Microsatellite DNA mutations in double-crested cormorants (Phalacrocorax auritus) associated with exposure to PAH-containing industrial air pollution.
Hamilton Harbour, Ontario, Canada is one of the most polluted sites on the Great Lakes, and is subject to substantial airborne pollution due to emissions from both heavy industry and intense vehicle traffic. Mutagenic Polycyclic aromatic hydrocarbons (PAHs) are present at very high concentrations in the air and sediment of Hamilton Harbour. We used five variable DNA microsatellites to screen for mutations in 97 families of Double-crested Cormorants (Phalacrocorax auritus) from three wild colonies, two in Hamilton Harbour and one in cleaner northeastern Lake Erie. Mutations were identified in all five microsatellites at low frequencies, with the majority of mutations found in chicks from the Hamilton Harbour site closest to industrial sources of PAH contamination. Microsatellite mutation rates were 6-fold higher at the Hamilton Harbour site closest to the industrial sources of PAH contamination than the other Hamilton Harbour site, and both were higher than the reference colony. A Phase I metabolite of the PAH benzo[a]pyrene identified by LC-MS/MS in bile and liver from Hamilton Harbour cormorant chicks suggests that these cormorants are exposed to and metabolizing PAHs, highlighting their potential to have caused the observed mutations.


Reconstitution of Enzymatic Carbon-Sulfur Bond Formation Reveals Detoxification-Like Strategy in Fungal Toxin Biosynthesis.
Gliotoxin is a virulence factor of the human pathogen Aspergillus fumigatus, the leading cause of invasive aspergillosis. The activity of this metabolite is mediated by a transannular disulfide bond, a hallmark of the epipolythiodiketopiperazine (ETP) family. Through the creation of fungal gene deletion mutants and heterologous protein expression, we unveiled the critical role of the cytochrome P450 monooxygenase (CYP450) GliC for the stepwise bishydroxylation of the diketopiperazine (DKP) core. We show for the first time the formation of the C-S bond from the DKP in a combined assay of GliC and the glutathione- S-transferase (GST) GliG in vitro. Furthermore, we present experimental evidence for an intermediary imine species. The flexible substrate scope of GliC and GliG in combination parallels P450/GST pairs used in eukaryotic phase I/II detoxification pathways.


Analysis of the characteristics of the Golay3 multiple-mirror telescope.
The sparse aperture system gives a novel solution for the design of large telescopes with high angular resolution. Such systems utilize several smaller subapertures to simulate the full aperture but are more promising by virtue of their lighter weight and lower cost. Multiple-mirror telescopes (MMTs) and multiple-telescope telescopes (MTTs) are two types of sparse aperture systems. Here, the entrance pupil characteristics are derived for the Golay 3 MMT by studying the relationships between the submirrors on the primary mirror and the shapes of the subapertures on the entrance pupil with different relative apertures and conic constants of the primary mirror of the Golay 3 MMT. Overlay and efficiency factors are proposed in order to obtain the optimal fill factor on the entrance pupil. Expressions for the point spread function (PSF) and the modulation transfer function (MTF) of the Golay 3 MMT are deduced, and the characteristics of the PSF and MTF are explored based on the derived equations and Matlab simulation. Designs for two Cassegrain telescopes with the Golay3 configuration have been developed. Based on the relationships between the fill factor and the overlay factor, optimal parameters for the submirrors on the primary mirror can be selected. The PSF and MTF for both Cassegrain MMT designs have been obtained by Zemax simulation to prove that our theoretical results are consistent with those of practical simulation.


Comparison of carotid plaque burden among healthy middle-aged men living in the US, Japan, and South Korea.
Carotid plaque has emerged as a marker of coronary heart disease (CHD) risk. Comparison of carotid plaque burden between different race/ethnic groups may provide a relative estimate of their future CHD risk. We conducted a population-based study among apparently healthy middle-aged men aged 40-49 years (ERA JUMP study (n = 924)) and recruited 310 Whites in Pittsburgh, US, 313 Japanese in Otsu, Japan, and 301 Koreans in Ansan, South Korea. The number of carotid plaque and CHD risk factors was assessed using a standardized protocol across all centers. The burden of carotid plaque was compared between race/ethnic groups after adjustment for age and BMI, and after multivariable adjustment for other CHD risk factors using marginalized zero-inflated Poisson regression models. Cross-sectional associations of risk factors with plaque were examined. Whites (22.8%) had more than four-fold higher prevalence (p < 0.01) of carotid plaque than Japanese men (4.8%) while the prevalence among Koreans was 10.6%. These differences remained significant after adjustment for age, BMI as well as other risk factors - incidence density ratio (95% confidence interval) for plaque was 0.13 (0.07, 0.24) for Japanese and 0.32 (0.18, 0.58) for Koreans as compared to Whites. Age, hypertension and diabetes were the only risk factors significantly associated with presence of carotid plaque in the overall population. Whites have significantly higher carotid plaque burden than men in Japan and Korea. Lower carotid plaque burden among Japanese and Koreans is independent of traditional CVD risk factors.


The Anti-fertility Effects of Acacia nilotica in Male Wistar Rats.
A bulk of contraceptives on the market is women-oriented today. The aim of this study was to investigate the effect of a medicinal herb, Acacia nilotica on various parameters of male fertility using a rat model. Male Wistar rats (n = 40) were randomly divided in to two groups. One group received Acacia nilotica, while the other acted as controls. Ten animals from each group were sacrificed after 16 weeks. Treatment was withdrawn for the remaining animals for 8 weeks. Blood was collected for hormonal analysis. The testis was removed for histological examination, while epididymal spermatozoa were retrieved for motility and morphological analysis. The data were analyzed using ANOVA and Bonferroni post hoc test. A value of p<0.05 was considered statistically significant. Sperm motility, progressive motility and sperm concentration significantly decreased in treated animals compared to the controls (p<0.05). Withdrawing the treatment did not restore these parameters (p<0.05). Abnormal sperm morphology significantly increased in both the treated and treatment withdrawn groups when compared to the controls (p<0.05). Testosterone concentrations were significantly lower in the treated group when compared to the controls (p<0.05) and no significant differences were observed between the controls and the treated animals when treatment was withdrawn. Histological observations showed that Acacia nilotica treatment disrupted semeniferous tubule architechture and consequently the spermatogenesis process. These results show that Acacia nilotica severely affects sperm morphology, progressive motility and sperm concentration irreversibly in Wistar rats.


The impact of ethnic population dynamics on neonatal ECMO outcomes: a single urban institutional study.
Neonatal extracorporeal membrane oxygenation ECMO has been clinically used for the last 25 y. It has been an effective tool for both cardiac and non cardiac conditions. The impact of ethno-demographic changes on ECMO outcomes however remains unknown. We evaluated a single institution's experience with non cardiac neonatal ECMO over a 28-y period. A retrospective review of all neonates undergoing noncardiac ECMO between the y 1984 and 2011 was conducted and stratified into year groups I, II, III (≤1990, 1991-2000, and ≥2001). Demographic, clinical, and outcome data were collected. The patient specifics, ECMO type, ECMO length, blood use, complications, and outcomes were analyzed. Univariate, bivariate, and multivariate analyses were then performed. Data was available for 827 patients. The number of African-American and Hispanic patients increased over the last 27 y (27.5% versus 45.0% and 3.3% versus 21.5%, year group I versus year group III, respectively). The proportion of congenital diaphragmatic hernia (CDH) patients by ethnicity also increased for African-Americans and Hispanics between the two year groups (22.0% to 33.0% and 4.9% to 33.0%, respectively). Similar pattern was noted for non-CDH diagnoses. Low birth weight, low APGAR scores, CDH, primary pulmonary hypertension, central nervous system hemorrhage, and ECMO were independent predictors of mortality. Ethnicity, in itself however, was not associated with mortality on adjusted analysis. More African-Americans and Hispanics have required ECMO over the years with a concurrent decrease in the number of Caucasians. While ethnicity was not an independent predictor of mortality, it appears to be a surrogate for fatal but sometime preventable diagnoses among minorities. Further investigations are needed to better delineate the reason behind this disparity.


Age effects on mediolateral balance control.
Age-related balance impairments, particularly in mediolateral direction (ML) may cause falls. Sufficiently sensitive and reliable ML balance tests are, however, lacking. This study is aimed to determine (1) the effect of age on and (2) the reliability of ML balance performance using Center of Mass (CoM) tracking. Balance performance of 19 young (26±3 years) and 19 older (72±5 years) adults on ML-CoM tracking tasks was compared. Subjects tracked predictable and unpredictable target displacements at increasing frequencies with their CoM by shifting their weight sideward. Phase-shift (response delay) and gain (amplitude difference) between the CoM and target in the frequency domain were used to quantify performance. Thirteen older and all young adults were reassessed to determine reliability of balance performance measures. In addition, all older adults performed a series of clinical balance tests and conventional posturography was done in a sub-sample. Phase-shift and gain dropped below pre-determined thresholds (-90 degrees and 0.5) at lower frequencies in the older adults and were even lower below these frequencies than in young adults. Performance measures showed good to excellent reliability in both groups. All clinical scores were close to the maximum and no age effect was found using posturography. ML balance performance measures exhibited small but systematic between-session differences indicative of learning. The ability to accurately perform ML-CoM tracking deteriorates with age. ML-CoM tracking tasks form a reliable tool to assess ML balance in young and older adults and are more sensitive to age-related impairment than posturography and clinical tests.


