Association between family factors and children's oral health behaviors--a cross-sectional comparative study of permanent resident and migrant children in large cities in China.
To examine the association of family factors on oral health behaviors of children and compare them between permanent residents and migrant children. A total of 3015 children in grades 4, 5, and 6 from 16 elementary schools and their parents in Beijing and Guangzhou, China, were selected through multistage stratified cluster random sampling. Questionnaires constructed for this study were self-completed by children and parents to collect information on children's oral health behaviors (COHB), parents' modeling behaviors (PMB), parents' direct controlling behaviors (PDCB), parents' indirect controlling behaviors (PICB), parents' oral health knowledge and attitudes (POHKA), and children's oral health knowledge and attitudes (COHKA). Correlation analysis and path analysis were used to explore the correlation between COHB and PMB, as well as the effects of family factors [socioeconomic status (SES), PMB, PDCB, PICB, and POHKA on COHB]. Considering all participants, the rates of behavioral similarities of parents and children were 63.8-86.1%, all showing statistical significance. For family factors included, PMB, SES, PICB, and POHKA demonstrated positive relationships with COHB with standardized coefficients of 0.200, 0.122, 0.040, and 0.059 in residents and 0.160, 0.121, 0.090, and 0.041 in migrants, respectively. Family SES was associated with COHB directly and indirectly to a similar degree. In migrants, the relationship between COHKA and COHB was greater than that between PMB and COHB. COHB scores were higher in younger children. In residents, the relationship between PMB and COHB was greater than that between COHKA and COHB. COHB scores were slightly higher in older children indirectly influenced by increases in COHKA. Parents' behaviors shared relatively high similarities with COHB and family factors were associated with COHB greatly. The relationship between PMB and COHB was less than that between COHKA and COHB in migrants. The association between family factors and COHB in disadvantaged populations should be considered when designing children's health education programs.


Immune-related biomarkers in myocardial infarction; diagnostic/prognostic value and therapeutic potential.
The incidence of myocardial infarction (MI) is increasing worldwide on an annual basis. The incorporation of circulating biomarkers, along with electrocardiography, echocardiography, coronary angiograms, and other diagnostic techniques, is essential in the evaluation, prediction, and therapeutic efficacy assessment of patients afflicted with MI. Biomarker evaluation has been employed in the diagnosis of MI for over five decades. Further biomarker research can be carried out as newer biomarkers have been discovered in pathways such as inflammatory response, neurohormonal stimulation, or myocardial stress that initiate significantly earlier than myocyte necrosis and the diagnostic establishment of cardiac troponins. The assessment of biomarkers for MI is on the brink of a significant transformation due to advancements in comprehending the intricate pathophysiology of the condition. This has led to a pursuit of innovative biomarkers that could potentially overcome the limitations of current biomarkers. For individuals with a high-risk profile, this may facilitate tailoring of appropriate treatment. This review places emphasis on a diverse array of biomarkers that have the potential to offer diagnostic and prognostic information, as well as the latest clinical and preclinical evidence that is driving theoretical advancements in cardiovascular immunotherapy.


Fitness study of the RDRio lineage and Latin American-Mediterranean family of Mycobacterium tuberculosis in the city of Rio Grande, Brazil.
RD(Rio) is a novel Mycobacterium tuberculosis lineage of the Latin American-Mediterranean (LAM) family. LAM has been found worldwide but is more predominant in South America. The aim of this study was to assess the presence of the RD(Rio) lineage and LAM family in the city of Rio Grande, Brazil, and to investigate the fitness of these strains based on determination of their growth rate. Fifty clinical isolates of M. tuberculosis were genotyped and 43 different patterns were found by spoligotyping and mycobacterial interspersed repetitive units-variable number of tandem repeats. The predominant genotypes belonged to the LAM family (54% of the strains) followed by clade T (22%) and Haarlem (16%). The RD(Rio) lineage represented 38% of the total strains and 70.4% of the LAM strains found in this study. Strains belonging to the LAM family showed a fitness advantage when comparing their rate of growth with that of non-LAM strains, but a significant difference between RD(Rio) and non-RD(Rio) strains was not confirmed.


[Endocarditis due to Aggregatibacter (formerly: Actinobacillus) actinomycetemcomitans, a bacterium that grows in characteristic star-shaped colonies].
A 72-year-old man, having had an artificial valve for almost 20 years now, presented with tiredness that had persisted for several weeks and reported weight loss of 5 kg. In more recent days he experienced fever and cold shivers, and an associated dry cough. Bearing in mind the potential for endocarditis, blood cultures were grown. In this, we identified a small, Gram-negative rod with a small, smooth, raised colony that grew slowly. We considered a micro-organism from the 'HACEK group', which is a group of micro-organisms including Haemophilus aphrophilus, Haemophilus paraphrophilus, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae and Aggregatibacter (formerly: Actinobacillus) actinomycetemcomitans. More careful observation revealed that the bacteria formed star-shaped colonies, proving that A. actinomycetemcomitans was the cause of this non-acute endocarditis. The patient received antibiotic treatment. Because non-acute endocarditis is often caused by hidden abnormalities in the mouth or teeth and A. actinomycetemcomitans plays an important role in severe cases of peridontitis, a dental surgeon was consulted. The dental surgeon diagnosed multifocal peridontitis and treated the patient, who was able to leave the hospital after 6 weeks of antibiotic treatment.


Assessment of tropism and effectiveness of new primate-derived hybrid recombinant AAV serotypes in the mouse and primate retina.
Adeno-associated viral vectors (AAV) have been shown to be safe in the treatment of retinal degenerations in clinical trials. Thus, improving the efficiency of viral gene delivery has become increasingly important to increase the success of clinical trials. In this study, structural domains of different rAAV serotypes isolated from primate brain were combined to create novel hybrid recombinant AAV serotypes, rAAV2/rec2 and rAAV2/rec3. The efficacy of these novel serotypes were assessed in wild type mice and in two models of retinal degeneration (the Abca4(-/-) mouse which is a model for Stargardt disease and in the Pde6b(rd1/rd1) mouse) in vivo, in primate tissue ex-vivo, and in the human-derived SH-SY5Y cell line, using an identical AAV2 expression cassette. We show that these novel hybrid serotypes can transduce retinal tissue in mice and primates efficiently, although no more than AAV2/2 and rAAV2/5 serotypes. Transduction efficiency appeared lower in the Abca4(-/-) mouse compared to wild type with all vectors tested, suggesting an effect of specific retinal diseases on the efficiency of gene delivery. Shuffling of AAV capsid domains may have clinical applications for patients who develop T-cell immune responses following AAV gene therapy, as specific peptide antigen sequences could be substituted using this technique prior to vector re-treatments.


Multiple sclerosis incidence rate in southern Iran: a Bayesian epidemiological study.
Multiple Sclerosis (MS) remains to be a public health challenge, due to its unknown biological mechanisms and clinical impacts on young people. The prevalence of this disease in Iran is reported to be 5.30 to 74.28 per 100,000-person. Because of high prevalence of this disease in Fars province, the purpose of this study was to assess the spatial pattern of MS incidence rate by modeling both the associations s of spatial dependence between neighboring regions and risk factors in a Bayesian Poisson model, which can lead to the improvement of health resource allocation decisions. Data from 5468 patients diagnosed with MS were collected, according to the McDonald's criteria. New cases of MS were reported by the MS Society of Fars province from 1991 until 2016. The association between the percentage of people with low vitamin D intake, smoking, abnormal BMI and alcohol consumption in addition to spatial structure in a Bayesian spatio-temporal hierarchical model were used to determine the relative risk and trend of MS incidence rate in 29 counties of Fars province. County-level crude incidence rates ranged from 0.22 to 11.31 cases per 100,000-person population. The highest relative risk was estimated at 1.80 in the county of Shiraz, the capital of Fars province, while the lowest relative risk was estimated at 0.11 in Zarindasht county in southern of Fars. The percentages of vitamin D supplementation intake and smoking were significantly associated with the incidence rate of MS. The results showed that 1% increase in vitamin D supplementation intake is associated with 2% decrease in the risk of MS and 1% increase in smoking is associated with 16% increase in the risk of MS. Bayesian spatio-temporal analysis of MS incidence rate revealed that the trend in the south and south east of Fars province is less steep than the mean trend of this disease. The lower incidence rate was associated with a higher percentage of vitamin D supplementation intake and a lower percentage of smoking. Previous studies have also shown that smoking and low vitamin D, among all covariates or risk factors, might be associated with high incidence of MS.


Neurophysiological Basis of Multi-Scale Entropy of Brain Complexity and Its Relationship With Functional Connectivity.
Recently, non-linear statistical measures such as multi-scale entropy (MSE) have been introduced as indices of the complexity of electrophysiology and fMRI time-series across multiple time scales. In this work, we investigated the neurophysiological underpinnings of complexity (MSE) of electrophysiology and fMRI signals and their relations to functional connectivity (FC). MSE and FC analyses were performed on simulated data using neural mass model based brain network model with the Brain Dynamics Toolbox, on animal models with concurrent recording of fMRI and electrophysiology in conjunction with pharmacological manipulations, and on resting-state fMRI data from the Human Connectome Project. Our results show that the complexity of regional electrophysiology and fMRI signals is positively correlated with network FC. The associations between MSE and FC are dependent on the temporal scales or frequencies, with higher associations between MSE and FC at lower temporal frequencies. Our results from theoretical modeling, animal experiment and human fMRI indicate that (1) Regional neural complexity and network FC may be two related aspects of brain's information processing: the more complex regional neural activity, the higher FC this region has with other brain regions; (2) MSE at high and low frequencies may represent local and distributed information processing across brain regions. Based on literature and our data, we propose that the complexity of regional neural signals may serve as an index of the brain's capacity of information processing-increased complexity may indicate greater transition or exploration between different states of brain networks, thereby a greater propensity for information processing.


