risk indicator (www.uroweb.org) was developed. This risk indicator is embedded in a leaflet that informs men about the pros and cons of PCa screening and enables calculation of the individual risk of having a biopsy detectable PCa. To assess the effect of providing a leaflet including individualized risk estimation on informed decision making of men, i.e. knowledge about PCa and PSA screening, attitude towards undergoing a PSA test and intention to have a PSA test. An intervention study among 2000 men, aged 55-65 years, randomly selected from the population registry of the city of Dordrecht, the Netherlands, in 2008. Men were sent a questionnaire on knowledge of PCa, attitude and intention to have a PSA test. Men without a history of (screening for) PCa were sent the leaflet and Questionnaire 2 within 2 weeks after returning Questionnaire 1. Validated health and anxiety measures were used. One thousand and twenty seven of 2000 men completed Questionnaire 1 (51%), of whom 298 were excluded due to a history of (screening for) PCa. Of the 729 remaining men, 601 completed Questionnaire 2 as well. At the second assessment significantly more men met the requirements of informed decision making (15% versus 33%, p<0.001), more men had relevant knowledge (284/601, 50% versus 420/601, 77%, p<0.001) and the intention to have a PSA test had increased (p<0.001). Providing information on PCa screening combined with individualized risk estimation enhanced informed decision making and may be used for shared decision making on PSA screening of physicians and patients.


Characterization of Rice NADPH oxidase genes and their expression under various environmental conditions.
Plasma membrane NADPH oxidases (Noxs) are key producers of reactive oxygen species under both normal and stress conditions in plants. We demonstrate that at least eleven genes in the genome of rice (Oryza sativa L.) were predicted to encode Nox proteins, including nine genes (OsNox1-9) that encode typical Noxs and two that encode ancient Nox forms (ferric reduction oxidase 1 and 7, OsFRO1 and OsFRO7). Phylogenetic analysis divided the Noxs from nine plant species into six subfamilies, with rice Nox genes distributed among subfamilies I to V. Gene expression analysis using semi-quantitative RT-PCR and real-time qRT-PCR indicated that the expression of rice Nox genes depends on organs and environmental conditions. Exogenous calcium strongly stimulated the expression of OsNox3, OsNox5, OsNox7, and OsNox8, but depressed the expression of OsFRO1. Drought stress substantially upregulated the expression of OsNox1-3, OsNox5, OsNox9, and OsFRO1, but downregulated OsNox6. High temperature upregulated OsNox5-9, but significantly downregulated OsNox1-3 and OsFRO1. NaCl treatment increased the expression of OsNox2, OsNox8, OsFRO1, and OsFRO7, but decreased that of OsNox1, OsNox3, OsNox5, and OsNox6. These results suggest that the expression profiles of rice Nox genes have unique stress-response characteristics, reflecting their related but distinct functions in response to different environmental stresses.


c-Jun N-terminal kinase negatively regulates epidermal growth factor-induced cyclooxygenase-2 expression in oral squamous cell carcinoma cell lines.
Epidermal growth factor (EGF)-induced cyclooxygenase-2 (COX-2) expression in squamous cell carcinomas is mediated through the extracellular signal-regulated kinase 1/2 and p38 pathways. Examination of a basaloid and a conventional oral squamous cell carcinoma cell line revealed that inhibition of c-Jun N-terminal kinase (JNK) with SP600125 increased EGF-induced (but not basal) COX-2 transcription 1.5-1.9-fold in extracellular signal-regulated kinase 1/2 and p38 pathway-dependent manners. Although JNK may phosphorylate the cyclosporine A-sensitive transcription factor, nuclear factor of activated T cells c3, it was seemingly not involved because cyclosporine A did not reduce EGF-induced COX-2 expression. Thus, JNK negatively regulated EGF-induced extracellular signal-regulated kinase 1/2 and/or p38-mediated COX-2 transcription, presumably through activating an unidentified phosphatase.


A model approach advocated.
Melvyn Langford, a former NHS estates and facilities manager with a number of Trusts and now an independent risk management consultant, describes the development and subsequent application of a model designed to help NHS Trusts, including their estates and facilities functions, to identify, monitor and manage key risks which, if not addressed, could impact on business continuity and patient care.


MUC1-induced immunosuppression in colon cancer can be reversed by blocking the PD1/PDL1 signaling pathway.
Mucin1 (MUC1) upregulation in colon cancer has been linked to poor patient outcomes and advanced stage at diagnosis. This is partially due to MUC1-mediated inhibition of T-cell proliferation affecting efficient lysis by cytotoxic lymphocytes, which contributes to escape from immune surveillance. In the present study, human colorectal cancer tissues were collected, and MUC1-positive and MUC1-negative colon cancer mouse models were prepared; subsequently, the number and function of immune cells in tumor tissues were measured using flow cytometry. The present study revealed that MUC1, as a tumor-associated antigen, can recruit more tumor-infiltrating lymphocytes into the tumor microenvironment compared with MUC1-negative colon cancer, but that these cells could not serve antitumor roles. Conversely, the present study demonstrated that MUC1-positive colon cancer attracted more regulatory T cells (Treg cells), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) to the tumor site than MUC1-negative colon cancer. Furthermore, the data suggested that programmed death protein 1 (PD1)-programmed death ligand 1 (PDL1) expression is greater in MUC1-positive colon cancer. Blocking the PD1-PDL1 signaling pathway reduced the percentage of Treg cells, MDSCs and TAMs in the tumor microenvironment, enhanced T-cell cytotoxicity and inhibited tumor growth, prolonging the survival time of MUC1-positive tumor-bearing mice. Therefore, the present study elucidated the role of MUC1 in tumor immune escape and provides a foundation for the application of PDL1 inhibitors to MUC1-positive colon cancer.