Utility of tumour-infiltrating CD25+FOXP3+ regulatory T cell evaluation in predicting local recurrence in vertical growth phase cutaneous melanoma.
Tumour-infiltrating lymphocytes (TILs) represent the local immune response to cancer, however, their correlation with tumour behaviour is not unanimously considered in the literature. Most studies have not characterized TILs, that are known to comprise distinct subsets, bearing different roles in the complex tumour microenvironment. Characterization of patient lymphocytes has been mainly performed in peripheral blood, that is not always representative of the local immune status. Only few investigations have been performed at the tissue level in cancer, including melanoma. TILs encompass different populations of effector and regulatory T cells (Tregs), and the relevance of the latter in tumour progression is widely accepted. The transcription factor gene product FOXP3 is considered the most reliable marker of Tregs. However, it has not been extensively evaluated in primary cutaneous melanoma. We analyzed 66 vertical growth phase primary cutaneous melanomas, aiming at finding differences in TIL subsets between two groups of cases, that behaved differently in terms of local recurrence. In our study, the percentage of Tregs, as characterized by CD25 and FOXP3 expression, both among tumour cells, inside tumour parenchyma and at its periphery, and among TILs, at the tumour-stroma boundary, was significantly higher in cases that recurred than in those that did not (p=0.00065; p=0.00014; p<0.00001, respectively). TIL characterization by immunohistochemistry in melanoma diagnostic reports, could add further information. The analysis of a larger series of patients and correlation with other clinical parameters, such as distant metastases and/or patient survival, are mandatory for validating its use as a prognostic indicator.


Platinum-catalyzed cycloisomerizations of a common enyne: a divergent entry to cyclopropane sesquiterpenoids. Formal synthesis of sarcandralactone A.
A common enyne scaffold, resembling the structures of natural elemanes was found to be an excellent substrate for highly regioselective cycloisomerizations to produce diverse cyclopropane sesquiterpenoids. Platinum-catalysis was utilized to produce either lindenane or myliol cores, found in natural products, starting from enyne acetate 10 and its corresponding allene 12 respectively. Based on this concept, a second generation strategy allows the formal synthesis of sarcandralactone A.


Ice Hockey Summit II: zero tolerance for head hits and fighting.
This study aimed to present currently known basic science and on-ice influences of sport-related concussion (SRC) in hockey, building upon the Ice Hockey Summit I action plan (2011) to reduce SRC. The prior summit proceedings included an action plan intended to reduce SRC. As such, the proceedings from Summit I served as a point of departure for the science and discussion held during Summit II (Mayo Clinic, Rochester, MN, October 2013). Summit II focused on (1) Basic Science of Concussions in Ice Hockey: Taking Science Forward, (2) Acute and Chronic Concussion Care: Making a Difference, (3) Preventing Concussions via Behavior, Rules, Education, and Measuring Effectiveness, (4) Updates in Equipment: Their Relationship to Industry Standards, and (5) Policies and Plans at State, National, and Federal Levels To Reduce SRC. Action strategies derived from the presentations and discussion described in these sectors were voted on subsequently for purposes of prioritization. The following proceedings include the knowledge and research shared by invited faculty, many of whom are health care providers and clinical investigators. The Summit II evidence-based action plan emphasizes the rapidly evolving scientific content of hockey SRC. It includes the most highly prioritized strategies voted on for implementation to decrease concussion. The highest-priority action items identified from the Summit include the following: (1) eliminate head hits from all levels of ice hockey, (2) change body checking policies, and (3) eliminate fighting in all amateur and professional hockey.


Pregnancy-induced metabolic phenotype variations in maternal plasma.
Metabolic variations occur during normal pregnancy to provide the growing fetus with a supply of nutrients required for its development and to ensure the health of the woman during gestation. Mass spectrometry-based metabolomics was employed to study the metabolic phenotype variations in the maternal plasma that are induced by pregnancy in each of its three trimesters. Nontargeted metabolomics analysis showed that pregnancy significantly altered the profile of metabolites in maternal plasma. The levels of six metabolites were found to change significantly throughout pregnancy, with related metabolic pathway variations observed in biopterin metabolism, phospholipid metabolism, amino acid derivatives, and fatty acid oxidation. In particular, there was a pronounced elevation of dihydrobiopterin (BH₂), a compound produced in the synthesis of dopa, dopamine, norepinephrine, and epinephrine, in the second trimester, whereas it was markedly decreased in the third trimester. The turnover of BH₂ and tryptophan catabolites indicated that the fluctuations of neurotransmitters throughout pregnancy might reveal the metabolic adaption in the maternal body for the growth of the fetus. Furthermore, 11 lipid classes and 41 carnitine species were also determined and this showed variations in the presence of long-chain acylcarnitines and lysophospholipids in later pregnancy, suggesting changes of acylcarnitines and lysophospholipids to meet the energy demands in pregnant women. To our knowledge, this work is the first report of dynamic metabolic signatures and proposed related metabolic pathways in the maternal plasma for normal pregnancies and provided the basis for time-dependent metabolic trajectory against which disease-related disorders may be contrasted.


An analysis of the reliability of detection and diagnostic value of various pathological features in Crohn's disease and ulcerative colitis.
Two pathologists have independently applied 95 separate pathological criteria to 50 cases of inflammatory large bowel disease firmly diagnosed clinically as 25 cases of Crohn's disease and 25 cases of ulcerative colitis. The observer agreement in the recording of each feature has been calculated and correlations have been made between the pathological features and the final agreed diagnosis in order to obtain an estimate of the value of each feature in differential diagnosis. The features which have been found to be most accurately observed and useful in the diagnosis of Crohn's disease include confluent linear ulcers, deep fissures, an aggregated inflammatory pattern, and sarcoid-like granulomata. The features which have been shown to be most accurate and valuable in the diagnosis of ulcerative colitis include a ;healed granular' mucosa, a continuous inflammatory pattern, an irregular gland pattern, and the absence of fissures. The authors consider that the use of such accurate and valuable pathological criteria in the examination of inflammatory bowel disease would facilitate retrospective correlation with the clinical findings and help to clarify those intermediate cases which are at present a source of diagnostic difficulty.


Perceived stigma, strain, and mental health among caregivers of veterans with traumatic brain injury.
Family caregivers of individuals with stigmatized conditions can experience stigma-by-association and discrimination. Moderate-to-severe traumatic brain injury (TBI) may elicit a stigma response if there are visible physical or neurobehavioral effects of the injury. Stigma is a considerable source of stress and may contribute to caregiver strain and stress-related mental health outcomes. We measured the frequency of perceived stigma and discrimination among caregivers of veterans with TBI and examined whether perceived stigma and discrimination are associated with caregiver strain, social isolation, depression, and anxiety. Seventy caregivers of veterans with TBI completed a mailed survey that assessed perceptions of discrimination toward themselves or their care recipient, stigma associated with caregiving, and whether they felt the need to cover up or provide an explanation for their care recipient's injury. Caregiver strain, social isolation, depression, and anxiety were also assessed via the questionnaire. Multivariate linear regression was used to test the associations between stigma and discrimination measures and outcomes, controlling for potential confounders and other caregiver or care recipient characteristics. Both perceptions of caregiver discrimination and stigma associated with caregiving were significantly associated with caregiver strain, social isolation, depression, and anxiety. Perceived discrimination against the individual with TBI was associated with caregiver strain and social isolation. Our findings suggest that perceived discrimination and stigma experienced by caregivers of individuals with TBI are stressors that may lead to poor caregiver mental health outcomes. In order to promote both caregiver and care recipient health, we suggest that mental health support services consider these important stressors.


Adaptive allocation of human visual working memory capacity during statistical and categorical learning.
Human brains are finite, and thus have bounded capacity. An efficient strategy for a capacity-limited agent is to continuously adapt by dynamically reallocating capacity in a task-dependent manner. Here we study this strategy in the context of visual working memory (VWM). People use their VWM stores to remember visual information over seconds or minutes. However, their memory performances are often error-prone, presumably due to VWM capacity limits. We hypothesize that people attempt to be flexible and robust by strategically reallocating their limited VWM capacity based on two factors: (a) the statistical regularities (e.g., stimulus feature means and variances) of the to-be-remembered items, and (b) the requirements of the task that they are attempting to perform. The latter specifies, for example, which types of errors are costly versus irrelevant for task performance. These hypotheses are formalized within a normative computational modeling framework based on rate-distortion theory, an extension of conventional Bayesian approaches that uses information theory to study rate-limited (or capacity-limited) processes. Using images of plants that are naturalistic and precisely controlled, we carried out two sets of experiments. Experiment 1 found that when a stimulus dimension (the widths of plants' leaves) was assigned a distribution, subjects adapted their VWM performances based on this distribution. Experiment 2 found that when one stimulus dimension (e.g., leaf width) was relevant for distinguishing plant categories but another dimension (leaf angle) was irrelevant, subjects' responses in a memory task became relatively more sensitive to the relevant stimulus dimension. Together, these results illustrate the task-dependent robustness of VWM, thereby highlighting the dependence of memory on learning.


Hsp27 Acts as a Master Molecular Chaperone and Plays an Essential Role in Hepatocellular Carcinoma Progression.
Hsp27, a master molecular chaperone, plays an important role in cancer. However, the specific co-chaperones that partner with Hsp27 and the role of Hsp27 in hepatocellular carcinoma (HCC) are not fully enumerated. The present study focuses on the role of Hsp27 in HCC and explores its potential co-chaperones in HCC development. Gene overexpression or knockdown was used to observe the role of Hsp27 in HCC. Co-immunoprecipitation and mass spectrometry were used to explore apoptosis resistance by regulating multiple co-chaperones of Hsp27. Hsp27 protein-protein interaction (PPI) networks were constructed by the MetaCore software. Hsp27 was upregulated in HCC tissues, and Hsp27 overexpression significantly facilitated formation of HCC cell colony and invasion in normoxia and tolerance in hypoxia by interacting with HIF-1α. Next, the analysis of microarrays revealed that Hsp27 regulated several cellular signaling pathways, including Wnt, ErbB and TGF-β signaling. Moreover, we characterized the Hsp27 PPI map, which indicated that Hsp27 along with its co-chaperones formed different complexes and exerts transcription regulation activity by activating sp1, c-Myc, p53 and ESR1. Hsp27 along with its co-chaperones was related to the development of HCC by regulating multiple signaling pathways, and drugs that target Hsp27 along with its co-chaperones may be a potential therapy for HCC.