Activation of human endothelial cells by viable or heat-killed gram-negative bacteria requires soluble CD14.
In response to bacterial lipopolysaccharides (LPS; endotoxin), endothelial cells are converted to an activation phenotype expressing both proinflammatory and procoagulant properties that include the induction of leukocyte adhesion molecules and tissue factor expression. LPS-induced endothelial cell activation requires a soluble form of the monocyte LPS receptor, sCD14. We evaluated the capacity of multiple strains of gram-negative and gram-positive bacteria to induce endothelial E-selectin and tissue factor expression through sCD14-dependent pathways with cultured human umbilical vein endothelial cells (HUVE). Both viable and heat-killed gram-negative bacteria (Bacteroides fragilis, Enterobacter cloacae, Haemophilus influenzae, and Klebsiella pneumoniae) but not viable or heat-killed gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae) induced prominent E-selectin surface expression detected by enzyme-linked immunosorbent assay. Tissue factor activity on HUVE, indicated by factor X activation, was induced in response to gram-negative bacteria but not in response to gram-positive bacteria. Gram-negative bacteria induced transcriptional activation in HUVE, indicated by the appearance of E-selectin-specific mRNA and by the demonstration of activation of NF-kappa B, a trans-activating factor necessary for E-selectin and tissue factor gene transcription. In contrast, neither E-selectin mRNA nor activation of NF-kappa B was detected in HUVE treated with gram-positive bacteria. Endothelial cell activation by gram-negative bacteria in each of these assays was inhibited with a monoclonal antibody (60bd) against CD14. Furthermore, CHO-K1 cells, transfected with human recombinant CD14, responded to all strains of gram-negative bacteria (viable or heat killed), indicated by CHO-K1 NF-kappa B activation. We conclude that gram-negative bacteria induce endothelial cell activation through a common sCD14-dependent pathway.


Patterns and kinetics of water uptake by soybean seeds.
Soybean [Glycine max (L.) Merr.] plants produce some seeds (called stone or impermeable seeds) that do not take up water for long periods of time. The present investigation confirmed that the stone seed trait is a feature of the seed coat: isolated embryos from both stone and permeable seeds took up water equally quickly. A whole, permeable seed typically imbibed water initially through its dorsal side, forming wrinkles in the seed coat and delivering water to the underlying cotyledons. Later, some lateral movement of water through the coat occurred, presumably through the air spaces of the osteosclereid layer. Imbibition by seeds was a two-phase process, the first dominated by hydration of the seed coat and the second by hydration of the cotyledons, which was rate-limited by the coat. When hydrated, coats of stone seeds were permeable to water but their hydraulic conductivity, as measured with a pressure probe, was smaller than that of coats from permeable seeds by a factor of five. Hydrated coats of both permeable and stone seeds showed weak osmometer properties.


Development of Meishan and Yorkshire littermate conceptuses in either a Meishan or Yorkshire uterine environment to day 90 of gestation and to term.
To investigate the impacts of uterine type and conceptus genotype on development through late gestation, Meishan and Yorkshire embryos were co-transferred into the uteri of either Meishan or Yorkshire recipients that were subsequently slaughtered on Day 90 of gestation. At slaughter, regardless of conceptus genotype, fetuses and placentae were markedly smaller when recovered from Meishan than from Yorkshire recipients. Whereas Meishan and Yorkshire fetuses recovered from Meishan uteri were similar in weight, Meishan fetuses were markedly lighter than littermate Yorkshire fetuses when recovered from Yorkshire uteri. Because of the marked differences between fetal weights observed in Yorkshire recipients on Day 90 of gestation, Meishan and Yorkshire embryos were co-transferred to Yorkshire recipients that were allowed to farrow. Surprisingly, Meishan and Yorkshire fetuses cogestated in Yorkshire recipients were born at similar weights, whereas Meishan placentae were markedly smaller. The weight of Meishan placentae were similar on Day 90 and at term, whereas the weight of Yorkshire placentae were markedly larger (approximately 70%) at term than on Day 90. The constant weight of Meishan placentae from Day 90 to farrowing appears to result from an ability to increase their vascularity during this interval. In contrast, Yorkshire placentae may be forced to increase their weight to keep pace with fetal growth during this period. Because uterine capacity sets the upper limit on litter size, the decreased endometrial surface area required per conceptus in the Meishan pig seems to explain its greater potential for increased litter size.


Eliciting unnatural immune responses by activating cryptic epitopes in viral antigens.
Antigenic variation in viral surface antigens is a strategy for escaping the host's adaptive immunity, whereas regions with pivotal functions for infection are less subject to antigenic variability. We hypothesized that genetically invariable and immunologically dormant regions of a viral surface antigen could be exposed to the host immune system and activated by rendering them susceptible to antigen-processing machinery in professional antigen-presenting cells (APCs). Considering the frequent antigen drift and shift in influenza viruses, we identified and used structural modeling to evaluate the conserved regions on the influenza hemagglutinin (HA) surface as potential epitopes. Mutant viruses containing the cleavage motifs of cathepsin S within HA were generated. Immunization of mice showed that the mutant, but not the wild-type virus, elicited specific antibodies against the cryptic epitope. Those antibodies were purified, and specific binding to HA was confirmed. These results suggest that an unnatural immune response can be elicited through the processing of target antigens in APCs, followed by presentation via the major histocompatibility complex, if not subjected to regulatory pathways. By harnessing the antigen-processing machinery, our study shows a proof-of-principle for designer vaccines with increased efficacy and safety by either activating cryptic, or inactivating naturally occurring, epitopes of viral antigens.-Lee, Y. J., Yu, J. E., Kim, P., Lee, J.-Y., Cheong, Y. C., Lee, Y. J., Chang, J., Seong, B. L. Eliciting unnatural immune responses by activating cryptic epitopes in viral antigens.


Oral cancer induced TRPV1 sensitization is mediated by PAR2 signaling in primary afferent neurons innervating the cancer microenvironment.
Oral cancer patients report sensitivity to spicy foods and liquids. The mechanism responsible for chemosensitivity induced by oral cancer is not known. We simulate oral cancer-induced chemosensitivity in a xenograft oral cancer mouse model using two-bottle choice drinking and conditioned place aversion assays. An anatomic basis of chemosensitivity is shown in increased expression of TRPV1 in anatomically relevant trigeminal ganglion (TG) neurons in both the xenograft and a carcinogen (4-nitroquinoline 1-oxide)-induced oral cancer mouse models. The percent of retrograde labeled TG neurons that respond to TRPV1 agonist, capsaicin, is increased along with the magnitude of response as measured by calcium influx, in neurons from the cancer models. To address the possible mechanism of TRPV1 sensitivity in tongue afferents, we study the role of PAR2, which can sensitize the TRPV1 channel. We show co-expression of TRPV1 and PAR2 on tongue afferents and using a conditioned place aversion assay, demonstrate that PAR2 mediates oral cancer-induced, TRPV1-evoked sensitivity in an oral cancer mouse model. The findings provide insight into oral cancer-mediated chemosensitivity.


Gamma-enolase: a well-known tumour marker, with a less-known role in cancer.
Gamma-enolase, known also as neuron-specific enolase (NSE), is an enzyme of the glycolytic pathway, which is expressed predominantly in neurons and cells of the neuroendocrine system. As a tumour marker it is used in diagnosis and prognosis of cancer; however, the mechanisms enrolling it in malignant progression remain elusive. As a cytoplasmic enzyme gamma-enolase is involved in increased aerobic glycolysis, the main source of energy in cancer cells, supporting cell proliferation. However, different cellular localisation at pathophysiological conditions, proposes other cellular engagements. The C-terminal part of the molecule, which is not related to glycolytic pathway, was shown to promote survival of neuronal cells by regulating neuronal growth factor receptor dependent signalling pathways, resulting also in extensive actin cytoskeleton remodelling. This additional function could be important also in cancer cells either to protect cells from stressful conditions and therapeutic agents or to promote tumour cell migration and invasion. Gamma-enolase might therefore have a multifunctional role in cancer progression: it supports increased tumour cell metabolic demands, protects tumour cells from stressful conditions and promotes their invasion and migration.


[Prevention of type 2 diabetes--an overview].
The incidence of type 2 diabetes is increasing. Epidemiological data indicate a need to investigate possible interventions to prevent or delay the onset. Diabetologic and pharmacologic information was retrieved from review papers. Additionally, the Cochrane library and PubMed were searched for relevant studies. Recent studies have demonstrated the efficacy of lifestyle intervention and metformin treatment in impaired glucose tolerance. Surgical treatment for obesity could be beneficial for individuals with BMI > 35. Recommendations from the American Diabetes Association for the prevention of type 2 diabetes are opportunistic screening, intervention on lifestyle factors such as physical activity and weight reduction, and also on cardiovascular risk factors. "Prediabetes" should be identified and treated by lifestyle intervention in primary health care. National guidelines for primary prevention should also be established.


Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer.
A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient's tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor's heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of six pair of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer.