[Features of adherence to treatment of patients with chronic rhinosinusitis with nasal polyps].
Chronic polypous rhinosinusitis (CPR) is characterized by refractory to drug therapy and a high potential for recurrence after surgical treatment. One of the important factors limiting the effectiveness of drug therapy of CPR, in particular intranasal glucocorticosteroids (inGCSs), is the insufficient level of adherence to treatment of patients with CPR. Generalization of data on the significance and ways to increase adherence to treatment of patients with CPR. Materials of scientific publications included in the Cochrane Library, Russian Science Citation Index, MEDLINE, PubMed information bases were used as a data source. The material was selected based on the following keywords: "chronic rhinosinusitis", "nasal polyps", "intranasal glucocorticosteroids", "adherence to treatment". Despite the fact that inGCSs are one of the main pathogenetically justified methods of treating CPR, their use is limited by many factors, one of which is the level of patient compliance with the treatment regimen. Improving adherence to treatment is one of the important reserves for increasing the effectiveness of drug therapy for chronic polypous rhinosinusitis.


The Lowe-Andersen thermostat as an alternative to the dissipative particle dynamics in the mesoscopic simulation of entangled polymers.
Dissipative Particle Dynamics (DPD) has shown a great potential in studying the dynamics and rheological properties of soft matter; however, it is associated with deficiencies in describing the characteristics of entangled polymer melts. DPD deficiencies are usually correlated to the time integrating method and the unphysical bond crossings due to utilization of soft potentials. One shortcoming of DPD thermostat is the inability to produce real values of Schmidt number for fluids. In order to overcome this, an alternative Lowe-Anderson (LA) method, which successfully stabilizes the temperature, is used in the present work. Additionally, a segmental repulsive potential was introduced to avoid unphysical bond crossings. The performance of the method in simulating polymer systems is discussed by monitoring the static and dynamic characteristics of polymer chains and the results from the LA method are compared to standard DPD simulations. The performance of the model is evaluated on capturing the main shear flow properties of entangled polymer systems. Finally the linear and nonlinear viscoelastic properties of such systems are discussed.


Basal regulatory promoter elements of the hsp27 gene in human breast cancer cells.
The small human heat shock protein hsp27 has been shown to play important roles in diverse cellular processes such as actin polymerization, thermotolerance, growth, and chemotherapeutic drug resistance. Two breast cancer cell lines MCF-7 and MDA-MB-231 were used as a model to study the molecular mechanisms important for basal hsp27 promoter transcriptional activity. A genomic clone containing 1.1 kb of the hsp27 promoter was sequenced and the regulatory elements were characterized. The first 200 bp within this 5'-flanking region holds the majority of the transcriptional activity, according to transient transfection assays using a series of hsp27 promoter deletion fragments in luciferase reporter vectors. The basal activity of this fragment is largely confined to a G/C-rich region containing overlapping SP1 and AP2 transcription factor binding sites.


Prolonged survival of hamster-to-rat pulmonary xenografts by tacrolimus (FK506) and cyclophosphamide.
Severe shortage of donor organs in clinical lung transplantation prompted us to investigate the potential use of pulmonary xenografts. The purpose of this study was to determine whether an immunosuppressive regimen of tacrolimus (FK506) and cyclophosphamide would prolong the survival of hamster-to-rat pulmonary xenografts. Left lung transplantation was done with male Golden Syrian hamsters used as donors and inbred male Lewis rats as recipients. Control animals (n = 10) received no immunosuppressive drugs whereas experimental animals (n = 6) were treated with tacrolimus and cyclophosphamide. Tacrolimus was administered intramuscularly at a dosage of 2 mg/kg per day on postoperative days 0 to 4, followed by 1 mg/kg per day on days 5 to 29 and 0.5 mg/kg per day on days 30 to 99. Cyclophosphamide (8 mg/kg per day) was administered orally from the day before transplantation to day 8. After transplantation the animals were monitored by chest radiography. Recipient animals were killed at timed intervals (days 60 and 100) and when the chest radiograph showed complete opacification of the transplanted lung. At necropsy, pulmonary xenografts were examined histologically for evidence of rejection, which was graded on a scale of 0 (no rejection) to 4 (severe rejection). Antihamster lymphocytotoxic antibody titer was also measured in recipient animals after transplantation. Pulmonary xenografts in the control animals had a median [correction of medium] survival time of 3 days, whereas the median survival in treated animals was more than 74 days. All pulmonary xenografts in control animals had severe rejection on day 3 after transplantation, whereas those in the treated animals had no rejection on days 60 and 100. The lymphocytotoxic antibody titers in control animals increased from 1:16 before operation to 1:4096 on day 3 (p < 0.01). In the treated animals, the lymphocytotoxic antibody titer on day 21 was 1: 8, which was not different from the preoperative value (1:16). These results indicate that a combination of tacrolimus and a short course of cyclophosphamide prolongs the survival of pulmonary xenografts in a hamster-to-rat model.