Telephoned BRCA1/2 genetic test results: prevalence, practice, and patient satisfaction.
While the traditional model of genetic evaluation for breast cancer risk recommended face-to-face disclosure of genetic testing results, BRCA1/2 testing results are increasingly provided by telephone. The few existing studies on telephone genetic counseling provide conflicting results about its desirability and efficacy. The current study aimed to (1) Estimate the prevalence among genetic counselors of providing BRCA1/2 genetic test results by phone (2) Assess patient satisfaction with results delivered by telephone versus in-person. A survey was sent to members of the Familial Cancer Risk Counseling Special Interest Group via the NSGC listserve and was completed by 107 individuals. Additionally, 137 patients who had received BRCA genetic testing results either by phone or in-person at UNC Chapel Hill Cancer Genetics Clinic were surveyed regarding satisfaction with the mode of their BRCA1/2 results delivery. The genetic counseling survey revealed that the majority of responding counselors (92.5%) had delivered BRCA1/2 genetic test results by telephone. Patients having received results either in person or by phone reported no difference in satisfaction. Most patients chose to receive results by phone and those given a choice of delivery mode reported significantly higher satisfaction than those who did not have a choice. Those who waited less time to receive results once they knew they were ready also reported higher satisfaction. This study found supportive results for the routine provision of BRCA1/2 genetic test results by telephone. Results suggest that test results should be delivered as swiftly as possible once available and that offering patients a choice of how to receive results is desirable. These are especially important issues as genetic testing becomes more commonplace in medicine.


Cardiovascular disease after renal transplantation.
Although cardiovascular disease is a major cause of morbidity and mortality after renal transplantation, its pathogenesis and treatment are poorly understood. We conducted separate analyses of risk factors for ischemic heart disease, cerebral, and peripheral vascular disease after 706 renal transplants, all of which functioned for at least 6 months. We used Cox proportional hazards analysis to examine the effects of multiple pretransplant and posttransplant risk factors and included time-dependent variables measured at 3, 6, and 12 months, and annually to last follow-up at 7.0 +/- 4.2 yr. The independent relative risk (RR) of diabetes was 3.25 for ischemic heart disease, 3.21 for cerebral vascular disease, and 28.18 peripheral vascular disease (P < 0.05). The RR of each acute rejection episode was 1.40 for ischemic heart disease and 1.24 for cerebral vascular disease. Among serum lipid levels, high-density lipoprotein cholesterol was the best predictor of ischemic heart disease (RR = 0.80 for each 10 mg/dL). Posttransplant ischemic heart disease was strongly predictive of cerebral (5.80) and peripheral vascular disease (5.22), whereas ischemic heart disease was predicted by posttransplant cerebral (8.25) and peripheral vascular disease (4.58). Other risk factors for vascular disease included age, gender, cigarette smoking, pretransplant splenectomy, and serum albumin. Hypertension and low-density lipoprotein cholesterol had no effect, perhaps because of aggressive pharmacologic treatment. Thus, the incidence of cardiovascular disease continues to be high after renal transplantation, and multiple risk factors suggest a number of possible strategies for more effective treatment and prevention.


Structural and magnetic properties of cobalt iron disulfide (CoxFe1-xS2) nanocrystals.
We report on synthesis and investigation of nanocrystalline cobalt-iron-pyrites with an emphasis on nanocrystal structure, morphology and magnetic behavior. The nanocrystals (NCs) were 5-25 nm in diameter as characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). With an increase in Fe fraction, X-ray diffraction and small-angle-X-ray scattering (SAXS) showed a systematic decrease in lattice constant, primary grain/NC size (15 to 7 nm), and nanoparticle (NP) size (70 to 20 nm), respectively. The temperature dependence of the DC magnetization and AC susceptibility versus frequency revealed a number of magnetic phases in Co x Fe1-xS2. Samples with x = 1 and x = 0.875-0.625 showed evidence of superspin glass (SSG) behavior with embedded ferromagnetic (FM) clusters of NPs. For x = 0.5, samples retained their mixed phases, but showed superparamagnetic (SPM) behavior with antiferromagnetic clusters suppressing magnetic dipolar interactions. Below x = 0.5, the pyrites show increasing paramagnetic character. We construct a phase diagram, which can be understood in terms of competition between the various dipolar, exchange, inter- and intracluster interactions. Our results suggest that NC size and shape can be tuned to engineer spin-polarized ferromagnetism of n-doped iron pyrite.


Quantum Speed Limit for States with a Bounded Energy Spectrum.
Quantum speed limits set the maximal pace of state evolution. Two well-known limits exist for a unitary time-independent Hamiltonian: the Mandelstam-Tamm and Margolus-Levitin bounds. The former restricts the rate according to the state energy uncertainty, while the latter depends on the mean energy relative to the ground state. Here we report on an additional bound that exists for states with a bounded energy spectrum. This bound is dual to the Margolus-Levitin one in the sense that it depends on the difference between the state's mean energy and the energy of the highest occupied eigenstate. Each of the three bounds can become the most restrictive one, depending on the spread and mean of the energy, forming three dynamical regimes which are accessible in a multilevel system. The new bound is relevant for quantum information applications, since in most of them, information is stored and manipulated in a Hilbert space with a bounded energy spectrum.


Laparoscopic primary choledochorrhaphy over endonasobiliary drainage tubes.
The T-tube is widely used in laparoscopic choledochotomy to decompress the biliary tree. However, there are high morbidity rates related to the T-tube. This study reviewed the results of laparoscopic primary choledochorrhaphy over endonasobiliary drainage (ENBD) tubes to find an effective alternative to the T-tube for the performance of laparoscopic choledochotomy. From March 2003 to September 2005, 23 patients (9 men and 14 women) with choledocholithiasis underwent laparoscopic choledochotomy over ENBD tubes. The mean age of these patients was 47 years (range, 32-73 years). At admission, six patients had cholangitis. All the patients had ENBD tubes placed preoperatively after the failure of endoscopic sphincterotomy. There was no conversion to open surgery. The mean operative time was 90 min (range, 70-150 min). There were no biliary complications such as bile leaks, biliary peritonitis, or pancreatitis. No residual stones were found by postoperative cholangiograms. The ENBD tubes were removed between postoperative days 7 and 9. The hospital stay ranged from 8 to 14 days, with 16 patients (70%) discharged on postoperative day 8. The complications were limited to one umbilical infection and one case of pneumonia. The median follow-up period was 24 months (range, 8-36 months), and none of the patients were readmitted with biliary symptoms. Laparoscopic choledochotomy over ENBD tubes proved to be technically feasible and safe. The ENBD tube decompresses the biliary tree and allows for cholangiography after surgery. Its removal does not need to wait for tract maturation, which allows an earlier removal of the tube and a shorter postoperative hospital stay. Laparoscopic choledochotomy over ENBD tubes is an effective alternative to the T-tube in laparoscopic choledochotomy.


Patient and public involvement to support liver disease research.
Patient and public involvement (PPI) has become increasingly important to ensure the needs of patients are fully considered when they participate in clinical trials. Most funders now require a plan for PPI in grant applications. When fully embraced and correctly implemented, PPI adds an important dimension to clinical trials, and its continuing development is critical if we are to maintain the public's support for clinical research. The development of a PPI panel for the National Institute for Health Research Birmingham Liver Biomedical Research Unit (NIHR BRU) has helped to: promote research locally and nationally; improve recruitment to and participation in trials; promote public engagement and education activities; and improve the quality and relevance of consent forms and information sheets for participants. The NIHR BRU has the support of a PPI panel which constantly champions the research being undertaken to the wider community. This paper describes how the panel was established and why it is so effective.


Near-infrared spectroscopy reveals link between chronic physical activity and anterior frontal oxygenated hemoglobin in healthy young women.
Cerebrovascular and cognitive functioning peak developmentally in young adults, yet recent evidence indicates they may benefit on these fronts from regular engagement in physical activity. In light of epidemiological trends for increasingly sedentary lifestyles and the importance of optimal cerebrovascular and cognitive functioning, here we investigated relationships between physical activity levels, anterior frontal hemodynamics, and cognitive performance in 52 healthy young women. Analyses positively linked chronic physical activity level (CPAL) with anterior frontal oxygenated hemoglobin and cognitive inhibitory control, indicating regular physical activity may lead to hemodynamic and cognitive benefits, even in a cohort at developmental peak. In addition, higher anterior frontal oxygenated hemoglobin was linked to better performance for the most difficult cognitive task. Given the importance of oxygen availability for cognitive functioning, the current discovery of a relationship with CPAL may provide important insight toward understanding exercise-cognition links.


Straight after the turn: the role of the parietal lobes in egocentric space processing.
Spatial information processing with respect to an egocentric reference frame has been shown to recruit a fronto-parietal network along the dorsal stream. The present study investigates how brain lesions in the relevant areas affect the ability to navigate through computer-simulated tunnels shown from a first person perspective. Our results suggest that parietal, but not frontal, patients are impaired in this task. They confused the direction of tunnel turns more frequently and made less accurate judgments about the location of the end position. Errors in map drawing suggest that the impairment may be linked to deficits in updating cognitive heading in the absence of corresponding perceptual information from the virtual environment.


Correcting the record: the dimers and trimers of trans-N-methylacetamide.
The dimer of trans-N-methylacetamide serves as a simple model for hydrogen bonds in peptides, free of any backbone distortions. Its preferred structures represent benchmark systems for an accurate quantum chemical description of protein interactions. The trimer allows for either two linear or three strained hydrogen bonds, with the former being the only structural motif considered so far in the literature, but the latter winning in energy by a large margin due to London dispersion. A combination of linear Raman and infrared supersonic jet techniques with B3LYP-D3/aug-cc-pVTZ quantum chemical predictions corrects earlier tentative spectroscopic assignments based on a hybrid density functional without dispersion correction. Linear Amide I-III infrared spectra of the jet-cooled monomer are compared to those recently obtained by action spectroscopy.