UNC51-like kinase 1 as a potential prognostic biomarker for hepatocellular carcinoma.
Autophagy is a fundamental cell biological process that confers stress tolerance, limits damage, and sustains viability under adverse conditions. Defective autophagy is associated with diverse diseases. The study aimed to investigate the relationship between UNC51-like kinase 1 (ULK1) expression and clinicopathological characteristics as well as survival in patients with hepatocellular carcinoma (HCC). Expression levels of ULK1 in 55 paired HCC and paracancerous tissues were examined using immunohistochemistry. Although not statistically significant, the expression of ULK1 in adjacent peritumoural tissue was lower than those in HCC tissues (P = 0.113). Expression level of ULK1 was significantly associated with tumor size (P = 0.015) after adjusted for age, sex, histologic grade, cirrhosis and TNM. Survival analysis showed that patients with high ULK1 expression had worse survival time than those with low ULK1 expression (hazard rate = 2.684, 95% CI 1.029-7.006, P = 0.044). The findings of the present study provide evidence that ULK1 represents a potential novel prognostic biomarker for HCC patients and may play an important role during the progression of HCC.


The 2009 US federal cigarette tax increase and quitline utilization in 16 states.
On April 1, 2009, the federal cigarette excise tax increased from 39 cents to $1.01 per pack. This study describes call volumes to 16 state quitlines, characteristics of callers and cessation outcomes before and after the tax. Calls to the quitlines increased by 23.5% in 2009 and more whites, smokers ≥ 25 years of age, smokers of shorter duration, those with less education, and those who live with smokers called after (versus before) the tax. Quit rates at 7 months did not differ before versus after tax. Descriptive analyses revealed that the federal excise tax on cigarettes was associated with increased calls to quitlines but multivariate analyses revealed no difference in quit rates. However, more callers at the same quit rate indicates an increase in total number of successful quitters. If revenue obtained from increased taxation on cigarettes is put into cessation treatment, then it is likely future excise taxes would have an even greater effect.


Chinese research into severe ulcerative colitis has increased in quantity and complexity.
To investigate the current state of research output from Chinese studies into severe ulcerative colitis (SUC) using a bibliometric analysis of publications. The contents of the Chinese periodical databases WANFANG, VIP, and China National Knowledge Infrastructure were searched for all papers regarding UC or SUC published in last the 15 years (from 2001 to 2015). The number of publications in each year was recorded to assess the temporal trends of research output. All SUC related publications were downloaded and the complexity of this research was evaluated with methods described previously. The number of patients with SUC reported each year was recorded and their clinical characteristics were analyzed using information available in the relevant papers. There were 13499 publications regarding UC published in Chinese medical journals between 2001 and 2015, of which 201 focused on SUC. The number of publications increased rapidly with more than half of all papers being published in the most recent 5-year period. There was a significant increase in analytical studies and clinical trials over the study period (P < 0.01), with research into the management of SUC, included pharmacotherapy, nutrition support as well as surgery, predominating. Almost half (46.2%) of the observational analytical studies and clinical trials focused on Traditional Chinese Medicine, with little research on the efficacy of cyclosporin and infliximab in disease management. About 6222 patients with SUC were reported in the 201 SUC relevant papers, with a ratio of male/female of 1.38. The number of patients reported in each 5-year period significantly increased. The colectomy rate and short-term mortality rate were 7.7% and 0.8% respectively. The most commonly employed operation was total proctocolectomy with ileal pouch-anal anastomosis. The output and complexity of research related to SUC in China increased significantly over the previous 15 years, however few of these studies focused on salvage therapy.


Snowflake morays, Echidna nebulosa, exhibit similar feeding kinematics in terrestrial and aquatic treatments.
Some species of durophagous moray eels (Muraenidae) have been documented emerging from the marine environment to capture intertidal crabs but how they consume prey out of water is unknown. Here, we trained snowflake morays, Echidna nebulosa, to undulate out of the aquatic environment to feed on land. On land, snowflake morays remove prey from the substrate by biting and swallow prey using pharyngeal jaw enabled transport. Although snowflake morays exhibit smaller jaw rotation angles on land when apprehending their prey, transport kinematics involving dorsoventral flexion of the head to protract the pharyngeal jaws and overall feeding times did not differ between terrestrial and aquatic treatments. We suggest that their elongate body plan, ability to rotate their heads in the dorsoventral and lateral directions, and extreme pharyngeal movements all contribute to the ability of durophagous morays to feed in the terrestrial environment.


Modified Plasmodium falciparum Ring-Stage Survival Assay with ML10 Kinase Inhibitor.
The ring-stage survival assay is the reference assay to measure in vitro Plasmodium falciparum artemisinin partial resistance. The main challenge of the standard protocol is to generate 0-to-3-h postinvasion ring stages (the stage least susceptible to artemisinin) from schizonts obtained by sorbitol treatment and Percoll gradient. We report here a modified protocol facilitating the production of synchronized schizonts when multiple strains are tested simultaneously, by using ML10, a protein kinase inhibitor, that reversibly blocks merozoite egress.


DsRNA Sequencing for RNA Virus Surveillance Using Human Clinical Samples.
Although viruses infect various organs and are associated with diseases, there may be many unidentified pathogenic viruses. The recent development of next-generation sequencing technologies has facilitated the establishment of an environmental viral metagenomic approach targeting the intracellular viral genome. However, an efficient method for the detection of a viral genome derived from an RNA virus in animal or human samples has not been established. Here, we established a method for the efficient detection of RNA viruses in human clinical samples. We then tested the efficiency of the method compared to other conventional methods by using tissue samples collected from 57 recipients of living donor liver transplantations performed between June 2017 and February 2019 at Kyushu University Hospital. The viral read ratio in human clinical samples was higher by the new method than by the other conventional methods. In addition, the new method correctly identified viral RNA from liver tissues infected with hepatitis C virus. This new technique will be an effective tool for intracellular RNA virus surveillance in human clinical samples and may be useful for the detection of new RNA viruses associated with diseases.


Telehealth and Rural-Urban Differences in Receipt of Pain Care in the Veterans Health Administration.
Examine changes in specialty pain utilization in the Veterans Health Administration (VHA) after establishing a virtual interdisciplinary pain team (TelePain). Retrospective cohort study. A single VHA healthcare system, 2015-2019. 33,169 patients with chronic pain-related diagnoses. We measured specialty pain utilization (in-person and telehealth) among patients with moderate to severe chronic pain. We used generalized estimating equations to test the association of time (pre- or post-TelePain) and rurality on receipt of specialty pain care. Among patients with moderate to severe chronic pain, the reach of specialty pain care increased from 11.1% to 16.2% in the pre- to post-TelePain periods (adjusted odds ratio [aOR]: 1.37, 95% confidence interval [CI]: 1.26-1.49). This was true of both urban patients (aOR: 1.62, 95% CI: 1.53-1.71) and rural patients (aOR: 1.16, 95% CI: 0.99-1.36), although the difference for rural patients was not statistically significant. Among rural patients who received specialty pain care, a high percentage of the visits were delivered by telehealth (nearly 12% in the post-TelePain period), much higher than among urban patients (3%). We observed increased use of specialty pain services among all patients with chronic pain. Although rural patients did not achieve the same degree of access and utilization overall as urban patients, their use of pain telehealth increased substantially and may have substituted for in-person visits. Targeted implementation efforts may be needed to further increase the reach of services to patients living in areas with limited specialty pain care options.


FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells.
Forkhead box (Fox) transcription factors are important regulators of cardiovascular development and several Fox-proteins have recently been shown to modulate embryonic and post-natal angiogenesis. However, the role of the FoxP subfamily, which is highly expressed in cardiovascular tissue, has not been investigated so far. Here, we show that the transcription factor FoxP1 is the highest expressed FoxP-protein in endothelial cells and that it is upregulated at the site of neovascularization during hindlimb ischemia in mice. Silencing of FoxP1 results in a strong inhibition of proliferation, tube formation and migration of cultured endothelial cells. Accordingly, knockdown of FoxP1 in zebrafish was followed by a disruption of intersomitic vascular formation. Using gene expression profiling, we show that FoxP1 induces a specific change of the endothelial transcriptome and functions as a suppressor of semaphorin 5B, which has previously been described as a neuronal inhibitory factor. Our findings now demonstrate that semaphorin 5B also acts as a FoxP1- dependent suppressor of endothelial cell proliferation, migration and sprouting, mediating the effects of FoxP1. In summary, our data indicate that the transcription factor FoxP1 is essential for the angiogenic function of endothelial cells and functions as a suppressor of the inhibitory guidance cue semaphorin 5B, suggesting an important function of FoxP1 in the regulation of neovascularization.


Diet of arthropodophagous bats (Mammalia, Chiroptera) from Northwestern Argentina.
The diet of arthropodophagous bats can be influenced by several factors. Furthermore, its study is critical for understanding their role in the ecosystem as regulators of arthropod abundance. The aim of this study was to analyze the diet of 12 species beloging to two families of arthropodophagous bats from the Yungas Forests, Northwestern Argentina. We also evaluated differences in diet between well-preserved and disturbed sites, sexes, and seasons. The specimens were collected with mist nets in eight different localities, four well-preserved and four disturbed sites of the Yungas Forests. Through the analysis of feces, arthropod remains were identified until the lowest possible taxonomic level. Volume and frequency of occurrence percentages for each food item and the niche breadth for the species were estimated. A total of 475 samples from 12 species were analyzed and their diet contained arthropods from eight orders and seven families; the highest number of consumed arthropod orders were registered for Eptesicus diminutus. A low niche breadth was recorded in general for all species. The diet was significantly influenced by season and site characteristics only in E. diminutus and E. furinalis, respectively. This showed that bats could modify its diet according to the different habitats and seasons.