Enzymatic hydrolysis of water hyacinth biomass for the production of ethanol: optimization of driving parameters.
An efficient conversion of lignocellulose into fermentable sugars is a key step in producing bioethanol in a cost effective and eco-friendly manner. Alternative source like water hyacinth biomass (WHB) (Eichhornia crassipes) may be used as a supplement for the routine feedstocks. The enzyme loading for optimum yield of total reducing sugar was investigated and the enzyme-substrate interaction optimised. The maximal reducing sugar and xylose yield was obtained using cellulase and xylanase loading of 46.12 and 289.98 U/g and 2.26% (w/v) substrate loading. The efficiencies of ethanol production from the WHB hydrolysate are very less and the maximal ethanol yield was 3.4969 g/L when Pichia stiptis was used, followed by 3.4496 and 3.1349 g/L for Candida shehatae and Saccharomyces cerevisiae.


Muscle fatigue, lactate, and pyruvate in mitochondrial myopathy with progressive external ophthalmoplegia.
We studied muscle fatigue and serum lactate and pyruvate levels in 20 patients with mitochondrial myopathy with progressive external ophthalmoplegia (PEO). Fatigue was assessed in the adductor pollicis muscle (AP) using a low-intensity exercise protocol (20 min). Forces (TFs) and relaxation times of ulnar nerve evoked twitches, compound muscle action potentials (CMAPs), and maximal voluntary contractions (MVCs) were monitored. Serum lactate and pyruvate levels were independently measured at rest and after exercise on a bicycle (15 min, 30 W). Most patients showed abnormal fatigue of the AP with a reduction of TFs and MVCs and normal CMAPs. The reduced TFs were significantly correlated with lactate levels at rest (r= - 0.60, P<0.05) and less so with those after exercise (r=- 0.47,P<0.05). Pyruvate levels revealed a similar correlation although they were widely scattered. We conclude that abnormal fatigue in PEO is metabolic, is localized beyond the muscle fiber membrane, and involves the electrome-chanical coupling and the contractile apparatus. Serum lactate levels at rest are good predictors of fatigue in PEO.


High velocity interparticle collisions driven by ultrasound.
Ultrasonic irradiation of slurries produces high velocity impacts between solid metal particles that are sufficient to cause interparticle melting. Sonication of 5 mum Zn powder as a slurry in alkanes, for example, produces dense agglomerates 50 mum in diameter consisting of approximately 1000 fused particles. Particle size was found to be the most influential parameter in inducing local melting during interparticle collisions. Ultrasonic irradiation of mixed powders resulted in formation of agglomerates with larger Zn particles "soldered" by the smaller ones. A simple kinematic model of the ultrasound-driven interparticle fusion predicts a melting criterion that is nonmonotonically dependent on particle size and is shown to be in agreement with experiment.


Pan-genome analysis provides much higher strain typing resolution than multi-locus sequence typing.
The most widely used DNA-based method for bacterial strain typing, multi-locus sequence typing (MLST), lacks sufficient resolution to distinguish among many bacterial strains within a species. Here, we show that strain typing based on the presence or absence of distributed genes is able to resolve all completely sequenced genomes of six bacterial species. This was accomplished by the development of a clustering method, neighbour grouping, which is completely consistent with the lower-resolution MLST method, but provides far greater resolving power. Because the presence/absence of distributed genes can be determined by low-cost microarray analyses, it offers a practical, high-resolution alternative to MLST that could provide valuable diagnostic and prognostic information for pathogenic bacterial species.


Non-purulent arthritis in Danish slaughter pigs. I. A study of field cases.
The pathology and microbiology of non-purulent arthritis in Danish slaughter pigs were studied in order to draw up an updated picture of the disease. Samples of one or more joints, their regional lymph nodes and the heart were collected from 101 arthritic pigs, totalling 137 joints, 86 lymph nodes and 96 hearts (group I). For another selected group including 25 pigs (group II), the preliminary diagnosis of mycoplasmic arthritis, based on the appearance of the corresponding regional lymph node, was assessed versus the appearance of the joint fluid. A total of 44 samples were examined. More than 70% of all joint samples in both groups were sterile. Erysipelothrix rhusiopathiae was isolated from 7% of the joints and Mycoplasma hyosynoviae from 9%. A contamination flora was isolated in 17% of the samples. Very few of the lymph nodes (5%) were infected, and none of the hearts were. In group-II M. hyosynoviae was isolated from 8% of the joints. From the remainder the isolates were contamination flora or low numbers of non-specific bacteria. The gross pathological changes of the lymph nodes and joints of the E. rhusiopathiae cases differed notably from those of the M. hyosynoviae cases. The pathological features of the lymph nodes, in particular, were type specific. This suggests that these features may be used to differentiate between the two types of arthritis. Considering the high number of sterile samples, it is necessary to test this hypothesis in greater detail. A programme is outlined to elucidate the zoonotic and hygienic consequences of a proposed alternative handling and removal procedures for the two types of arthritis at slaughter.


Microwave-Assisted Extraction Combined with Ultra-High-Performance Liquid Chromatography and Quadrupole/Q-Exactive High-Resolution Mass Spectrometry for the Determination of Main Flavor Substances in Green Tea.
In order to make up for the efficacy of sensory assessment of green tea quality and taste, main flavor substances should be quantitatively characterized based on efficient extraction and frontier determination scheme. A new, relatively simple sample preparation and detection workflow has been developed for the quantification and confirmation of flavor substances in green tea by microwave-assisted extraction combined with ultra-high-performance LC and quadrupole/Q-Exactive high-resolution MS system. The method identified main flavor substances (i.e., catechins, free amino acids, and caffeine) that were the main components in the formation of tea taste. After crushing pretreatment, tea was extracted and purified simultaneously in a microwave extraction jar by matrix-dispersed solid-phase extraction. The extracting solution was determined by LC coupled to high-resolution Orbitrap mass spectrometry. In this study, extraction solvent and purification materials were selected, extraction temperature and time were optimized, and the amount and proportion of solid-phase extraction packing were optimized. The method enabled detection of multiple catechins, amino acids, and caffeine in tea by LC coupled to high-resolution Orbitrap MS, and a database of tea flavor substances was established. The method could be used for screening and confirmation of the main flavor substances in tea as well as assisting the sensory evaluation to grade the quality of tea.