Dynamic changes of intrinsic brain activity in cirrhotic patients after transjugular intrahepatic portosystemic shunt: a resting-state FMRI study.
The majority of cirrhotic patients who underwent transjugular intrahepatic portosystemic shunt (TIPS) experienced the first post-TIPS hepatic encephalopathy (HE) episode within the first three months after TIPS insertion. However, so far, little is known about the exact neuro-pathophysiological mechanism of TIPS's effects on brain function. We aimed to investigate the dynamics of brain function alteration of post-TIPS patients using resting-state functional MRI (rs-fMRI). Sixteen cirrhotic patients who were scheduled for TIPS and 16 healthy controls were included in the rs-fMRI scans. Ten patients repeated the MRI study in a median 8-day follow-up interval following TIPS and seven in a median 3-month follow-up. The amplitude of low frequency fluctuation (ALFF), an index reflecting the spontaneous brain activity, was compared between patients before TIPS and healthy controls as well as patients pre- and post-TIPS. Compared with healthy controls, patients showed decreased ALFF in frontal and parietal regions and increased ALFF in insula. Patients who underwent the median 8-day follow-up fMRI examinations showed decreased ALFF in posterior cingulate cortex (PCC)/precuneus and increased ALFF in anterior cingulate cortex (ACC). Of 10 patients in this group, 9 had moderate to large increase rate of ALFF value (>20%, mean 49.19%) in ACC, while only one patient with the smallest increase rate of ALFF value (<10%) in ACC, who experienced three episodes of overt HE during the 3-month follow-up. In the median 3-month follow up observation, patients displayed persistently decreased ALFF in PCC, ACC and medial prefrontal cortex (MPFC), while no increased regional ALFF was observed. TIPS insertion alters cirrhotic patients' ALFF patterns in the resting state, which may imply different short-term and moderate-term effects on cirrhotic patients, i.e., both impairment and compensatory mechanism of brain functions in peri-TIPS and continuous impairment of brain function 3 months following TIPS.


β-Arrestin2 mediates progression of murine primary myelofibrosis.
Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between βarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor βarr2-knockout (βarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted βarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of βarr2-/- cells. In order to assess the effect of acute loss of βarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional βarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that βarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.


[Effect of ozone on Staphylococcus aureus colonization in patients with atopic dermatitis].
To verify the effect of ozone on Staphylococcus aureus (S. aureus) colonization in patients with atopic dermatitis (AD) and its correlation with the patient's status. Methods: A total of 12 patients with moderate or severe AD, aged from 6 to 65 years, were recruited from outpatient of the Third Xiangya Hospital. The treatment sides were showered with ozonated water and smeared with ozonated oil for 7 days (twice a day), while the control sides were washed with warm running water and smeared with base oil. At different time points, the severity scoring of atopic dermatitis (SCORAD) scores, sleep and pruritus scores were assessed and compared between the two sides. Meanwhile, plate cultivation was used to quantitatively detect the changes of S. aureus colonization in skin lesions. Results: After 7 days treatment, erythema and pimples were decreased in the treatment sides. The clear skin texture, smooth skin, improved skin lesions were also observed by dermoscopic examination. The results of reflectance confocal microscopy (RCM) demonstrated that the parakeratosis was improved, the structures were clearer, and the inflammatory cells infiltration was reduced after ozone treatment for 7 days. After ozone treatment for 3 and 7 days, the S. aureus colonization in the treatment sides decreased by (75.55±21.81)% and (97.24±2.64)% respectively. Compared to that of control sides, the percentage of S. aureus colony after ozone treatment for 7 days decreased significantly (P<0.01). After ozone treatment for 7 days, the SCORAD scores, sleep and pruritus scores were significantly decreased (all P<0.01). There was a linear correlation between the decreasing percentage of S. aureus colony and the declining percentage of SCORAD scores in AD patients. Conclusion: Topical ozone therapy can effectively reduce S. aureus colony in skin lesions and alleviate the severity of AD patients with moderate to severe degree.


Complex Age- and Cancer-Related Changes in Human Blood Transcriptome-Implications for Pan-Cancer Diagnostics.
Early cancer detection is the key to a positive clinical outcome. While a number of early diagnostics methods exist in clinics today, they tend to be invasive and limited to a few cancer types. Thus, a clear need exists for non-invasive diagnostics methods that can be used to detect the presence of cancer of any type. Liquid biopsy based on analysis of molecular components of peripheral blood has shown significant promise in such pan-cancer diagnostics; however, existing methods based on this approach require improvements, especially in sensitivity of early-stage cancer detection. The improvement would likely require diagnostics assays based on multiple different types of biomarkers and, thus, calls for identification of novel types of cancer-related biomarkers that can be used in liquid biopsy. Whole-blood transcriptome, especially its non-coding component, represents an obvious yet under-explored biomarker for pan-cancer detection. In this study, we show that whole transcriptome analysis using RNA-seq could indeed serve as a viable biomarker for pan-cancer detection. Furthermore, a class of long non-coding (lnc) RNAs, very long intergenic non-coding (vlinc) RNAs, demonstrated superior performance compared with protein-coding mRNAs. Finally, we show that age and presence of non-blood cancers change transcriptome in similar, yet not identical, directions and explore implications of this observation for pan-cancer diagnostics.


Evolution of reproductive morphology in leaf endophytes.
The endophytic lifestyle has played an important role in the evolution of the morphology of reproductive structures (body) in one of the most problematic groups in fungal classification, the Leotiomycetes (Ascomycota). Mapping fungal morphologies to two groups in the Leiotiomycetes, the Rhytismatales and Hemiphacidiaceae reveals significant divergence in body size, shape and complexity. Mapping ecological roles to these taxa reveals that the groups include endophytic fungi living on leaves and saprobic fungi living on duff or dead wood. Finally, mapping of the morphologies to ecological roles reveals that leaf endophytes produce small, highly reduced fruiting bodies covered with fungal tissue or dead host tissue, while saprobic species produce large and intricate fruiting bodies. Intriguingly, resemblance between asexual conidiomata and sexual ascomata in some leotiomycetes implicates some common developmental pathways for sexual and asexual development in these fungi.


Correlation of hematocrit, platelet concentration, and plasma coagulation factors with results of thromboelastometry in canine whole blood samples.
To evaluate the components of canine whole blood samples that contribute to results of thromboelastometry (TEM). 127 healthy dogs. For each dog, a blood sample was collected from a jugular vein into tubes containing no anticoagulant, EDTA, or citrate anticoagulant. Citrated whole blood samples underwent TEM with tissue factor and TEM with ellagic acid. Indicators of RBC mass and platelet concentration were evaluated, and plasma coagulation tests were performed; data obtained were compared with results of TEM. For technical reasons, samples were not available from all dogs for all tests. Coagulation time was correlated with concentrations of primarily extrinsic pathway coagulation factors for TEM with tissue factor and with most factors via TEM with ellagic acid. Clot formation time, α angle, and maximum clot firmness were highly correlated with fibrinogen and platelet concentrations and some individual factor concentrations. Sample Hct was strongly correlated with most measured variables; low Hct was associated with relative hypercoagulability, and high Hct was associated with relative hypocoagulability. For TEM of canine blood samples, coagulation time was primarily a function of coagulation factor concentrations, whereas other variables were dependent on platelet and fibrinogen concentrations. Sample Hct strongly influenced the results of TEM, likely because RBCs act as a diluent for plasma coagulation factors. Thromboelastometry appeared to be affected by abnormalities of coagulation factors, platelet concentrations, and RBC mass. In samples from anemic patients, results of TEM indicative of hypercoagulability may be artifactual because of low RBC mass.


Intraoperative radiotherapy combined with posterior decompression and stabilization for non-ambulant paralytic patients due to spinal metastasis.
Retrospective examination of 96 nonambulant paralytic patients with spinal cord compression caused by metastatic cancer treated with intraoperative radiotherapy combined with conventional posterior surgery. To improve local control of spinal metastasis by conducting posterior surgery combined with intraoperative radiotherapy (IORT) in patients with severe neurologic deficits. Few studies of conventional posterior surgery demonstrated satisfactory neurologic recovery for nonambulant paralytic patients with advanced spinal metastases. Ninety-six patients underwent IORT (107 procedures) for the treatment of severe spinal cord compression because of spinal metastases. All patients were nonambulatory before surgery. Eighty-three cases (86%) were in an advanced stage of multiple spinal metastases (types 6 or 7 of the surgical classification of vertebral tumors). After posterior decompression, a single large dose of electron beam irradiation was delivered to the exposed metastatic lesion while the spinal cord was protected using a lead shield. Posterior instrumentation was also performed for most patients. Ninety-five of 107 cases (89%) obtained at least one level of neurologic improvement according to Frankel's classification and 86 cases (80%) became ambulatory after surgery. The main factors related to a nonambulatory status after surgery were preoperative neurologic status, performance status, and the presence of internal organ metastases. Of 86 postoperative ambulatory cases, only 3 became nonambulatory because of local recurrence during the follow-up period. The IORT procedure is a useful technique for the treatment of spinal cord compression because of spinal metastasis, offering significant neurologic recovery and a low rate of local recurrence.


Cutting edge: flow cytometry in myelodysplastic syndromes.
Flow cytometry (FC) is recognized as one of the important tools in the diagnosis of myelodysplastic syndromes (MDS), especially when cytomorphology and cytogenetics are inconclusive. Minimal requirements to analyze dysplasia using FC have been proposed by the International Workshops from the European LeukemiaNet on Standardization of FC in MDS. These should enable a categorization of FC results in cytopenic patients as "normal," "suggestive of," or "indicative of" MDS. Notably, FC should be considered as part of an integrated diagnosis, rather than as a separate technique. This article highlights tools to implement FC in the diagnostic workup of MDS. Current advances in FC for diagnosis and prognosis of MDS are also introduced.