Hsp90 inhibitors sensitise human colon cancer cells to topoisomerase I poisons by depletion of key anti-apoptotic and cell cycle checkpoint proteins.
Hsp90 and topoisomerase I are both targets for chemotherapeutic agents. Topoisomerase I poisons are standard clinical treatments, whilst Hsp90 inhibitors are progressing through clinical trials. We have demonstrated that when an Hsp90 inhibitor and topoisomerase I poison are combined they produce a synergistic increase in apoptosis in both p53⁺/⁺ and p53⁻/⁻ HCT116 human colon cancer cells. Lack of p53 is associated with an increase in sensitivity to the combination treatment; p53⁺/⁺ cells treated with the topoisomerase I poison topotecan (TPT) arrest at G2, whereas in p53⁻/⁻ cells the additional presence of the Hsp90 inhibitor geldanamycin (GA) selectively abrogates the G2M checkpoint. More importantly we report that there is a common underlying p53-independent mechanism behind the observed synergistic combined drug effect. We show that concurrent treatment with GA and TPT is able to reverse TPT induced up-regulation of the anti-apoptotic protein Bcl2 in both p53⁺/⁺ and p53⁻/⁻ HCT116 cells. The data suggests that inhibition of Hsp90 mediates down-regulation of Bcl2 following the combination treatment and cause a synergistic increase in apoptosis in both p53⁺/⁺ and p53⁻/⁻ HCT116 cells; p53⁻/⁻ HCT116 cells are more sensitive to the treatment because they also fail to arrest at G2 in the cell cycle.


Heterologous RNA-silencing suppressors from both plant- and animal-infecting viruses support plum pox virus infection.
HCPro, the RNA-silencing suppressor (RSS) of viruses belonging to the genus Potyvirus in the family Potyviridae, is a multifunctional protein presumably involved in all essential steps of the viral infection cycle. Recent studies have shown that plum pox potyvirus (PPV) HCPro can be replaced successfully by cucumber vein yellowing ipomovirus P1b, a sequence-unrelated RSS from a virus of the same family. In order to gain insight into the requirement of a particular RSS to establish a successful potyviral infection, we tested the ability of different heterologous RSSs from both plant- and animal-infecting viruses to substitute for HCPro. Making use of engineered PPV chimeras, we show that PPV HCPro can be replaced functionally by some, but not all, unrelated RSSs, including the NS1 protein of the mammal-infecting influenza A virus. Interestingly, the capacity of a particular RSS to replace HCPro does not correlate strictly with its RNA silencing-suppression strength. Altogether, our results suggest that not all suppression strategies are equally suitable for efficient escape of PPV from the RNA-silencing machinery. The approach followed here, based on using PPV chimeras in which an under-consideration RSS substitutes for HCPro, could further help to study the function of diverse RSSs in a 'highly sensitive' RNA-silencing context, such as that taking place in plant cells during the process of a viral infection.


Host Induced Gene Silencing Targeting Aspergillus flavus aflM Reduced Aflatoxin Contamination in Transgenic Maize Under Field Conditions.
Maize (Zea mays L.) is one of the major crops susceptible to Aspergillus flavus infection and subsequent contamination with aflatoxins, the most potent naturally produced carcinogenic secondary metabolites. This pathogen can pose serious health concerns and cause severe economic losses due to the Food and Drug Administration (FDA) regulations on permissible levels of aflatoxins in food and feed. Although biocontrol has yielded some successes in managing aflatoxin contamination, enhancing crop resistance is still the preferred choice of management for long-term sustainability. Hence, host induced gene silencing (HIGS) strategy was explored in this study. The A. flavus gene aflM encoding versicolorin dehydrogenase, a key enzyme involved in the aflatoxin biosynthetic pathway, was selected as a possible target for suppression through HIGS. An RNAi vector containing a portion of the aflM gene was constructed and introduced into immature B104 maize zygotic embryos through Agrobacterium transformation. PCR analysis of the genomic DNA from T0 leaf tissue confirmed the presence of the transgene in six out of the seven events. The seeds from the lines that showed reduced aflatoxin production in laboratory aflatoxin kernel screening assay (KSA) have been increased from T1 to T4 generation in the past four years. Changes in aflatoxin resistance in these transgenic kernels have been evaluated under both field and laboratory conditions. The T2 generation kernels containing the transgene from two events out of four examined had less aflatoxin (P ≤ 0.01 and P ≤ 0.08) than those without the transgene. Field-inoculated homozygous T3 and T4 transgenic kernels also revealed lower levels of aflatoxins (P ≤ 0.04) than kernels from the null (segregated non-transgenic samples) or B104 controls. A similar result was observed when the harvested T3 and T4 homozygous transgenic kernels were evaluated under KSA conditions without inoculation (P ≤ 0.003-0.05). These two events were crossed with LH195, LH197, LH210, and PHW79 elite breeding lines and the resulting crosses supported less aflatoxin (P ≤ 0.02) than the crosses made with non-transgenic lines. In addition, significantly higher levels of aflM gene-specific small RNAs were detected in the transgenic leaf and kernel tissues, indicating that the enhanced aflatoxin resistance in the homozygous transgenic kernels is likely due to suppression of aflM expression through HIGS.


Syphilis on the rise: A prolonged syphilis outbreak among HIV-infected patients in Northern Greece.
Sexually transmitted diseases (STDs) are a major public health issue in Europe. Numerous outbreaks of syphilis have been described recently and an increased prevalence of high-risk sexual practices has raised concern about the transmission of HIV and other STDs. Similarly, an increase in sexually transmitted infections has been recorded in Northern Greece. This report describes a recent outbreak of syphilis in people living with HIV. The demographic, clinical, and serologic data of HIV patients diagnosed with syphilis were recorded and analyzed. Data on syphilis incidence from the general population was also compared to HIV patients' data. Fifty-eight HIV-patients of the Infectious Diseases Unit of a tertiary hospital (5.2%) were diagnosed with syphilis during a three-year period (2008-2010). Highly active antiretroviral therapy (HAART) and coexistence of other STDs were independent predictors of syphilis (OR: 2.4, 95CI%: 1.26, 4.63, p=0.008; OR: 9.4, 95%CI: 4.49, 19.64, p<0.001, respectively). Origin from a country other than Greece (p=0.005), and homosexual contact (p=0.003), were separate risk factors for syphilis in the general population in the same area. Diagnosis of a sexually transmitted disease in an HIV patient is a crucial clinical event that should trigger the clinician's suspicion for high-risk sexual behavior. Sexual health assessments should be a routine process for HIV patients.


The effect of hyperbaric oxygen therapy on gene expression: microarray analysis on wound healing.
Hyperbaric oxygen (HBO2) therapy can have a positive effect on wound healing, angiogenesis and blood flow. No prior study has described the effects of HBO2 therapy and gene expression of this process. The goal of our research was to show the effects of HBO2 and its impact at the molecular level on angiogenesis, proliferation, differentiation, oxidative stress, inflammation, and extracellular matrix formation. Live animal subjects were used for simulating the process of wound healing under standard conditions and under the influence of HBO2. Two experimental groups were created using injured rabbits (N=24), one group (N=12) treated with hyperbaric therapy twice a day and one (N=12) with standard wound care management. Wounds were surgical, uninfected, and in healthy animal test subjects. We compared the whole genomic analysis of the transcriptome with the use of microarray technology at three intervals during treatment. The induction of the wounds in rabbit skin increased expression of hundreds of genes in both treatment groups. The numbers of elevated and decreased genes gradually reduced as the wound healed. Gene expression analysis showed elevated expression of several genes associated with inflammation in both groups of injured animals. Genes connected to the process of angiogenesis, proliferation, differentiation, oxidative stress and extracellular matrix formation were without statistically significant changes. The evidence did not support that HBO2 had any significant effect on gene expression during wound healing. Additionally, there was no evidence to support that there were changes in gene expression in either treatment group.


Inflammation, hemostasis, and the risk of kidney function decline in the Atherosclerosis Risk in Communities (ARIC) Study.
Inflammation and hemostasis may increase the risk of kidney function decline; however, data from prospective studies are sparse. The Atherosclerosis Risk in Communities (ARIC) Study, a prospective observational cohort. We used data from 14,854 middle-aged adults from 4 different US communities. Markers of inflammation and hemostasis were examined. The risk of kidney function decrease associated with these markers was studied. Glomerular filtration rate (GFR) was calculated from serum creatinine levels using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. Chronic kidney disease (CKD) was defined as: (1) a decrease in estimated GFR to less than 60 mL/min/1.73 m2 from greater than 60 mL/min/1.73 m2 at baseline, or (2) a hospitalization discharge or death coded for CKD. Serum creatinine was measured at baseline and the 3- and 9-year follow-up visits. Hazard ratios (HRs) of CKD associated with increased levels of inflammatory and hemostatic variables were estimated by using multivariate Cox proportional hazards regression. 1,787 cases of CKD developed between 1987 and 2004. After adjusting for demographics, smoking, blood pressure, diabetes, lipid levels, prior myocardial infarction, antihypertensive use, alcohol use, year of marker measurement, and baseline renal function using estimated GFR, the risk of incident CKD increased with increasing quartiles of white blood cell count (HR quartile 4 versus quartile 1, 1.30; 95% confidence interval [CI], 1.12 to 1.50; P trend = 0.001), fibrinogen (HR, 1.25; 95% CI, 1.09 to 1.44; P < 0.001), von Willebrand factor (HR, 1.46; 95% CI, 1.26 to 1.68; P < 0.001), and factor VIIIc (HR, 1.39; 95% CI, 1.20 to 1.60; P < 0.001). A strong inverse association was found between serum albumin level and risk of CKD (HR, 0.63; 95% CI, 0.55 to 0.72; P < 0.001). No independent association was found with factor VIIc level. Although we lacked a direct measure of kidney function, associations were robust to case definitions. Markers of inflammation and hemostasis are associated with greater risk of kidney function decrease. Findings suggest that inflammation and hemostasis are antecedent pathways for CKD.