Delayed greening in phosphorus-efficient Hakea prostrata (Proteaceae) is a photoprotective and nutrient-saving strategy.
Hakea prostrata R.Br. (Proteaceae) shows a 'delayed greening' strategy of leaf development characterised by reddish young leaves that become green as they mature. This trait may contribute to efficient use of phosphorus (P) during leaf development by first investing P in the development of leaf structure followed by maturation of the photosynthetic machinery. In this study, we investigated the properties of delayed greening in a highly P-efficient species to enhance our understanding of the ecological significance of this trait as a nutrient-saving and photoprotective strategy. In glasshouse-grown plants, we assessed foliar pigments, fatty acids and nutrient composition across five leaf developmental stages. Young leaves had higher concentrations of anthocyanin, P, nitrogen (N), copper (Cu), xanthophyll-cycle pigments and saturated fatty acids than mature leaves. As leaves developed, the concentration of anthocyanins decreased, whereas that of chlorophyll and the double bond index of fatty acids increased. In mature leaves, ~60% of the fatty acids was α-linolenic acid (C18:3 n-3). Mature leaves also had higher concentrations of aluminium (Al), calcium (Ca) and manganese (Mn) than young leaves. We conclude that delayed greening in H. prostrata is a strategy that saves P as well as N and Cu through sequential allocation of these resources, first to cell production and structural development, and then to supplement chloroplast development. This strategy also protects young leaves against photodamage and oxidative stress during leaf expansion under high-light conditions.


1 x 2 precise electro-optic switch in periodically poled lithium niobate.
A 1 x 2 precise electro-optic switch was demonstrated in a periodically poled lithium niobate crystal. In the experiment, the optical signal was shifted to different channels by adjusting external applied electric fields. The bandwidth of the working wavelength for the switch is nearly 2 nm, which makes this device has large tolerance to the drift of the working wavelength in the practical applications. Theoretical discussion about 1 x 2 precise electro-optic switch based on this structure is also presented.


[Synthesis and DNA-cleaving activity of a series of substituted arenediazonium ions].
We investigated the reactions of substituted aryl radicals and aryl cations derived from arenediazonium ions and their ability to cause cleavage of supercoiled DNA and their tendency toward free radical or cation formation in the presence and absent of copper (I) chloride. It was found that the substituted arenediazonium salts can cleave supercoiled DNA to the open circular form II DNA and linear form III DNA. Results of methodical studies indicate that both carbon-centered radicals and aryl cations participate in the cleavage pathways.


Expression of the CD2 activation epitope T11-3 (CD2R) on T cells in rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and Lyme disease: phenotypic and functional analysis.
CD2R is an activation-associated epitope unmasked by a conformational change of the CD2 cell-surface glycoprotein. In spite of elaborate studies on the role of CD2 and CD2R in adhesion and stimulation of T cells in vitro, no instances of CD2R expression in vivo were known to date. We report high levels of CD2R observed on blood and synovial fluid T cells in rheumatoid arthritis and on peripheral blood T cells in juvenile rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and Lyme disease. In vivo, expression of CD2R was restricted to T cells, not limited to a particular T-cell subset and not correlated with the expression of p55 interleukin 2R (IL-2R) (CD25) or major histocompatibility complex (MHC) class II molecules. When stimulated to proliferation via CD2 or CD3, ex vivo CD2R+ T cells showed the same basic activation requirements as CD2R-T cells.


Wide spectrum screening keratin as a marker of metaplastic spindle cell carcinoma of the breast: an immunohistochemical study of 24 patients.
Metaplastic spindle cell carcinomas may be difficult to distinguish histologically from other spindle cell lesions in the breast. Variable staining with cytokeratin immunomarkers has been reported for metaplastic carcinomas. We evaluated the diagnostic utility of anti-cytokeratin polyclonal antibody, wide spectrum screening keratin, to assess spindle cell breast lesions. Twenty-four patients with spindle cell breast carcinoma and 31 patients with benign or malignant spindle cell tumours were studied using a panel of antibodies directed against multiple cytokeratins (AE1/AE3, CAM5.2, wide spectrum screening keratin), epithelial membrane antigen (EMA), and vimentin. Sites of origin for the 31 controls included breast, bone, and soft tissue. All but one (95.8%) metaplastic carcinomas stained positively with wide spectrum screening keratin. Only rare or focal immunoreactivity was observed with AE1/AE3 in four cases; however, sensitivity of AE1/AE3 was improved in 13 cases using steam EDTA as an antigen retrieval technique. Three cases were immunoreactive with CAM5.2 and eight cases were immunoreactive with EMA. All control cases lacked immunoreactivity with the cytokeratin panel and EMA. The spindle cells in the metaplastic breast tumours (88%) and in the controls (97%) stained with vimentin. Wide spectrum screening keratin may be the most useful and convenient antibody in differentiating metaplastic spindle cell carcinoma from other spindle cell lesions in the breast.