Mutual inactivation of Notch receptors and ligands facilitates developmental patterning.
Developmental patterning requires juxtacrine signaling in order to tightly coordinate the fates of neighboring cells. Recent work has shown that Notch and Delta, the canonical metazoan juxtacrine signaling receptor and ligand, mutually inactivate each other in the same cell. This cis-interaction generates mutually exclusive sending and receiving states in individual cells. It generally remains unclear, however, how this mutual inactivation and the resulting switching behavior can impact developmental patterning circuits. Here we address this question using mathematical modeling in the context of two canonical pattern formation processes: boundary formation and lateral inhibition. For boundary formation, in a model motivated by Drosophila wing vein patterning, we find that mutual inactivation allows sharp boundary formation across a broader range of parameters than models lacking mutual inactivation. This model with mutual inactivation also exhibits robustness to correlated gene expression perturbations. For lateral inhibition, we find that mutual inactivation speeds up patterning dynamics, relieves the need for cooperative regulatory interactions, and expands the range of parameter values that permit pattern formation, compared to canonical models. Furthermore, mutual inactivation enables a simple lateral inhibition circuit architecture which requires only a single downstream regulatory step. Both model systems show how mutual inactivation can facilitate robust fine-grained patterning processes that would be difficult to implement without it, by encoding a difference-promoting feedback within the signaling system itself. Together, these results provide a framework for analysis of more complex Notch-dependent developmental systems.


Indications for cobalamin level assessment in departments of internal medicine: a prospective practice survey.
Cobalamin (Cb) blood levels are frequently measured among inpatients, but the relevance of Cb determination has not been correctly assessed in this clinical setting. We aimed to prospectively evaluate current indications compared to traditional guidelines for assessing Cb blood levels among inpatients from internal medicine departments. This study was conducted in French departments of internal medicine between 2008 and 2009. Inpatients who underwent Cb blood level determination during a 6-week study period were eligible. 380 consecutive adult patients were included. The three most common indications for Cb assessment were anaemia (62.6%), cognitive impairment (20.2%) and undernutrition (17.4%). Traditional indications (ie, macrocytic non-regenerative anaemia, isolated macrocytosis, dementia and proprioceptive disorders) accounted for only 33.9% of all tests. Cb deficiency was identified in 40 (10.5%) of the 380 patients tested. Overall, traditional indications were not associated with a significantly higher prevalence of patients with low Cb levels than current guidelines (14% vs 8.8%; p=0.119). Non-regenerative macrocytic anaemia was the only indication with a significantly better performance compared to all other indications (11 of 62 patients (17.7%) vs 29 of 318 patients (9.1%); OR 2.15 (1.01-4.57), p=0.047). The main aetiological causes of Cb deficiency were intake deficiency, pernicious anaemia and food-Cb malabsorption. Homocysteine or methylmalonic acid dosage testing was very rarely performed. Traditional indications did not perform better than other indications observed in current practice for identifying low Cb levels among inpatients from internal medicine departments. Future studies are needed to establish robust guidelines for inpatient screening.


Bioenergetic abnormalities associated with severe left ventricular hypertrophy.
Transmurally localized 31P-nuclear magnetic resonance spectroscopy (NMR) was used to study the effect of severe pressure overload left ventricular hypertrophy (LVH) on myocardial high energy phosphate content. Studies were performed on 8 normal dogs and 12 dogs with severe left ventricular hypertrophy produced by banding the ascending aorta at 8 wk of age. Spatially localized 31P-NMR spectroscopy provided measurements of the transmural distribution of myocardial ATP, phosphocreatine (CP), and inorganic phosphate (Pi); spectra were calibrated from measurements of ATP content in myocardial biopsies using HPLC. Blood flow was measured with microspheres. In hypertrophied hearts during basal conditions, ATP was decreased by 42%, CP by 58%, and the CP/ATP ratio by 32% in comparison with normal. Increasing myocardial blood flow with adenosine did not correct these abnormalities, indicating that they were not the result of persistent hypoperfusion. Atrial pacing at 200 and 240 beats per min caused no change in high energy phosphate content in normal hearts but resulted in further CP depletion with Pi accumulation in the inner left ventricular layers of the hypertrophied hearts. These changes were correlated with redistribution of blood flow away from the subendocardium in LVH hearts. These findings demonstrate that high energy phosphate levels and the CP/ATP ratio are significantly decreased in severe LVH. These abnormalities are proportional to the degree of hypertrophy but are not the result of persistent abnormalities of myocardial perfusion. In contrast, depletion of CP and accumulation of Pi during tachycardia in LVH are closely related to the pacing-induced perfusion abnormalities and likely reflect subendocardial ischemia.


Increased 3-hydroxykynurenine serum concentrations differentiate Alzheimer's disease patients from controls.
Increased degradation of tryptophan (TRP) through the kynurenine (KYN) pathway (KP) is known to be involved in the molecular mechanisms resulting in the neuropathogenesis of Alzheimer's disease (AD). Activation of the KP leads to the production of neurotoxic metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) by immune cells and neuroprotective derivates kynurenic acid (KYNA) and picolinic acid (PIC) by astrocytes and neurons. We therefore investigated whether an imbalance between neurotoxic and neuroprotective kynurenine metabolites could be detected in patients with AD. We measured serum levels of TRP, KYNA, 3-HK, PIC and QUIN in 20 patients with AD and for comparison in 20 patients with major depression, and 19 subjectively cognitive impaired subjects. Serum levels of 3-HK were markedly increased in AD patients compared to the comparison groups (p < .0001). Serum levels of the other KP metabolites were not significantly different between groups. Our data indicate an increased production of the neurotoxic KP metabolite 3-HK in AD. In contrast to its downstream metabolites QUIN and PIC, 3-HK can cross the blood-brain barrier via an active transport process. Our data therefore indicate an enhanced availability of 3-HK in the brain of AD patients, which may be related to the previously reported higher production of QUIN in AD brains.


Improved properties of fine active pharmaceutical ingredient powder blends and tablets at high drug loading via dry particle coating.
It has been shown that dry coating cohesive active pharmaceutical ingredients (APIs) with nano-silica can improve packing and flow of their blends, facilitating high speed direct compression tableting. This paper examines the broader scope and generality of previous work by examining three fine APIs; micronized Acetaminophen (mAPAP), coarse Acetaminophen (cAPAP) and micronized Ibuprofen (mIBU), and considers dry coating with both hydrophobic or hydrophilic nano-silica to examine the effect not only on packing density and flow of their blends, but also dissolution and tensile strength of their tablets. The impact of the excipient size on blend and tablet properties are also investigated, indicating blend flow is most improved when matching API particle size with excipient particle size. In all cases where the API is dry coated, the blend packing and flow improve, so as to suggest such high drug loaded blends could enable direct compression. Using dry coated API along with finer excipients in blends lead to improved hardness of the corresponding tablets. Interestingly, dissolution profiles show dry coated API tablets generally have faster dissolution rates, regardless of silica hydrophilicity, suggesting API powder deagglomeration via nano-silica coating plays a crucial role. The most significant conclusion is that, although there are differences in properties of blends that depend on the API, hydrophobic or hydrophilic nano-silica coating, as well as large or fine excipients, in all cases, dry coating of APIs significantly improves the possibility of using the specific blend at high drug loading in direct compression tableting.


Spatiotemporal conditional inference and hypothesis tests for neural ensemble spiking precision.
The collective dynamics of neural ensembles create complex spike patterns with many spatial and temporal scales. Understanding the statistical structure of these patterns can help resolve fundamental questions about neural computation and neural dynamics. Spatiotemporal conditional inference (STCI) is introduced here as a semiparametric statistical framework for investigating the nature of precise spiking patterns from collections of neurons that is robust to arbitrarily complex and nonstationary coarse spiking dynamics. The main idea is to focus statistical modeling and inference not on the full distribution of the data, but rather on families of conditional distributions of precise spiking given different types of coarse spiking. The framework is then used to develop families of hypothesis tests for probing the spatiotemporal precision of spiking patterns. Relationships among different conditional distributions are used to improve multiple hypothesis-testing adjustments and design novel Monte Carlo spike resampling algorithms. Of special note are algorithms that can locally jitter spike times while still preserving the instantaneous peristimulus time histogram or the instantaneous total spike count from a group of recorded neurons. The framework can also be used to test whether first-order maximum entropy models with possibly random and time-varying parameters can account for observed patterns of spiking. STCI provides a detailed example of the generic principle of conditional inference, which may be applicable to other areas of neurostatistical analysis.


A Use of 56-kDa Recombinant Protein of Orientia tsutsugamushi Karp Serotype in Serodiagnosis of Scrub Typhus by Enzyme-Linked Immunosorbent Assay in Thais.
Scrub typhus is a mite-borne disease caused by a Gram-negative obligately intracellular bacillus, Orientia tsutsugamushi. The disease is endemic in the Asia-Australia-Pacific region, including Thailand. Scrub typhus generally manifests as acute undifferentiated febrile fever along with myalgia, rash, and lymphadenopathy. An eschar can be a valuable diagnostic clue, but this skin lesion may be missed in some patients. The disease symptoms resemble those of other febrile illnesses such as leptospirosis, typhoid, murine typhus, malaria, and dengue fever, making a laboratory diagnosis necessary for the definitive diagnosis. In this study, we expressed a recombinant protein derived from 56-kDa type-specific antigen of O. tsutsugamushi Karp serotype and tested its ability to detect and differentiate scrub typhus infection. IgM and IgG antibodies were determined in sera from scrub typhus (n = 92) and other febrile illness patients (murine typhus (n = 25), melioidosis (n = 36), leptospirosis (n = 42), and dengue (n = 35)) from Thailand. Sensitivities of 87.0% and 59.8% with a specified assay cut-off were obtained for IgM and IgG indirect ELISAs, respectively, with a specificity of 100% in both tests. The sensitivity was increased to 95.7% when a combination of IgM and IgG ELISAs results was considered. Our study suggested a potential of the 56-kDa recombinant protein for further development and evaluation for use in scrub typhus serodiagnosis.