The role of insulin receptor substrate 2 in hypothalamic and beta cell function.
Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.


Echogenic carotid artery plaques are associated with vertebral fractures in postmenopausal women with low bone mass.
Although low bone mass has been associated with atherosclerosis even after adjustment for age, little is known about the association between vertebral fractures and calcified atherosclerotic plaques. Our objective was to investigate whether osteoporotic vertebral fractures are independently related to the prevalence of atherosclerotic carotid plaques in postmenopausal women with low bone mass. We enrolled 195 postmenopausal women with osteopenia or osteoporosis. Bone mineral density and the presence of vertebral fractures were assessed. Intima media thickness and atherosclerotic plaques of the carotid artery were assessed using ultrasonography. Of the 195 subjects in the study, 84 had no plaques and 111 had at least one. The percentage of women with vertebral fractures was significantly higher in subjects with echogenic carotid plaques than in those without (27% vs. 11%, respectively; P < 0.05). However, there was no difference in the prevalence of vertebral fractures between women with echolucent plaques and those without (10.9% vs. 10.7%, respectively; P = nonsignificant). By logistic regression analysis with multivariate adjustment, age (P < 0.01), dyslipidemia (P < 0.05), and the presence of vertebral fracture (P < 0.05) were independent risk factors for echogenic carotid plaques. Osteoporotic vertebral fractures are associated with an increased risk of echogenic atherosclerotic plaques in postmenopausal women with low bone mass. It appears that the high association of echogenic atherosclerotic plaques and vertebral fractures could partially explain why osteoporotic vertebral fractures are linked to increased mortality.


Dermatoscopy in inflammatory and infectious skin disorders.
Dermatoscopy is a non-invasive technique that allows a rapid and magnified in vivo observation of the skin surface. By definition, it is performed with handheld devices (dermatoscopes) allowing X10 magnification. More expensive, computer-assisted digital systems (videodermatoscopes) may be equipped with lenses that ensure magnifications up to X1000; in this case the term videodermatoscopy is generally used. Dermatoscopy is mainly utilized for the evaluation of pigmented skin lesions, and has increasing applications in dermatology. In this paper the use of dermatoscopy in a variety of inflammatory (psoriasis, lichen planus, pityriasis lichenoides, rosacea, lichen sclerosus, Darier's disease, pigmented purpuric dermatoses) and infectious (human papillomaviruses infections, molluscum contagiosum, tinea capitis, tinea nigra, scabies, head and pubic lice, tungiasis, cutaneous leishmaniasis and cutaneous larva migrans) cutaneous disorders will be analyzed. In these conditions, dermatoscopy may assist the clinical diagnosis, reducing the need of semi-invasive or invasive procedures such as skin scrapings and/or biopsy. Depending on the disease, the choice to use low or high magnifications may be crucial. Dermatoscopy may also be useful for prognostic evaluation and monitoring of response to treatment, representing an important and relatively simple aid in daily clinical practice.


Synovial cell synthesis of a substance immunologically like cartilage proteinpolysaccharide.
Fluids from joints contain a substance that reacts immunologically like one of two known antigenic components of articular cartilage proteinpolysaccharide. This newly recognized substance occurs in the lining cells of synovial membranes as shown by indirect immunofluorescence. The localization of this substance in tissue culture cells derived from synovial membranes and its identification in the culture medium supports the suggestion that it is synthesized by lining cells. Rheumatoid synovial cells contain less of this substance.


Electromagnetic interference shielding with 2D transition metal carbides (MXenes).
Materials with good flexibility and high conductivity that can provide electromagnetic interference (EMI) shielding with minimal thickness are highly desirable, especially if they can be easily processed into films. Two-dimensional metal carbides and nitrides, known as MXenes, combine metallic conductivity and hydrophilic surfaces. Here, we demonstrate the potential of several MXenes and their polymer composites for EMI shielding. A 45-micrometer-thick Ti3C2Tx film exhibited EMI shielding effectiveness of 92 decibels (>50 decibels for a 2.5-micrometer film), which is the highest among synthetic materials of comparable thickness produced to date. This performance originates from the excellent electrical conductivity of Ti3C2Tx films (4600 Siemens per centimeter) and multiple internal reflections from Ti3C2Tx flakes in free-standing films. The mechanical flexibility and easy coating capability offered by MXenes and their composites enable them to shield surfaces of any shape while providing high EMI shielding efficiency.


Type 1 diabetes and low carbohydrate diets-Defining the degree of nutritional ketosis.
Adopting a low- or very low-carbohydrate (LCD or VLCD) diet in type 1 diabetes mellitus (T1D) is a controversial intervention. The main fear is that these diets may increase the risk of diabetic ketoacidosis. However, there is little data about the ketoacidosis risk and the level of physiological nutritional ketosis in individuals following these diets. We aimed to define the level of ketosis in those with T1D following carbohydrate restricted diets in a real-world observational study. Patients with T1D who had self-selected dietary carbohydrate restriction were enrolled from local clinics and were compared to those following an unrestricted regular carbohydrate control diet (RCCD). Participants completed a 3-day diary, documenting food intake, ketones, and blood/interstitial glucose concentrations. Participants were divided into three groups according to mean carbohydrate intake: VLCD (<50 g carbohydrates/day) n = 6, LCD (50-130 g carbohydrates/day) n = 6, and RCCD (>130 g carbohydrates/day) n = 3. Mean beta-hydroxybutyrate (BOHB) concentrations were 1.2 mmol/l (SD 0.14), 0.3 mmol/l (SD 0.12) and 0.1mmol/l (SD 0.05) in the VLCD, LCD and RCCD groups, respectively (p = 0.02). Post hoc Dunn test demonstrated this reached statistical significance between the VLCD and RCCD groups (p = 0.02). Carbohydrate restricted diets, in particular VLCDs, are associated with a higher BOHB level. However, the degree of ketosis seen is much lower than we expected, and significantly lower than the level typically associated with diabetic ketoacidosis. This may suggest the risk of ketoacidosis is lower than feared, although safety will need to be evaluated further in large scale randomised trials.


Drug-free patients with major depression show an increased electrophysiological response to valid and invalid feedback.
Depressed patients are biased in their response to negative information. They have been found to show a maladaptive behavioral and aberrant electrophysiological response to negative feedback. The aim of this study was to investigate the behavioral and electrophysiological response to feedback validity in drug-free depressed patients. Fifteen drug-free in-patients with unipolar major depression disorder (MDD) and 30 demographically matched controls performed a time-estimation task in which they received valid and invalid (i.e. related and unrelated to performance) positive and negative feedback. The number of behavioral adjustments to the feedback and the feedback-related negativity (FRN) were measured. Patients made fewer correct adjustments after valid negative feedback than controls, and their FRNs were larger. Neither patients nor controls adjusted their time estimates following invalid negative feedback. The FRN results suggest that depressed drug-free in-patients have an atypical rostral anterior cingulate response to feedback that is independent of feedback validity. Their behavioral response to invalid negative feedback, however, is not impaired. This study confirms the notion that the behavioral responses of depressed individuals to negative feedback are context dependent.


Dual-Antigen COVID-19 Vaccine Subcutaneous Prime Delivery With Oral Boosts Protects NHP Against SARS-CoV-2 Challenge.
We have developed a dual-antigen COVID-19 vaccine incorporating genes for a modified SARS-CoV-2 spike protein (S-Fusion) and the viral nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) to increase the potential for MHC class II responses. The vaccine antigens are delivered by a human adenovirus serotype 5 platform, hAd5 [E1-, E2b-, E3-], previously demonstrated to be effective in the presence of Ad immunity. Vaccination of rhesus macaques with the hAd5 S-Fusion + N-ETSD vaccine by subcutaneous prime injection followed by two oral boosts elicited neutralizing anti-S IgG and T helper cell 1-biased T-cell responses to both S and N that protected the upper and lower respiratory tracts from high titer (1 x 106 TCID50) SARS-CoV-2 challenge. Notably, viral replication was inhibited within 24 hours of challenge in both lung and nasal passages, becoming undetectable within 7 days post-challenge.