Occult primary tumors of the head and neck: detection with 2-[F-18] fluoro-2-deoxy-D-glucose SPECT.
To evaluate 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) single photon emission computed tomography (SPECT) in the detection of clinically occult primary tumors of the upper aerodigestive tract. Eighteen patients with histologically proved cervical nodal metastasis from squamous cell carcinoma (SCC) underwent FDG SPECT; 17 also underwent computed tomography (CT) and one underwent magnetic resonance (MR) imaging. All 18 patients underwent direct panendoscopy and biopsy. Biopsy and imaging results were correlated. Among 11 histologically proved primary tumors, FDG SPECT depicted nine tumors; CT depicted four lesions. Five patients had abnormal FDG uptake with negative biopsy results. Among five patients with normal SPECT findings, biopsy results were positive in two and negative in three. FDG SPECT at the initial reading had sensitivity of 81%, specificity of 38%, positive predictive value of 64%, and negative predictive value of 60% for detection of occult primary tumors. FDG SPECT guidance of endoscopic biopsies in patients with occult primary SCCs of the head and neck has the potential to yield a higher rate of positive biopsy results than that traditionally expected from "blind" endoscopic procedures with "random" or "speculative" biopsy. FDG SPECT and CT are likely to remain complementary studies for the detection of occult primary tumors of the head and neck.


Transition-metal-free highly efficient aerobic oxidation of sulfides to sulfoxides under mild conditions.
A highly efficient transition-metal-free catalytic system Br2/NaNO2/H2O has been developed for a robust and economic acid-free aerobic oxidation of sulfides. It is noteworthy that the sulfide function reacts under mild conditions without over-oxidation to sulfone. The role of NaNO2as an efficient NO equivalent for the activation of molecular oxygen was identified. Under the optimal conditions, a broad range of sulfide substrates were converted into their corresponding sulfoxides in high yields by molecular oxygen. The present catalytic system utilizes cheap and readily available agents as the catalysts, exhibits high selectivity for sulfoxide products and releases only innocuous water as the by-products.


Development and validation of the 4-Factor Critical Consciousness Scale.
Assessment of critical consciousness among individuals can provide a proxy measure of the readiness of communities, and individual decision-makers within, for social changes that address root causes of ill health. Critical consciousness, as conceived by Paolo Freire, emerges as a consequence of praxis. This iterative, recursive process of reflection and co-created knowledge enables community members to identify salient issues and the actions they want to take to address those issues. Public health and other social science researchers who engage in social- and population-level intervention work need a validated instrument that measures critical consciousness. Our purpose was to develop an instrument that can measure 4 key constructs of critical consciousness (passive adaptation, emotional engagement, cognitive awakening, and intentions to act) in an individual, relative to any salient community issue. We conducted two studies (Initial: June 2018; Retest: October 2019) to develop and validate this instrument. The same sampling strategy was used for both studies, but each study was conducted with a discrete cohort of participants. We used Amazon's Mechanical Turk to recruit and incentivize study participants. Data from the Initial study were used in an iterative process to evaluate construct validity and test our theoretical assumptions. Exploratory factor analyses were used to determine the best model fit that gave the greatest subscale reliability and validity. In the Retest study, confirmatory factor analysis was conducted and construct validity was verified. Our results indicated adequate construct validity as evidenced by good model fit. Additionally, the good fit of the data to the 4-factor structure confirmed our theoretical understanding of critical consciousness.


MyD88-dependent signaling protects against anthrax lethal toxin-induced impairment of intestinal barrier function.
MyD88-deficient mice were previously shown to have increased susceptibility to Bacillus anthracis infection relative to wild-type animals. To determine the mechanism by which MyD88 protects against B. anthracis infection, knockout mice were challenged with nonencapsulated, toxigenic B. anthracis or with anthrax toxins. MyD88-deficient mice had increased susceptibility to B. anthracis and anthrax lethal toxin but not to edema toxin. Lethal toxin alone induced marked multifocal intestinal ulcers in the knockout animals, compromising the intestinal epithelial barrier. The resulting enteric bacterial leakage in the knockout animals led to peritonitis and septicemia. Focal ulcers and erosion were also found in MyD88-heterozygous control mice but with far lower incidence and severity. B. anthracis infection also induced a similar enteric bacterial septicemia in MyD88-deficient mice but not in heterozygous controls. We show that lethal toxin and B. anthracis challenge induce bacteremia as a result of intestinal damage in MyD88-deficient mice. These results suggest that loss of the intestinal epithelial barrier and enteric bacterial septicemia may contribute to sensitizing MyD88-deficient mice to B. anthracis and that MyD88 plays a protective role against lethal toxin-induced impairment of intestinal barrier.