Graphene-based macroscopic assemblies and architectures: an emerging material system.
Due to the outstanding physicochemical properties arising from its truly two-dimensional (2D) planar structure with a single-atom thickness, graphene exhibits great potential for use in sensors, catalysts, electrodes, and in biological applications, etc. With further developments in the theoretical understanding and assembly techniques, graphene should enable great changes both in scientific research and practical industrial applications. By the look of development, it is of fundamental and practical significance to translate the novel physical and chemical properties of individual graphene nanosheets into the macroscale by the assembly of graphene building blocks into macroscopic architectures with structural specialities and functional novelties. The combined features of a 2D planar structure and abundant functional groups of graphene oxide (GO) should provide great possibilities for the assembly of GO nanosheets into macroscopic architectures with different macroscaled shapes through various assembly techniques under different bonding interactions. Moreover, macroscopic graphene frameworks can be used as ideal scaffolds for the incorporation of functional materials to offset the shortage of pure graphene in the specific desired functionality. The advantages of light weight, supra-flexibility, large surface area, tough mechanical strength, and high electrical conductivity guarantee graphene-based architectures wide application fields. This critical review mainly addresses recent advances in the design and fabrication of graphene-based macroscopic assemblies and architectures and their potential applications. Herein, we first provide overviews of the functional macroscopic graphene materials from three aspects, i.e., 1D graphene fibers/ribbons, 2D graphene films/papers, 3D network-structured graphene monoliths, and their composite counterparts with either polymers or nano-objects. Then, we present the promising potential applications of graphene-based macroscopic assemblies in the fields of electronic and optoelectronic devices, sensors, electrochemical energy devices, and in water treatment. Last, the personal conclusions and perspectives for this intriguing field are given.


Characteristics of the adhesive determinants of Lactobacillus fermentum 104.
The adhesion of Lactobacillus fermentum 104-R and the variant strain 104-S to porcine gastric squamous epithelium was investigated. An epithelium-specific adhesion was detected for strain 104-S; however, strain 104-R expressed enhanced adhesion capacity to the control surfaces of polystyrene and bovine serum albumin. To characterize the adhesive determinants, the bacterial cells were exposed to various treatments. The adhesion pattern of bacterial cells in buffers of pH values ranging from 2 to 7 was determined. The adhesion of strain 104-S to epithelium was greater in a buffer with a higher pH value. On the other hand, adhesion of strain 104-R to the epithelium was rather unaffected by a change in pH. To the control surfaces of polystyrene or bovine serum albumin, the adhesion of both strains was greatest at pH 2 to 4. Treatment of strain 104-S with metaperiodate did not affect the adhesion to epithelium or polystyrene; however, protease treatment dramatically decreased the adhesion of both strains, thus suggesting that the determinants responsible for the adhesion were proteinaceous. Carbohydrates may be partially involved in the adhesion of 104-R because metaperiodate-treated cells adhered more poorly than control, iodate-treated cells. The adhesion-promoting components are most probably tightly bound to the cell wall, because washing with low-pH buffer (pH 1.2) or sodium dodecyl sulfate had no major effect on the adhesion.


The use of dichloromethylene diphosphonate for the management of hypercalcaemia in multiple myeloma.
We have assessed the effects of the diphosphonate, dichloromethylene diphosphonate (Cl2MDP), in 19 patients with hypercalcaemia and increased bone resorption due to myeloma. Cl2MDP (800-3200 mg daily by mouth or 300 mg daily by intravenous infusion) decreased plasma calcium and biochemical indices of increased bone resorption in 16 of 19 patients. This effect persisted for the duration of treatment (up to 14 weeks). Prolonged treatment was associated with a progressive rise in serum alkaline phosphatase and only a transient fall in hydroxyproline suggesting the stimulation of bone repair. Since myeloma is associated with significant morbidity and mortality due to progressive bone loss, these results suggest that long-term treatment of myeloma with Cl2MDP is worthy of further study.


Transparent organic photodetector using a near-infrared absorbing cyanine dye.
Organic photodetectors are interesting for low cost, large area optical sensing applications. Combining organic semiconductors with discrete absorption bands outside the visible wavelength range with transparent and conductive electrodes allows for the fabrication of visibly transparent photodetectors. Visibly transparent photodetectors can have far reaching impact in a number of areas including smart displays, window-integrated electronic circuits and sensors. Here, we demonstrate a near-infrared sensitive, visibly transparent organic photodetector with a very high average visible transmittance of 68.9%. The transmitted light of the photodetector under solar irradiation exhibits excellent transparency colour perception and rendering capabilities. At a wavelength of 850 nm and at -1 V bias, the photoconversion efficiency is 17% and the specific detectivity is 10(12) Jones. Large area photodetectors with an area of 1.6 cm(2) are demonstrated.


Water and urea permeation pathways of the human excitatory amino acid transporter EAAT1.
Glutamate transport is coupled to the co-transport of 3 Na(+) and 1 H(+) followed by the counter-transport of 1 K(+). In addition, glutamate and Na(+) binding to glutamate transporters generates an uncoupled anion conductance. The human glial glutamate transporter EAAT1 (excitatory amino acid transporter 1) also allows significant passive and active water transport, which suggests that water permeation through glutamate transporters may play an important role in glial cell homoeostasis. Urea also permeates EAAT1 and has been used to characterize the permeation properties of the transporter. We have previously identified a series of mutations that differentially affect either the glutamate transport process or the substrate-activated channel function of EAAT1. The water and urea permeation properties of wild-type EAAT1 and two mutant transporters were measured to identify which permeation pathway facilitates the movement of these molecules. We demonstrate that there is a significant rate of L-glutamate-stimulated passive and active water transport. Both the passive and active L-glutamate-stimulated water transport is most closely associated with the glutamate transport process. In contrast, L-glutamate-stimulated [(14)C]urea permeation is associated with the anion channel of the transporter. However, there is also likely to be a transporter-specific, but glutamate independent, flux of water via the anion channel.


Electrostatic interactions between the syntaxin membrane anchor and neurotransmitter passing through the fusion pore.
Recent experiments have shown that flux through the fusion pore is sensitive to manipulations of the side-chain size of certain residues in the syntaxin (syx) membrane anchor. These residues were proposed to line the wall of the fusion pore of Ca(2+)-triggered exocytosis. Here we continued this line of experimentation to examine possible electrostatic interactions between the pore lining residues and the neurotransmitter norepinephrine (NE). Replacing syx pore-lining residues with aspartate enhanced NE flux above that expected for the size of the aspartate side chain. In contrast, substitution with arginine reduced NE flux below that expected for the size of its side chain. Substituting aspartate and arginine into the nonpore-lining residues did not alter the fusion pore flux. Other amino acids with ionizable side chains had variable effects. These results indicate an electrostatic interaction between the pore-lining residues of syx and NE, and provide additional evidence that the syx membrane anchor is a structural component of the fusion pore.


Having and being a personal physician: vision of the Pisacano scholars.
Having a strong relationship with a personal physician can improve patient health outcomes. Yet achieving and sustaining this type of patient-physician relationship is often not possible in the current American health care system. Pisacano scholars and alumni, a group of young physician leaders supported by the American Board of Family Medicine, gathered for a 2-day symposium in June 2010 to explore the meaning of personal doctoring and its importance to our work as family physicians. Using the techniques of appreciative inquiry, the group discussed three questions: What is it like to have a personal physician? What is it like to be a personal physician? and, What are some feasible next steps toward making this possible? Symposium participants concluded that achieving the ideal patient-physician relationship for all patients and physicians would involve extensive alterations to the current health care system beyond what is outlined in the 2010 Patient Protection and Affordable Care Act. However, in the context of current health reform efforts, individual physicians, researchers, and policy makers must not lose sight of the importance of the patient-physician relationship and should continue to take concrete steps on an individual and system level to move us closer to this ideal.


Operative debridement of pressure ulcers.
Infection in severe pressure ulcers can lead to sepsis with a 6-month mortality as high as 68%. Operative records of 142 consecutive operative debridements on 60 patients in a dedicated wound healing inpatient unit were reviewed, from the Wound Electronic Medical Record, for identification of key steps in debridement technique, mortality, unexpected returns, and time to discharge following debridement. The mean age of the patients was 73.1 years, and 45% were men. Most wounds (53%) were located on the hip (ischial or trochanteric); others were on the sacrum (32%) and the heels (14%). The mean initial wound area prior to debridement was 14.0 cm(2), and 83% of debridements were performed on stage IV pressure ulcers. The postoperative hospital stay averaged 4.1 days. Key steps in the technique included (1) exposure of areas of undermining by excising overlying tissue; (2) removal of callus from wound edges; (3) removal of all grossly infected tissue; and (4) obtaining a biopsy of the deep tissue after debridement of all nonviable or infected tissue for culture and pathology to determine the presence of infection, fibrosis, and granulation tissue. There was one death 9 days post-debridement of a sacral ulcer and one unplanned return to the operating room for bleeding 8 days post-debridement. Operative debridement of pressure ulcers is safe, despite the medical co-morbidities in patients with severe pressure ulcers. Proper debridement technique may prevent sepsis and death in patients with multiple co-morbid conditions.


A multi-stable isotope framework to understand eutrophication in aquatic ecosystems.
Eutrophication is a globally significant challenge facing aquatic ecosystems, associated with human induced enrichment of these ecosystems with nitrogen (N) and phosphorus (P). However, the limited availability of inherent labels for P and N has constrained understanding of the triggers for eutrophication in natural ecosystems and appropriate targeting of management responses. This paper proposes and evaluates a new multi-stable isotope framework that offers inherent labels to track biogeochemical reactions governing both P and N in natural ecosystems. The framework couples highly novel analysis of the oxygen isotope composition of phosphate (δ(18)OPO4) with dual isotope analysis of oxygen and N within nitrate (δ(15)NNO3, δ(18)ONO3) and with stable N isotope analysis in ammonium (δ(15)NNH4). The River Beult in England is used as an exemplar system for initial evaluation of this framework. Our data demonstrate the potential to use stable isotope labels to track the input and downstream fate of nutrients from point sources, on the basis of isotopic differentiation for both P and N between river water and waste water treatment work effluent (mean difference = +1.7‰ for δ(18)OPO4; +15.5‰ for δ(15)NNH4 (under high flow); +7.3‰ for δ(18)ONO3 and +4.4‰ for δ(15)NNO3). Stable isotope data reveal nutrient inputs to the river upstream of the waste water treatment works that are consistent with partially denitrified sewage or livestock sources of nitrate (δ(15)NNO3 range = +11.5 to +13.1‰) and with agricultural sources of phosphate (δ(18)OPO4 range = +16.6 to +19.0‰). The importance of abiotic and metabolic processes for the in-river fate of N and P are also explored through the stable isotope framework. Microbial uptake of ammonium to meet metabolic demand for N is suggested by substantial enrichment of δ(15)NNH4 (by 10.2‰ over a 100 m reach) under summer low flow conditions. Whilst the concentration of both nitrate and phosphate decreased substantially along the same reach, the stable isotope composition of these ions did not vary significantly, indicating that concentration changes are likely driven by abiotic processes of dilution or sorption. The in-river stable isotope composition and the concentration of P and N were also largely constant downstream of the waste water treatment works, indicating that effluent-derived nutrients were not strongly coupled to metabolism along this in-river transect. Combined with in-situ and laboratory hydrochemical data, we believe that a multi-stable isotope framework represents a powerful approach for understanding and managing eutrophication in natural aquatic ecosystems.