Identification of effective siRNA against K-ras in human pancreatic cancer cell line MiaPaCa-2 by siRNA expression cassette.
We shall construct the small interfering RNA (siRNA) expression cassette (SEC) targeting activated K-ras gene sequence, identify more effective siRNA sequence against K-ras gene in human pancreatic cancer cell line MiaPaCa-2 by SEC and reveal the anti-cancer effects of RNA interference (RNAi) and its therapeutic possibilities. Three different sites of SECs were constructed by PCR. K1/siRNA, K2/siRNA and K3/siRNA are located at sites 194, 491 and 327, respectively. They were transfected into MiaPaCa-2 cells by liposome to inhibit the expression of activated K-ras. In the interfering groups of sites 194 and 491, we detected the apoptosis in cells by FACS after they were incubated for 48 h, then we tested the alternation of K-ras gene in MiaPaCa-2 cells by RT-PCR immunofluorescence, respectively. Introduction of the K1/siRNA and K2/siRNA against K-ras into MiaPaCa-2 cells leads to increased apoptosis, and the number of apoptotic cells is increased compared with control cells. The tests of RT-PCR immunofluorescence show the effects of inhibiting expression of activated K-ras gene by RNA interference in the K1/siRNA and K2/siRNA groups. We also find that the introduction of K3/siRNA has no effect on MiaPaCa-2 cells. K1/siRNA and K2/siRNA can inhibit the expression of activated K-ras but K3/siRNA has no effect, demonstrating that K1/siRNA and K2/siRNA are effective sequences against K-ras gene and K3/siRNA are not. We conclude that specific siRNA against K-ras expression may be a powerful tool to be used therapeutically against human pancreatic cancer.


Chiral hetero- and carbocyclic compounds from the asymmetric hydrogenation of cyclic alkenes.
Several types of chiral hetero- and carbocyclic compounds have been synthesized by using the asymmetric hydrogenation of cyclic alkenes. N,P-Ligated iridium catalysts reduced six-membered cyclic alkenes with various substituents and heterofunctionality in good to excellent enantioselectivity, whereas the reduction of five-membered cyclic alkenes was generally less selective, giving modest enantiomeric excesses. The stereoselectivity of the hydrogenation depended more strongly on the substrate structure for the five- rather than the six-membered cyclic alkenes. The major enantiomer formed in the reduction of six-membered alkenes could be predicted from a selectivity model and isomeric alkenes had complementary enantioselectivity, giving opposite optical isomers upon hydrogenation. The utility of the reaction was demonstrated by using it as a key step in the preparation of chiral 1,3-cis-cyclohexane carboxylates.


Lipopolysaccharide-binding protein (LBP) blockade augments the protective effect of granulocyte colony-stimulating factor (G-CSF) in a rat sepsis model.
The effect of granulocyte colony-stimulating factor (G-CSF) on sepsis is discussed controversially in clinical studies. We previously demonstrated that G-CSF treatment induced lipopolysaccharide (LPS) sensitization via up-regulation of LPS-binding protein (LBP). We hypothesized that the futile effect of G-CSF-treatment in sepsis might be due to its ability to up-regulate LBP. Therefore, blockade of LBP may attenuate the G-CSF-induced LPS sensitization and protect animals from polymicrobial sepsis. Endogenous LBP levels were up-regulated by pretreatment with G-CSF, and the LBP protein was blocked by administration of a specific blocking peptide-LBPK95A. Polymicrobial sepsis was induced by intraperitoneal injection of feces slurry. Rats were monitored every 3 up to 72 h to observe the survival rate. Tissue injury, bacterial infiltration, local inflammatory response, and neutrophil infiltration at 0, 2, and 12 h after the septic insult were analyzed. The survival benefit of G-CSF pretreatment was improved when combined with LBPK95A treatment (control vs. G-CSF vs. combi: 36% vs. 56% vs. 93%; P < 0.05). Combined treatment of G-CSF and LBPK95A was associated with the minimal tissue damage. Treatment with LBPK95A significantly inhibited the neutrophil infiltration without interfering with the bacterial clearance. The G-CSF-induced inflammatory sensitization effect was inhibited by LBPK95A, indicated by the decrease of cytokines expression, and the activation of nuclear factor kappa B and signal transducer and activator of transcription 3 signaling pathway. In conclusion, these results suggested that the effect of prophylactic augmentation of the host's response via G-CSF pretreatment was further enhanced by inhibition of the up-regulation of LBP.


Pilot studies to demonstrate that intestinal mucosal afferent nerves are functionally linked to visceral adipose tissue.
Dietary capsaicin reduces rodent visceral fat weight. We tested the hypothesis that intact intestinal mucosal afferent nerve function is necessary for fat deposition in visceral adipose tissue sites. Rats were treated daily for 2 weeks with intragastric (chronic treatment) vehicle or capsaicin. Superior mesenteric artery blood flow and mesenteric and inguinal fat blood flow were measured before and after capsaicin was administered into the duodenum (acute treatment). Fat from all sites was dissected and weighed. Chronic capsaicin significantly attenuated acute capsaicin-induced mesenteric hyperemia but did not abolish the reflex wiping of the eye exposed to capsaicin, indicating that functional ablation was limited to the intestinal mucosal afferent nerves. The associated vasoconstriction in adipose tissue was inhibited at the visceral (mesenteric) site and maintained but attenuated at the subcutaneous (inguinal) site. The onset of vasoconstriction was instantaneous, indicating a reflex mechanism. There was a redistribution of fat from visceral to subcutaneous sites, reflected by a decrease and an increase in the percentage of body fat in the visceral and subcutaneous sites, respectively. These pilot studies reveal for the first time that normal intestinal mucosal afferent nerve function is necessary for the physiologic accumulation of fat in visceral adipose tissue sites.


Binding and functional characterization of alpha-2 adrenergic receptor subtypes on pig vascular endothelium.
Alpha-2 adrenergic receptor subtypes were characterized in membranes of pig vascular endothelium using [3H]rauwolscine. Alpha-2 adrenergic receptor subtypes that mediate endothelium-dependent vascular relaxation were studied in vitro by using ring segments of pig epicardial coronary arteries. Specific [3H]rauwolscine binding in endothelial membranes was saturable and to a single class of high-affinity sites with a mean KD of 0.217 +/- 0.05 nM and Bmax of 156 +/- 28 fmol/mg of protein. Nonlinear regression analysis indicated that competition binding curves for drugs that distinguish the alpha-2A adrenergic receptor subtype from the alpha-2C adrenergic receptor subtype fit best to two-site binding models. Kl values for drugs in binding to endothelial alpha-2 adrenergic receptors correlated well with their Kl values for alpha-2A (r = .98) and alpha-2C (r = .97) adrenergic receptor subtypes identified in other tissues. Vascular endothelium contained 23% alpha-2A and 77% alpha-2C adrenergic receptors. In the presence of indomethacin, the rank order of potency for agonists that cause endothelium-dependent vascular relaxation was p-iodoclonidine > clonidine > UK-14,304 > guanabenz > epinephrine > norepinephrine. KB values for antagonist inhibition of epinephrine-induced, endothelium-dependent vascular relaxation correlated best with Kl values for antagonist binding at the alpha-2A adrenergic receptor subtype. These results suggest that the alpha-2A and alpha-2C adrenergic receptor subtypes are present on pig vascular endothelium and that the alpha-2A adrenergic receptor subtype mediates indomethacin-insensitive, endothelium-dependent relaxation of pig epicardial coronary arteries.


Awareness and perception of heart failure among European cardiologists, internists, geriatricians, and primary care physicians.
To assess awareness of heart failure (HF) management recommendations in Europe among cardiologists (C), internists and geriatricians (I/G), and primary care physicians (PCPs). The Study group on HF Awareness and Perception in Europe (SHAPE) surveyed randomly selected C (2041), I/G (1881), and PCP (2965) in France, Germany, Italy, the Netherlands, Poland, Romania, Spain, Sweden, and the UK. Each physician completed a 32-item questionnaire about the diagnosis and treatment of HF (left ventricular ejection fraction <40%). This report provides an analysis of HF awareness among C, I/G, and PCP. Seventy-one per cent I/G and 92% C use echocardiography, and 43% I/G and 82% C use echo-Doppler as a routine diagnostic test (both P < 0.0001). In contrast, 75% PCP use signs and symptoms to diagnose HF. Fewer I/G would use an angiotensin-converting enzyme (ACE)-inhibitor in >90% of their patients (64 vs. 82% C, P < 0.0001), whereas only 47% PCP would routinely prescribe an ACE-inhibitor. Worsening HF was considered a risk of ACE-inhibitor therapy by 35% PCP. I/G and PCP consistently do not prescribe target ACE-inhibitor doses (P < 0.0001 vs. C). Only 39% I/G would use a beta-blocker in >50% of their patients (vs. 73% C, P < 0.0001). Also, only 5% PCP would always, and 35% often, prescribe a beta-blocker and reach target doses in only 7-29%. Moreover, 34% PCP and 26% I/G vs. 11% C (P < 0.0001) do not start a beta-blocker in patients with mild HF, who are already on an ACE-inhibitor and are on diuretic. In mild, stable HF, 39% PCP and 18% I/G would only prescribe diuretics, vs. 7% C (P < 0.0001). In patients with worsening HF in sinus rhythm and on an optimal ACE-inhibitor, beta-blockade and diuretics, significantly more C would add spironolactone, but I/G would more often add digoxin. Although each physician group lacks complete adherence to guideline-recommended management strategies, these are used significantly less well by I, G, and PCPs, indicating the need for education of these essential healthcare providers.