Serum zinc level and hepatic fibrosis in patients with nonalcoholic fatty liver disease.
This study aimed to investigate the relationship between serum zinc level and hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). A cross-sectional study was conducted using nationally representative samples from the Korea National Health and Nutrition Examination Survey 2010. Significant hepatic fibrosis was defined as Fibrosis-4 (FIB-4) index>1.3. Zinc level was measured using inductively coupled plasma mass spectrometry. Univariable and multivariable logistic regression analyses were performed to assess risk factors for significant hepatic fibrosis in patients with NAFLD. A total of 300 patients with NAFLD were analyzed in this study. The mean serum zinc level was 139.8±29.9 μg/dL. FIB-4 index was significantly increased as the serum zinc level decreased (Adjusted correlation coefficient = -0.177, p = 0.003). Significant liver fibrosis was observed in 62 patients (21%). The multivariable analysis showed that significant liver fibrosis in NAFLD was associated with diabetes mellitus (odds ratio [OR], 3.25; 95% confidence interval [CI], 1.71-6.19; p<0.001), male (OR, 2.59; 95% CI, 1.31-5.12; p = 0.006), and zinc level <140 μg/dL (OR, 2.14; 95% CI, 1.16-3.94; p = 0.015). There was an inverse relationship between serum zinc level and FIB-4 index in NAFLD. Low levels of serum zinc were an independent risk factor for significant hepatic fibrosis in NAFLD.


[Intravenous injection of metallic mercury--case report].
A case of a 16 year old male who injected intravenously metallic mercury is presented. The patient was admitted to the hospital due to slightly elevated fever and hemoptysis. Both symptoms presented themselves 18 months following intravenous injection of metallic mercury. Radiological examination disclosed fine metallic interstitial shadowing in the lung parenchyma. Metallic shadows were also present in the subcutaneous region of the cubital fossa. CT scans and USG examination disclosed similar deposition of metal in the liver, kidneys, lymph nodes and heart. The mercury serum and urine levels exceeded the normal values by hundreds. Encountered diagnostic problems are presented, also prognosis basing on data from literature is discussed.


Fe uptake mechanism in fe-efficient cucumber roots.
Fe-efficient plants respond to iron stress both by morphological and physiological modifications. In roots of a Fe-efficient plant (Cucumis sativus L.) grown in the presence or in the absence of iron, the capacity to acidify the external medium, change in the transmembrane electrical potential, and the ATPase activity have been determined. Roots from plants grown in the absence of iron showed a great capacity to acidify the external medium, a higher transmembrane electrical potential difference (-145 millivolts, versus -105 millivolts), and a higher ATPase activity (+30%). The administration of Fe(2+), but not Fe(3+), caused a block of the acidification capacity, a great decrease in the transmembrane electrical potential difference in root cells, and a large inhibition of the ATPase activity of isolated microsomal membrane vesicles.


Therapeutic potential of mangiferin against kidney disorders and its mechanism of action: A review.
There is a swing in research developments concerning the utilization of natural products as effective pharmacotherapeutic agents due to their comparatively lower toxicities than synthetic compounds. Among natural products, mangiferin is a natural C-glucosyl xanthonoid polyphenol with remarkable pharmacological activities. Emerging evidence indicates the therapeutic benefits of mangiferin against various kidney disorders, including renal injury, diabetic nephropathy, renal fibrosis, hyperuricemic nephropathy, and lupus nephritis, in experimental animal models. The mangiferin induced antioxidant response resulting in vital functions, such as protection against renal inflammation, inhibits renal cell apoptosis, activates autophagy, causes immunomodulation, regulates renal urate transporters and modulates cell signalling pathways. The purpose of this review provide a brief overview of the in vitro/in vivo reno-protective effect of mangiferin and the underlying mechanism(s) in protecting against kidney disorders. Understanding the pharmacological actions of mangiferin is prominence due to its excellent therapeutic potential in managing kidney disorders. Thus, in addition to this review, in-silico molecular docking is performed against nuclear factor kappa B (NF-κB) and soluble epoxide hydrolase (sEH) to study the mechanism of action of mangiferin. It is believed that mangiferin is a safe reno-protective molecule. The observed positive effects are attributed to the inhibition of inflammation caused by NF-κB and sEH upregulation and oxidative stress activation. Studies on the efficacy and safety of mangiferin in clinical trials are further warranted to confirm its medicinal potential as therapeutic agent for kidney disorders in humans.


Induction of viable but nonculturable Escherichia coli O157:H7 by high pressure CO2 and its characteristics.
The viable but nonculturable (VBNC) state is a survival strategy adopted by many pathogens when exposed to harsh environmental stresses. In this study, we investigated for the first time that whether high pressure CO2 (HPCD), one of the nonthermal pasteurization techniques, can induce Escherichia coli O157:H7 into the VBNC state. By measuring plate counts, viable cell counts and total cell counts, E. coli O157:H7 in 0.85% NaCl solution (pH 7.0) was able to enter the VBNC state by HPCD treatment at 5 MPa and four temperatures (25°C, 31°C, 34°C and 37°C). Meanwhile, with the improvement of treatment temperature, the time required for E. coli O157:H7 to enter VBNC state would shorten. Enzymatic activities in these VBNC cells were lower than those in the exponential-phase cells by using API ZYM kit, which were also reduced with increasing the treatment temperature, but the mechanical resistance of the VBNC cells to sonication was enhanced. These results further confirmed VBNC state was a self-protection mechanism for some bacteria, which minimized cellular energetic requirements and increased the cell resistance. When incubated in tryptic soy broth at 37°C, the VBNC cells induced by HPCD treatment at 25°C, 31°C and 34°C achieved resuscitation, but their resuscitation capabilities decreased with increasing the treatment temperature. Furthermore, electron microscopy revealed changes in the morphology and interior structure of the VBNC cells and the resuscitated cells. These results demonstrated that HPCD could induce E. coli O157:H7 into the VBNC state. Therefore, it is necessary to detect if there exist VBNC microorganisms in HPCD-treated products by molecular-based methods for food safety.