Chapter 6. The new story: on the possibility of liberating oneself from the drug self.
This chapter explores the meaning(s) of "treatment effect" within the psychodynamic tradition. The conventional wisdom is that a successful treatment presupposes a transformation of unconscious "material" to a conscious level. The "treatment effect" is reinterpreted as being better understood as changing an old (and detrimental) story into a new tale-an alternative narrative about the self. New possibilities following this conceptual change are introduced with the aid of some concrete examples.


Electromechanical actuation of single-walled carbon nanotubes: an ab initio study.
The mechanical actuation of a (5, 5) single-walled carbon nanotube as a result of added charge is simulated using first-principles calculations. It is observed that while both positive and negative charging tend to expand the nanotube in the axial direction for most levels of charge, radial actuation is less even and symmetric with respect to charge. The spin distribution of the additional charges is investigated, and it is predicted that in some cases unpaired spin configurations are energetically favourable, significantly affecting actuation strains.


Patterns of Eating Associated with Sleep Characteristics: A Pilot Study among Individuals of Mexican Descent at the US-Mexico Border.
Introduction: Previous studies have linked sleep to risk of diabetes and obesity, at least partially via alterations in food intake. Diabetes and obesity are common among Hispanics/Latinos, and studies are needed to better clarify the role of sleep in health among this group. Utilizing the revised TFEQ-R-18, this study will examine whether eating behaviors such as cognitive restraint, emotional eating and uncontrolled eating are related to self-reported sleep experiences. Specifically, we hypothesized that poor eating habits would be associated with (1) more insomnia symptoms, (2) overall worse sleep quality, (3) increased daytime sleepiness, and (4) shorter sleep duration.Methods: Data were collected from N = 100 adults (age 18-60, 47% female) of Mexican descent in the city of Nogales, AZ (34% not born in the US). Surveys were presented in English or Spanish. Eating Patterns were assessed with the Three-Factor Eating Questionnaire (TFEQ), which resulted in a total score and subscales for "cognitive restraint," "uncontrolled eating," and "emotional eating." Insomnia was assessed with the use of the Insomnia Severity Index (ISI), Sleepiness with the use of the Epworth Sleepiness Scale (ESS), Sleep quality with the use of the Pittsburgh Sleep Quality Index (PSQI), and weekday and weekend sleep duration with the use of the Sleep Timing Questionnaire (STQ). Covariates included age, sex, Body Mass Index (BMI), education and immigrant status.Results: Overall TFEQ score (problematic eating) was positively associated with greater insomnia, poorer sleep quality, more sleepiness, and less weekend (but not weekday) sleep. Mean TFEQ score in the sample was 18.7 (range 0-51). In adjusted analyses, every point on the TFEQ was associated with 0.6 ISI points, 0.8 PSQI points, 0.5 ESS points, and 1.1 minutes of less weekend sleep duration. Regarding subscale scores, relationships were generally seenbetween sleep and emotional eating and unrestricted eating, and not cognitive restraint.Conclusions: Greater insomnia, poorer sleep quality, increased daytime sleepiness and decreased weekend sleep duration were associated with eating patterns at the US-Mexico border, particularly in the area of unrestricted eating and emotional eating. This suggests possible mechanisms linking sleep and obesity in Hispanic/Latinos.


Elements in human placentae in Jamaica.
To investigate the relationships, if any, between elemental content of the placenta with age of mother birthweight and the Apgar scores of a neonate. Placental samples were collected, stored at -20 degrees C and then dried and analysed using neutron activation with the SLOWPOKE II reactor at the International Centre for Environmental and Nuclear Sciences (ICENS). A questionnaire was administered at the time of delivery to determine the level of fish consumption, numbers of dental amalgam fillings and use of cough syrups. Placental concentrations of bromine, calcium, chlorine, iron, mercury, potassium, rubidium, selenium, sodium and zinc were determined. The placentae of 52 Jamaican mothers with a mean age 29 years (range 18-42 years) delivering singleton neonates with a mean birthweight of 3.1 kg (1.3-5.5 kg) at term were collected. With the exception of iron and bromine, all results for elemental determinations are very similar to those found elsewhere. Correlation was observed for Apgar 2 (5 minutes), calcium and zinc with birthweight, with p-values of 0.002, 0.007 and 0.07, respectively. Negative correlation was observed for the Apgar 2 and potassium (p = 0.056) and age of mother at birth and bromine (p = 0.02). The mercury concentration in the measured placentae (7.29 +/- 9.1 microg/kg w/w) was slightly lower than the mean concentration found in the literature (8 microg/kg w/w). Approximately 93% of the measured placentae in this study are below the derived placentae upper limit of 22 microg/kg. Of the 7% above the upper limit none exceeded the conservative estimated limit of 115 microg/kg at which neural developmental problems start. The significant associations noted are of unknown clinical relevance and need further study.


Endometrial thickness and risk of breast and endometrial carcinomas in the prostate, lung, colorectal and ovarian cancer screening trial.
Postmenopausal women with higher circulating estrogen levels are at increased risk of developing breast and endometrial carcinomas. In the endometrium, excess estrogen relative to progesterone produces a net proliferative stimulus, which may result in endometrial thickening. Therefore, the hypothesis that endometrial thickness is a biological marker of excess estrogen stimulation that is associated with risk of breast and endometrial carcinomas was tested. Endometrial thickness was measured in 1,272 postmenopausal women, aged 55-74 years, who underwent transvaginal ultrasound (TVU) screening as part of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Serial endometrial thickness measurements were available for a subset of women at 1 year (n = 1,018), 2 years (n = 869) and 3 years (n = 641) after baseline. The associations between endometrial thickness and breast (n = 91) and endometrial (n = 14) carcinoma were evaluated by estimating relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression with age as the time metric. Models incorporating baseline endometrial thickness and as a time-varying covariate using all measurements were examined. Median follow-up among study participants was 12.5 years (range: 0.3-13.8 years). Compared to baseline endometrial thickness of 1.0-2.99 mm, women with baseline endometrial thickness greater than or equal to 5.0 mm had an increased risk of breast (RR = 2.00, 95% CI = 1.15-3.48) and endometrial (RR = 5.02, 95% CI = 0.96-26.36) carcinomas in models adjusted for menopausal hormone use and BMI. These data suggest that increased endometrial thickness as assessed by TVU was associated with increased risk of breast and endometrial carcinomas.


A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia.
The development of new treatments for older patients with acute myeloid leukaemia (AML) is an active area, but has met with limited success. Sapacitabine is a novel orally administered nucleoside analogue that has shown encouraging activity in unrandomised early-stage trials. We randomised 143 untreated patients with AML or with high-risk myelodysplastic syndrome (>10% marrow blasts) between sapacitibine and low-dose ara-C (LDAC) in our 'Pick a Winner' trial design. At the planned interim analysis there was no difference between LDAC and sapacitibine in terms of remission rate (CR/CRi, 27% vs 16% hazard ratio (HR) 1.98(0.90-4.39) P=0.09), relapse-free survival (10% vs 14% at 2 years, HR 0.73(0.33-1.61) P=0.4) or overall survival (OS; 12% vs 11% at 2 years, HR 1.24(0.86-1.78) P=0.2). Sapacitibine was well tolerated, apart from more grade 3/4 diarrhoea. On the basis of these findings sapacitibine did not show sufficient evidence of benefit over LDAC for the trial to be continued.


Differential human renal tubular responses to dopamine type 1 receptor stimulation are determined by blood pressure status.
We performed the present studies to determine whether a proximal renal tubular dopamine D1-like receptor defect exists in human essential hypertension. Twenty-four subjects were studied (13 normotensive and 11 hypertensive) in a randomized, double-blind, vehicle-controlled study using fenoldopam, a selective D1-like receptor agonist. Subjects were studied in sodium metabolic balance at 300 mEq/d, after which the salt sensitivity of their blood pressure was determined. Fenoldopam at peak doses of 0.1 to 0.2 microgram/kg per minute decreased mean arterial pressure in hypertensive subjects but did not change mean pressure in normotensive subjects. Fenoldopam increased renal plasma flow to a greater extent in hypertensive than normotensive subjects. Fenoldopam increased both urinary and fractional sodium excretions in the hypertensive and normotensive groups. In normotensive but not hypertensive subjects, fenoldopam increased the fractional excretion of lithium and distal sodium delivery. In contrast, both distal fractional sodium reabsorption and sodium-potassium exchange fell significantly in hypertensive subjects. We conclude that human essential hypertension is associated with a reduction in the proximal tubular response to D1-like receptor stimulation compared with normotensive subjects. Hypertensive subjects appear to have a compensatory upregulation of renal vascular and distal tubular D1-like receptor function that offsets the proximal tubular defect, resulting in an enhanced natriuretic response to D1-like receptor stimulation.