Reliability and validity of gait analysis by android-based smartphone.
Smartphones are very common devices in daily life that have a built-in tri-axial accelerometer. Similar to previously developed accelerometers, smartphones can be used to assess gait patterns. However, few gait analyses have been performed using smartphones, and their reliability and validity have not been evaluated yet. The purpose of this study was to evaluate the reliability and validity of a smartphone accelerometer. Thirty healthy young adults participated in this study. They walked 20 m at their preferred speeds, and their trunk accelerations were measured using a smartphone and a tri-axial accelerometer that was secured over the L3 spinous process. We developed a gait analysis application and installed it in the smartphone to measure the acceleration. After signal processing, we calculated the gait parameters of each measurement terminal: peak frequency (PF), root mean square (RMS), autocorrelation peak (AC), and coefficient of variance (CV) of the acceleration peak intervals. Remarkable consistency was observed in the test-retest reliability of all the gait parameter results obtained by the smartphone (p<0.001). All the gait parameter results obtained by the smartphone showed statistically significant and considerable correlations with the same parameter results obtained by the tri-axial accelerometer (PF r=0.99, RMS r=0.89, AC r=0.85, CV r=0.82; p<0.01). Our study indicates that the smartphone with gait analysis application used in this study has the capacity to quantify gait parameters with a degree of accuracy that is comparable to that of the tri-axial accelerometer.


Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and in its experimental autoimmune model.
Peroxidase-conjugated alpha-bungarotoxin (P-BGT) was used for the ultrastructural localization of the acetylcholine receptor in end-plates in external intercostal muscles of four patients with myasthenia gravis, in forelimb digit extensor muscles of rats with advanced chronic experimental autoimmune myasthenia gravis, and in suitable human and rat controls. In control end-plates, the previously reported localization of acetylcholine receptor on the terminal expansions of the postsynaptic folds and, in traces, on the presynaptic membrane was confirmed. By contrast, in myasthenia gravis some postsynaptic regions bound no P-BGT; in other regions, the folds displayed only faint traces of the reaction product, or only some segments of the postsynaptic membrane showed the reaction product; finally, in some regions there was no apparent decrease in reaction product. In general, those postsynaptic regions showing the greatest decrease in P-BGT binding were also the simplest or showed the most degenerative changes, and the presynaptic staining was decreased in proportion to the decrease in the adjacent postsynaptic P-BGT binding. In the experimental animals, the abnormalities in the amount and distribution of the acetylcholine receptor were essentially like those in the more severely affected patients. Morphometric estimates of the postsynaptic acetylcholine receptor surface correlated well with the patients' clinical status and linearly with the miniature end-plate potential amplitude.


Screening bioactive compounds from natural product and its preparations using capillary electrophoresis.
Bioactive ingredients of natural products can protect human body from harm, as well as prevent and treat disease. Screening bioactive compounds from natural products is attracting particular attention. It is a great challenge to separate and detect the active compounds from complex matrix natural products. CE plays a vital role in screening active compounds because of its unique features such as high-efficiency separation, short-analysis time, minimal sample consumption, and ease to realize automatization etc. Additionally, CE has been developed various modes owing to its abundant advantages in analysis and separation of compounds. The purpose of this work is to review previous developments and applications of CE in screening bioactive compounds derived from natural products from 2007 to 2017. This review does not only summarize the traditional methods of detecting active ingredients but also briefly introduces some novel assays. The trends in the application of CE in active compounds screening are addressed in the article.


Positive expression of ERCC1 predicts a poorer platinum-based treatment outcome in Chinese patients with advanced non-small-cell lung cancer.
The goal of this study is to determine role of excision repair cross-complementing group 1 gene (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) expression in predicting response and survival in Chinese patients with advanced stage non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. Formalin-fixed, paraffin-embedded biopsy tissues were retrospectively obtained from 124 advanced NSCLC patients. Protein expression levels of ERCC1 and RRM1 were determined by immunohistochemistry (IHC). Associations between expression of ERCC1 and RRM1 and clinic-pathologic parameters were analyzed. The study shows that ERCC1 and RRM1 expression was detected in 43 (35%) and 50 (40%) of the 124 tumor samples, respectively. Expression of ERCC1 and RRM1 was negatively associated with tumor response. Fifty-four percent patients whose tumors did not express ERCC1 had partial response (PR) compared to 33% whose tumors expressed the protein (P = 0.022). Similarly, 54% patients whose tumor did not express RRM1 had PR compared to 36% whose tumors expression the protein (P = 0.042). Further, patients whose tumors lacked of ERCC1 but not RRM1 expression had a longer median survival time than those tumors expressed ERCC1 (13.4 months versus 9.1 months; P = 0.006), which is independent of other prognostic factors (P = 0.0066). In conclusion, tumor ERCC1 expression is associated with tumor response and patients' survival in Chinese advanced NSCLC patients treated with platinum-based regimen and may serve as a biomarker in predicting tumor response and clinical outcome in the patient population.


Current status on plastic scintillators modifications.
Recent developments of plastic scintillators are reviewed, from 2000 to March 2014, distributed in two different chapters. First chapter deals with the chemical modifications of the polymer backbone, whereas modifications of the fluorescent probe are presented in the second chapter. All examples are provided with the scope of detection of various radiation particles. The main characteristics of these newly created scintillators and their detection properties are given.


Obesity does not impact outcomes for appendicitis.
Obesity has long been considered a risk factor for surgery. The purpose of this study was to evaluate the impact of obesity on outcomes after appendectomy. A retrospective study was performed using discharge abstract data obtained from patients with documented body mass index (BMI) undergoing appendectomy for appendicitis (n = 2919). Complications and length of stay for different BMI categories were compared. Obese patients (BMI > 30 kg/m(2)) had similar rates of perforation (20%) and were as likely to undergo a laparoscopic approach (85%) as nonobese patients. On multivariable and univariate analysis, no significant differences were observed when comparing obese and nonobese patients for the outcomes of length of stay, infectious complications, and need for readmission. On multivariate analysis, laparoscopy predicted lower complication rates and decreased length of stay. In this study, obesity did not significantly impact rates of perforation, operative approach, length of stay, infectious complications, or readmission.


[Parodontal tissues microcirculatory status of the abutment teeth in cases of restricted dentition defect prosthetic treatment].
The study of the parodontal tissues microcirculatory status of the abutment teeth in restricted dentition defect has established that microvessel reaction in gingival tissues at the stage of supporting teeth preparation was accompanied by development of congestion development in microcirculatory bed that was relieved in 2 weeks in intact parodontium and in case of its inflammation--increased even greater. Functional loading of supporting teeth in case of restricted dentition defect prosthetic treatment with bridge constructions led to congestive hyperemia in gingival microcirculatory bed that was relieved in 1-3 months depending upon the parodontium status.


Subependymal giant cell astrocytoma: a clinicopathologic study with HMB45 and MIB-1 immunohistochemical analysis.
Subependymal giant cell astrocytomas (SEGAs) occur in approximately 6% of patients with tuberous sclerosis (TS) and are often considered to be a forme fruste or partial expression of this disorder. Recently, a number of other TS-associated lesions, including pulmonary and uterine lymphangiomyomatosis, renal angiomyolipoma, and cardiac rhabdomyoma, were shown to stain with the monoclonal antibody HMB45, suggesting a pathogenetic relationship among these lesions. Seven SEGAs in six patients (three men and three women; age range, 2-55 yr; mean, 24 yr) were studied. Cutaneous and other central nervous system features of TS were present in two patients. All of the SEGAs were intraventricular in location and were characterized by large, round, eosinophilic and spindle-shaped cells, with nuclear pseudoinclusions and mild nuclear pleomorphism, arranged in a vaguely perivascular pattern. All of the SEGAs were negative with HMB45 immunostaining. MIB-1 immunostaining was also performed in all of the cases, and MIB-1 indices (the percentage of MIB-1-positive nuclei) ranged from 0.1 to 3.8 (mean, 1.1). Two patients required an additional surgical procedure for residual/recurrent tumor; three patients are alive without evidence of disease 5 to 11 years after diagnosis; and one patient was lost to follow-up. SEGAs are generally slowly growing intraventricular neoplasms, as evidenced by their low MIB-1 labeling. Unlike other TS-associated lesions, SEGAs do not stain with HMB45.


Clinical and Pain-Related Characteristics of Idiopathic First Bite Syndrome Induced by Taste in Japanese Patients without Diabetes: A Retrospective Study of Five Cases.
First bite syndrome (FBS) is a condition in which the first bite of each meal causes parotid pain. Etiologies of FBS include prior surgery of the upper cervical region and, rarely, head and neck tumors. Idiopathic FBS rarely presents in patients without a history of surgery or evidence of an underlying tumor. Idiopathic FBS may be categorized into two subtypes: that in patients with diabetes and that in patients without diabetes. Idiopathic FBS in patients without diabetes may be overlooked or misdiagnosed because the condition has been described only in a few case reports. We aimed to identify the clinical and pain-related characteristics of idiopathic FBS in patients without diabetes. We retrospectively analyzed the clinical data of five patients without diabetes who were diagnosed with idiopathic FBS in our department between January 2010 and December 2016. Four of the five patients were female, and the overall median age was 52 years (range: 13-61). All patients immediately experienced parotid pain upon tasting food without chewing. Addition of an acidic solution to the ipsilateral posterior third of the tongue evoked parotid pain. The median degree of pain intensity and interference with eating due to pain was 9 (range: 3-10) and 9 (range: 5-10) on a numerical rating scale of 0-10, respectively. Idiopathic FBS was bilateral in two patients. Two patients had tenderness on mild pressure over the affected parotid region. Two patients presented with ipsilateral idiopathic Horner's syndrome. Our findings indicate that the characteristics of idiopathic FBS in patients without diabetes are largely consistent with those previously reported in postoperative FBS, supporting the notion that idiopathic FBS is a subtype of FBS. Thus, it is necessary to consider idiopathic FBS during the evaluation of facial pain triggered at the beginning of a meal.