New approaches to the therapy of HSV infections.
Two recent studies have demonstrated single-day regimens of high-dose antiviral therapy (famciclovir 1000 mg twice daily for genital herpes, and famciclovir 1500 mg single dose for herpes labialis) to be effective episodic treatment strategies. Both have the potential to improve patient compliance and therapeutic satisfaction. Patient-initiated episodic therapy (PIE) regimens such as these may improve the time to treatment initiation, which can halt lesion development: PIE allows antiviral drugs to be administered in the narrow therapeutic window that occurs early in the course of a herpes simplex virus (HSV) infection episode. This review article discusses short-course antiviral therapy, which may offer an effective alternative to traditional episodic or suppressive antiviral regimens for HSV-related disease outbreaks.


Technology-Assisted Collaborative Care Program for People with Diabetes and/or High Blood Pressure Attending Primary Health Care: A Feasibility Study.
The comorbidity of depression with physical chronic diseases is usually not considered in clinical guidelines. This study evaluated the feasibility of a technology-assisted collaborative care (TCC) program for depression in people with diabetes and/or high blood pressure (DM/HBP) attending a primary health care (PHC) facility in Santiago, Chile. Twenty people diagnosed with DM/HBP having a Patient Health Questionnaire-9 score ≥ 15 points were recruited. The TCC program consisted of a face-to-face, computer-assisted psychosocial intervention (CPI, five biweekly sessions), telephone monitoring (TM), and a mobile phone application for behavioral activation (CONEMO). Assessments of depressive symptoms and other health-related outcomes were made. Thirteen patients completed the CAPI, 12 received TM, and none tried CONEMO. The TCC program was potentially efficacious in treating depression, with two-thirds of participants achieving response to depression treatment 12 weeks after baseline. Decreases were observed in depressive symptoms and healthcare visits and increases in mental health-related quality of life and adherence to treatment. Patients perceived the CPI as acceptable. The TCC program was partially feasible and potentially efficacious for managing depression in people with DM/HBP. These data are valuable inputs for a future randomized clinical trial.


Mining chemical and biological information from the drug literature.
The mining of information from the drug literature covers a broad set of disciplines that include chemistry, biology and medicine. It is not possible for any one scientist to keep up to date on the wide breadth of published pharmaceutical information. The need for researchers to find and integrate information from the drug literature with other information is apparent. This article highlights some of the key themes of 2008 publications on mining chemical and biological information, and indicates that the drug literature has exhibited a significant transformation in 2008.


Preparation and anti-inflammatory activity of triptolide ethosomes in an erythema model.
The aim of this work was to evaluate the suitability of ethosomes as carriers for the topical application of triptolide in a rat model of erythema. We determined the optimal conditions for preparing ethosomes, and we measured their vesicle size by a laser particle-size analyzer and the efficiency of entrapment of triptolide by ultracentrifugation. The in vitro percutaneous permeation of triptolide-loaded ethosomes was investigated by measuring diffusion across a sample of rat skin. To explore the transdermal delivery in vivo, we used a model in which erythema was induced in rats by methyl nicotinate and determined the change in erythema index caused by the anti-inflammatory activity of triptolide by a reflection spectrophotometer. The optimal conditions for preparing triptolide ethosomes consisted of ultrasonication of 45% (v/v) ethanol and 2% (w/v) DPPC for 5 minutes, which produced an average vesicle size of 51.4 nm and an entrapment efficiency of 98%. This ethosomal formulation of triptolide caused the greatest in vitro 24-hour accumulation of triptolide (83.7%) with no permeation time delay, and it reduced erythema in vivo more rapidly and more completely than other formulations. Ethosomes might be a promising carrier that would enable the beneficial properties of triptolide to be safely delivered in a topical formulation.


An annulative approach to highly substituted indoles: unusual effect of phenolic additives on the success of the arylation of ketone enolates.
A novel palladium-catalyzed arylation of ketone enolates with o-nitrohaloarenes was achieved through the addition of phenol additives. The mild reaction conditions employed allowed for the inclusion of a wide variety of functional groups in both substrates to be tolerated. The products of this reaction were then readily reductively cyclized to give highly substituted indoles in moderate to excellent overall yields.


Differential sensitivity of interleukin-1 alpha and -beta precursor proteins to cleavage by calpain, a calcium-dependent protease.
In view of the observations that the calcium ionophores, A23187 and ionomycin, enhance the processing and secretion of interleukin-1 (IL-1 alpha) and IL-1 beta from macrophages, and IL-1 alpha processing is mediated by calpain, a calcium-dependent protease, we evaluated the possibility that calpain might also play a role in the processing of IL-1 beta. Whereas calpain-containing P388D1 macrophage lysates and purified calpain processed precursor IL-1 alpha to its mature 17-kDa form, precursor IL-1 beta was degraded by both sources of calpain. However, the activation of calpain in P388D1 cells that were transiently transfected with a cDNA expression vector encoding the precursor form of IL-1 beta did not result in the degradation of precursor IL-1 beta, but did result in the processing and secretion of IL-1 alpha, implying that precursor IL-1 beta is protected from calpain degradation in vivo. Furthermore, calpain did not enhance the processing of the IL-1 beta precursor by the IL-1 beta-converting enzyme. These results indicate that calpain is not involved in the processing of precursor IL-1 beta in vitro or in vivo. The IL-1 beta precursor may be protected from calpain degradation by a sequestering mechanism that involves a cytoplasmic factor(s) that reduces the sensitivity of IL-1 beta to attack by calpain or localizes IL-1 beta to a site that precludes any interaction with the protease. Although MDL 28,170, a calpain inhibitor, prevented the ionomycin-induced processing of precursor IL-1 alpha to the mature protein in P388D1 cells, it did not inhibit the ionomycin-induced secretion of the mature IL-1 alpha and -beta proteins expressed in these cells. These results indicate that a calcium-dependent factor other than calpain is involved in the secretion of the mature IL-1 proteins.