Bimodal exciton-plasmon light sources controlled by local charge carrier injection.
Electrical charges can generate photon emission in nanoscale quantum systems by two independent mechanisms. First, radiative recombination of pairs of oppositely charged carriers generates sharp excitonic lines. Second, coupling between currents and collective charge oscillations results in broad plasmonic bands. Both luminescence modes can be simultaneously generated upon charge carrier injection into thin C60 crystallites placed in the plasmonic nanocavity of a scanning tunneling microscope (STM). Using the sharp tip of the STM as a subnanometer-precise local electrode, we show that the two types of electroluminescence are induced by two separate charge transport channels. Holes injected into the valence band promote exciton generation, whereas electrons extracted from the conduction band cause plasmonic luminescence. The different dynamics of the two mechanisms permit controlling their relative contribution in the combined bimodal emission. Exciton recombination prevails for low charge injection rates, whereas plasmon decay outshines for high tunneling currents. The continuous transition between both regimes is described by a rate model characterizing emission dynamics on the nanoscale. Our work provides the basis for developing blended exciton-plasmon light sources with advanced functionalities.


Alumina-on-alumina total hip arthroplasty: a concise follow-up, at a minimum of ten years, of a previous report.
We previously reported the five-to-six-year results of the use of third-generation alumina-on-alumina bearings in a consecutive series of 100 primary cementless total hip arthroplasties. This report presents the longer-term outcomes of these same bearings, at a minimum of ten years postoperatively. Eighty-six of eighty-eight hips available for the study retained the original bearings at the time of the latest follow-up. Thirteen hips were associated with noise, and six hips demonstrated fretting of the femoral neck on radiographs. Two hips required a change of the bearings because of a ceramic head fracture. The ten-year survival rate of the alumina-on-alumina total hip prostheses, with revision of any implant for any reason as the end point, was 99.0%. On the basis of those results, we concluded that the rate of survival of primary cementless total hip prostheses with third-generation alumina-on-alumina bearings is excellent at ten years. However, the risk of ceramic fracture, noise, and impingement between the metal neck and the ceramic liner should be a concern to surgeons, and patients should be informed of these risks before surgery.


Discrimination of orbital angular momentum modes of the terahertz vortex beam using a diffractive mode transformer.
We present an efficient method to discriminate orbital angular momentum (OAM) of the terahertz (THz) vortex beam using a diffractive mode transformer. The mode transformer performs a log-polar coordinate transformation of the input THz vortex beam, which consists of two 3D-printed diffractive elements. A following lens separates each transformed OAM mode to a different lateral position in its focal plane. This method enables a simultaneous measurement over multiple OAM modes of the THz vortex beam. We experimentally demonstrate the measurement of seven individual OAM modes and two multiplexed OAM modes, which is in good agreement with simulations.


Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44.
Cancer cells metastasize to the other site after escaping from the immune system and CD70, CD44 and vascular endothelial growth factor (VEGF) play important roles in this process. It is recently reported that interleukin (IL)-18 is closely related with the pathogenesis of skin tumor. Therefore, we investigated the role of endogenous IL-18 from stomach cancer on the immune escape mechanism and metastasis via the regulation of CD70, CD44 and VEGF expression. IL-18 and IL-18R expressions were not only investigated on tumor tissues (n = 10), and sera (n = 20) from stomach cancer patients, but also on human stomach cancer cell lines. IL-18 and IL-18R expressions were found on stomach cancer cell lines and tumor tissues. In addition, IL-18 levels were elevated in sera from cancer patients (P < 0.05), compared with sera from normal individuals. Changes in CD70, CD44 and VEGF expression by flow cytometry, immunoblotting and enzyme-linked immunosorbent assay and immune susceptibility by (51)Cr-release assay were investigated, after silencing or neutralization of endogenous IL-18. CD70 expression was increased and it increases immune susceptibility of cancer cells. In contrast, CD44 and VEGF expression was decreased and it suppresses neovascularization and the metastasis of stomach cancer. After inoculation of IL-18 small interfering RNA (siRNA)-transfected stomach cancer cells into Balb/C (nu/nu) mice, regression of tumor mass was determined by measuring of tumor size. And the number and location of metastatic lesions were investigated by hematoxylin and eosin staining. The regression of tumor mass and the suppression of metastasis were observed in the mice, which are injected with IL-18 siRNA-transfected cell lines. Our data suggest that endogenous IL-18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF.


The effects of temperature and pH on the contractile properties of skinned muscle fibres from the terrapin, Pseudemys scripta elegans.
Fibre types in the iliofibularis muscle of the freshwater terrapin Pseudemys scripta elegans have been characterized on the basis of their histochemical characteristics, nerve endings and contractile properties. Three types of focally innervated fibres are present, corresponding to the fast glycolytic (Fg), fast oxidative glycolytic (FOG) and slow oxidative (SO) fibre types of other vertebrates. Single fibres or small bundles of fibres representing each histochemical type were identified on the basis of their light scattering properties under dark-field illumination. Fibres were detergent-skinned using Brij 58, and their maximum isometric tension (P0) and unloaded contraction velocity (V0) were determined by the slack test method. At 15 degrees C, fast glycolytic fibres generated maximum isometric tensions of 184 +/- 5 kNm-2 and V0 values of 5.5 +/- 0.3 muscle lengths per second (L0s-1). Slow oxidative fibres produced tensions of 70.6 +/- 3 kNm-2 and had V0 values of 1.3 L0s-1. Tensions and V0 values of fast oxidative glycolytic fibres were between those of Fg and SO fibres. The force-velocity (P-V) characteristics of slow oxidative fibres were studied at 5 degrees and 15 degrees C. Points below 0.6 P0 on the curves could be fitted by a linear form of Hill's equation. Maximum contraction velocities (Vmax) extrapolated from the P-V relationship were 0.62 L0s-1 at 5 degrees C and 0.91 L0s-1 at 15 degrees C. The curvature of the P-V relationship was relatively independent of temperature over the range 5 to 15 degrees C. Values for Hill's constant a/P0 were 0.29 and 0.33 at 5 degrees C and 15 degrees C, respectively. The temperature dependence of P0 and contraction velocity at near zero load (Vi) were studied at constant pH, and under conditions designed to simulate the changes in intracellular pH which occur with temperature in vivo (delta pH/delta T = -0.0186). Changes in pH in the range 6.6 to 7.8 had no effect on either tension or Vi at temperatures between 0 degrees and 20 degrees C. However, below and above this pH range, both tension and Vi were depressed. It is concluded that pH changes within the normal physiological range (6.7-7.8) have no effect on the temperature dependence of P0 and Vi.


Hybrid finite element method for describing the electrical response of biological cells to applied fields.
A novel hybrid finite element method (FEM) for modeling the response of passive and active biological membranes to external stimuli is presented. The method is based on the differential equations that describe the conservation of electric flux and membrane currents. By introducing the electric flux through the cell membrane as an additional variable, the algorithm decouples the linear partial differential equation part from the nonlinear ordinary differential equation part that defines the membrane dynamics of interest. This conveniently results in two subproblems: a linear interface problem and a nonlinear initial value problem. The linear interface problem is solved with a hybrid FEM. The initial value problem is integrated by a standard ordinary differential equation solver such as the Euler and Runge-Kutta methods. During time integration, these two subproblems are solved alternatively. The algorithm can be used to model the interaction of stimuli with multiple cells of almost arbitrary geometries and complex ion-channel gating at the plasma membrane. Numerical experiments are presented demonstrating the uses of the method for modeling field stimulation and action potential propagation.


Segmental distraction osteogenesis of the anterior alveolar process using tooth-borne devices: is it skeletal movement or mainly dental tipping?
Segmental distraction osteogenesis of the anterior alveolar process has been introduced as a technique designed to avoid extractions in patients with severe dental crowding. The aim of this study was to quantify the degree of dental tipping within the alveolar segment after distraction osteogenesis. Patients treated for dental crowding, retruded anterior alveolar process, or flat curves of Spee using segmental distraction osteogenesis of the anterior alveolar process were included in the study. Dental-borne distraction devices were used while measuring points, and angles were defined to analyze the amount of dental tipping of the lower incisors after distraction. The measurements were performed using cone-beam computed tomographic scans. Periodontal health (eg, gingival recession, tooth mobility, and dental socket depths) was evaluated after distraction. A descriptive statistical analysis was performed. Fifteen patients were included in the study. The amount of dental tipping within the total movement of the alveolar process showed a mean of 24% after distraction osteogenesis, whereas the skeletal movement was 76%. Dental socket depths and tooth mobility remained at the same levels as those before distraction osteogenesis. In one third of patients, gingival recession was observed around the canines. Segmental distraction osteogenesis of the anterior process is a powerful technique that can prevent extractions in patients with dental crowding. The technique can also compensate for retruded anterior alveolar process and accelerate or decelerate the curve of Spee. Patients with constricted periodontal health and those with a thin mandibular symphysis, however, cannot be treated with this technique because of the increased risk of dental tipping. Severe gingival recession must also be considered a possible side effect associated with this technique.


Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase by a stavudine analogue, 4'-ethynyl stavudine triphosphate.
2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), a recently discovered nucleoside reverse transcriptase (RT) inhibitor, exhibits 5- to 10-fold-higher activity against human immunodeficiency virus type 1 (HIV-1) and less cytotoxicity than does its parental compound d4T (stavudine). Using steady-state kinetic approaches, we have previously shown that (i) 4'-ethynyl-d4T triphosphate (4'-Ed4TTP) inhibits HIV-1 RT more efficiently than d4TTP does and (ii) its inhibition efficiency toward the RT M184V mutant is threefold less than that toward wild-type (wt) RT. In this study we used pre-steady-state kinetic approaches in an attempt to understand its mechanism of inhibition. With wt and the M184V mutant RTs, 4'-Ed4TTP has three- to fivefold-lower K(d) (dissociation constant) values than d4TTP, while d4TTP has up to eightfold-higher K(d) values than dTTP. Inhibition is more effective in DNA replication with RNA template than with DNA template. In general, the M184V mutant exhibits poorer binding for all three nucleoside triphosphates than does wt RT. The structural basis for the lower binding affinity of d4TTP than of dTTP could be the lack of hydrogen bonds from the missing 3'-hydroxyl group in d4TTP to the backbone amide of Y115 and also to the side chain of Q151. The structural basis for the higher binding affinity of 4'-Ed4TTP than of d4TTP could be the additional binding of the 4'-ethynyl group in a preformed hydrophobic pocket by A114, Y115, M184, F160, and part of D185.