Analysis of the activity of DNA, RNA, and protein synthesis inhibitors on Xenopus embryo development.
The teratogenic and growth-inhibiting potential of DNA, RNA, and protein synthesis inhibitors was explored using the Frog Embryo Teratogenesis Assay: Xenopus (FETAX). Endpoints measured in 96-h static tests were survival, malformation, ability to swim, skin pigmentation, stage of development, and growth. The DNA synthesis inhibitors hydroxyurea, cytosine arabinoside, and ethidium bromide proved to be teratogenic by the severity of malformations induced. Hydroxyurea gave an LC50 of 1.82 mg/ml, an EC50 (malformation) of 0.43 mg/ml, while the values for cytosine arabinsode were 5.41 and 0.76, respectively. The values for ethidium bromide were 0.05 and 0.035. The RNA synthesis inhibitor actinomycin D and the protein synthesis inhibitor cycloheximide were more embryolethal than teratogenic but significantly inhibited growth as determined by head-tail length measurements. Actinomycin D caused severe malformations, while cycloheximide caused relatively minor abnormalities. The LC50 for actinomycin D was 1.89 mg/ml, while the EC50 (malformation) was 2.17 mg/ml. For cycloheximide, the values were 1.59 and 1.19, respectively. FETAX advantages include rapid data collection, the ability to measure stage-dependent effects, and the ability to use a large number of embryos to obtain excellent dose-response curves with narrow confidence limits. Disadvantages include lack of a metabolic activation system, absence of a placental relationship, and the inability to detect specific abnormalities such as limb defects in 96 h.


The Berlin principles on one health - Bridging global health and conservation.
For over 15-years, proponents of the One Health approach have worked to consistently interweave components that should never have been separated and now more than ever need to be re-connected: the health of humans, non-human animals, and ecosystems. We have failed to heed the warning signs. A One Health approach is paramount in directing our future health in this acutely and irrevocably changed world. COVID-19 has shown us the exorbitant cost of inaction. The time to act is now.


[Frequency of encountering markers of viral hepatitis A, B, and C in the aboriginal inhabitants of the northwest region of Siberia].
A minor population of Nenets living near the village of Samburg in the Purov District, Tyumen region was screened for serological markers of virus hepatitides A, B, and C (VHA, HVB, and HVC, respectively). Commercial kits manufactured by VectorBest JSC, Russia, were used. All the tested sera contained antiHVA IgG; IgM antibodies to VHA were detected in none of the tested sera, anti-HVC IgG were found in 1 (0.93%) serum, antiHBc IgG in 11 (10.2%), and HBsAg was detected in 2 (1.85%) serum samples. The sera positive by antiHBc IgG and HBsAg were tested for DNA by the polymerase chain reaction. HVB DNA was found in two HBsAg-positive sera with the HBsAg subtype determined as "non ad".


Impacts of school-wide positive behaviour support: Results from National Longitudinal Register Data.
Problem behaviour in schools may have detrimental effects both on students' well-being and academic achievement. A large literature has consistently found that school-wide positive behaviour support (SWPBS) successfully addresses social and behavioural problems. In this paper, we used population-wide longitudinal register data for all Norwegian primary schools and a difference-in-difference (DiD) design to evaluate effects of SWPBS on a number of primary and secondary outcomes, including indicators of externalising behaviour, school well-being, pull-out instruction, and academic achievement. Indications of reduced classroom noise were found. No other effects were detected. Analyses revealed important differences in outcomes between the intervention and control schools, independent of the implementation of SWPBS, and that a credible design like DiD is essential to handle such school differences.


Three methods for estimation of changes in frequency characteristics of potentials elicited by long-lasting (fatiguing) activity of isolated muscle fibres.
The present study was assigned to compare the applicability and sensitivity of three different methods (discrete wavelet transforms (DWT), median frequency (MDF) - calculated on the basis of fast Fourier transform, and spectral indices) for analysis of frequency content changes in potentials produced by repetitive stimulation from isolated slow (SMFs)- and fast (FMFs)-fatigable muscle fibers during uninterrupted activity. In order to affect fatigue, prior to starting the fatiguing stimulation (5 Hz), some of the fibres were exposed to microwave electromagnetic field and others were sham exposed. All the methods studied demonstrated that during a long-lasting fibre activity, the shift of the potential frequency content to lower frequencies was a consequence of lowering in higher frequency components and increasing in low frequency ones. The changes were faster in FMFs than SMFs and stronger in sham exposed fibres vs. microwave exposed. The MDF alterations in both fibre types and protocols were quite similar to other methods characterizing either individual changes in low and high frequency scales of the signal (discrete wavelet transform - DWT) or changes in their spectral ratio (spectral indices). The spectral indices showed sensitivity to fatigue effect at the final stages that made their changes considerably non-linear. DWT allowed processing the temporal occurrence of frequency content changes that corresponded to the alterations in the separate potential phases as well as earlier detection and precise evaluation of fatigue onset and progressing. All methods are applicable but DWT is a preferable for study of muscle fibre fatigue in clinical and experimental neurophysiology.