Prognostic value of FDG-PET radiomics with machine learning in pancreatic cancer.
Patients with pancreatic cancer have a poor prognosis, therefore identifying particular tumor characteristics associated with prognosis is important. This study aims to investigate the utility of radiomics with machine learning using 18F-fluorodeoxyglucose (FDG)-PET in patients with pancreatic cancer. We enrolled 161 patients with pancreatic cancer underwent pretreatment FDG-PET/CT. The area of the primary tumor was semi-automatically contoured with a threshold of 40% of the maximum standardized uptake value, and 42 PET features were extracted. To identify relevant PET parameters for predicting 1-year survival, Gini index was measured using random forest (RF) classifier. Twenty-three patients were censored within 1 year of follow-up, and the remaining 138 patients were used for the analysis. Among the PET parameters, 10 features showed statistical significance for predicting overall survival. Multivariate analysis using Cox HR regression revealed gray-level zone length matrix (GLZLM) gray-level non-uniformity (GLNU) as the only PET parameter showing statistical significance. In RF model, GLZLM GLNU was the most relevant factor for predicting 1-year survival, followed by total lesion glycolysis (TLG). The combination of GLZLM GLNU and TLG stratified patients into three groups according to risk of poor prognosis. Radiomics with machine learning using FDG-PET in patients with pancreatic cancer provided useful prognostic information.


Chronic stability of a neuroprosthesis comprising multiple adjacent Utah arrays in monkeys.
Objective. Electrical stimulation of visual cortex via a neuroprosthesis induces the perception of dots of light ('phosphenes'), potentially allowing recognition of simple shapes even after decades of blindness. However, restoration of functional vision requires large numbers of electrodes, and chronic, clinical implantation of intracortical electrodes in the visual cortex has only been achieved using devices of up to 96 channels. We evaluated the efficacy and stability of a 1024-channel neuroprosthesis system in non-human primates (NHPs) over more than 3 years to assess its suitability for long-term vision restoration.Approach.We implanted 16 microelectrode arrays (Utah arrays) consisting of 8 × 8 electrodes with iridium oxide tips in the primary visual cortex (V1) and visual area 4 (V4) of two sighted macaques. We monitored the animals' health and measured electrode impedances and neuronal signal quality by calculating signal-to-noise ratios of visually driven neuronal activity, peak-to-peak voltages of the waveforms of action potentials, and the number of channels with high-amplitude signals. We delivered cortical microstimulation and determined the minimum current that could be perceived, monitoring the number of channels that successfully yielded phosphenes. We also examined the influence of the implant on a visual task after 2-3 years of implantation and determined the integrity of the brain tissue with a histological analysis 3-3.5 years post-implantation.Main results. The monkeys remained healthy throughout the implantation period and the device retained its mechanical integrity and electrical conductivity. However, we observed decreasing signal quality with time, declining numbers of phosphene-evoking electrodes, decreases in electrode impedances, and impaired performance on a visual task at visual field locations corresponding to implanted cortical regions. Current thresholds increased with time in one of the two animals. The histological analysis revealed encapsulation of arrays and cortical degeneration. Scanning electron microscopy on one array revealed degradation of IrOxcoating and higher impedances for electrodes with broken tips.Significance. Long-term implantation of a high-channel-count device in NHP visual cortex was accompanied by deformation of cortical tissue and decreased stimulation efficacy and signal quality over time. We conclude that improvements in device biocompatibility and/or refinement of implantation techniques are needed before future clinical use is feasible.


[Psychosis associated to megacisterna magna].
Megacisterna magna is a developmental malformation of the middle-line brain structures, which exists along a continuum with cerebellum hypoplasia (Dandy-Walker variant) and cerebellum agenesia (Dandy-Walker syndrome). Psychotic disorders, and particularly schizophrenia, are now conceptualised as disorders of neurodevelopment. We report on a patient who presented a psychotic disorder (delusional type), and mega cisterna magna. This is the first report of such an association, and it is suggested that both the psychotic disorder and the mega cisterna magna may be the expression of a single underlying neurodevelopment abnormality.


Distribution of [2-14C]merbarone in mice by autoradiography of whole-body cryosections.
The distribution of radiolabel in male mice was studied by autoradiography of whole-body cryosections at intervals during 24 h after i.v. injection (46.6 mg/kg) and during 4 h after oral administration (140 mg/kg) of [2-14C]merbarone. Following injection, radioactivity levels in the blood and highly vascular tissues declined to 8 h at which time only low levels were present in the systemic circulation. Only very low levels were seen in the brain and spinal cord at 0.5-3 min after dosing and levels were barely above background in autoradiograms obtained at 0.5-1 h. Radiolabel was concentrated in those regions which lack an effective blood-brain barrier particularly within the choroid plexuses. Radioactivity was rapidly taken up by the liver and kidneys and as the blood and body radioactivity levels decreased, these organs remained densely labeled. Significant biliary excretion had occurred by 30 min and the autoradiograms to 24 h showed radiolabeled compounds in the intestinal lumen. Between 1 and 8 h, the liver exhibited a stippled appearance as a result of labeling around branches of the portal vein due to enterohepatic recycling. The stippling was substantially diminished at 16 h. High levels of radioactivity were present in the kidney at 0.5-3 min after injection with both the kidney cortex and medulla initially densely labeled. At 4 h and thereafter, the radioactivity levels in the kidney were lower with most of the labeled compounds in the medulla. Accumulation in the liver and kidney was very low at 16-24 h after dosing and most of the merbarone dose had cleared from the body. Rapid absorption of merbarone occurred after oral administration with radiolabel first observed in the liver and kidney at 3-6 min after dosing. Peak levels in these organs and systemically were seen between 0.5 and 2 h. At 4 h, the radioactivity had largely cleared from the systemic circulation. The liver exhibited a stippled appearance soon after oral dosing similar to that observed following i.v. dosing affording evidence for enterohepatic recycling after i.v. administration. The relatively low systemic levels observed after oral dosing suggests that the liver binds much of the absorbed drug and its metabolites limiting the levels which reach the systemic circulation.


Carbene-mediated synthesis of a germanium tris(dithiolene)dianion.
While the 1 : 1 reaction of 3 with an N-heterocyclic carbene ({(Me)CN(i-Pr)}2C:) in THF resulted in ligand-substituted product 4, the corresponding 1 : 2 reaction (in the presence of H2O) gives the first structurally characterized germanium tris(dithiolene)dianion 5 as the major product and the "naked" dithiolene radical 6˙ as a minor by-product. The structure and bonding of 4 and 5 were probed by experimental and theoretical methods. Our study suggests that carbene-mediated partial hydrolysis may represent a new method to access tris(dithiolene) complexes of main-group elements.


Removal of uraemic plasma factor(s) using different dialysis modalities reduces phosphatidylserine exposure in red blood cells.
Solute(s) retained during uraemia cause increased exposure of aminophospholipid phosphatidylserine (PS) on the outer surface of erythrocyte membranes, and this phenomenon may be involved in the pathophysiology of uraemia by promoting abnormal erythrocyte interactions. We examined in a prospective randomized cross-over fashion the ability of various dialysis modalities to remove the circulating uraemic factor(s) causing increased PS externalization in red cells. Each patient was treated with haemodialysis (HD) and with on-line haemodiafiltration (HDF) using standard high-flux polysulphone membranes or with the new polisulphone-based Helixone membrane to compare the effects of dialysis technique and membrane type on PS exposure. Removal of PS was assessed indirectly by measuring PS-expressing normal erythrocytes exposed to uraemic plasma or to ultrafiltrate obtained at various time points during the extracorporeal session. Removal of the uraemic plasma factor(s) causing PS exposure was demonstrated by the reduced ability of uraemic plasma at the end of dialysis to induce PS exposure in normal erythrocytes, and by the capacity of ultrafiltrate from the dialysate side of the dialyzer membrane to markedly increase PS-positive red cells. However, the degree of removal varied according to the dialyzer type and to dialysis technique. Removal was greater for on-line HDF using the Helixone membrane, intermediate and comparable with HD with Helixone and with on-line HDF using standard polysulphone, and lower for HD using polysulphone membrane. The putative uraemic compound causing PS exposure seems to be highly lipophilic, somehow associated with plasma proteins, and apparently having a molecular weight between 10 and 10.8 kDa. Uraemia is associated with retention of compound(s) that are lipophilic, possibly protein-bound and which cause an abnormal exposure of PS in erythrocytes. Our findings, that such compound(s) can be removed during dialysis and at higher rates with convection techniques, indicate a potential benefit for uraemic patients. The present results also seem to confirm the marked ability of high-flux Helixone membranes to eliminate high molecular weight solutes.


Postsynaptic modifications in long-term facilitation in Aplysia: upregulation of excitatory amino acid receptors.
Long-term sensitization of the gill and siphon withdrawal in Aplysia is accompanied by facilitation of sensorimotor synaptic connections that depends on new protein synthesis. This phenomenon has been previously shown to involve presynaptic growth. At the postsynaptic level, a reorganization should occur to parallel the formation of new synaptic contacts. We show here that 24 hr following an application of 5-HT, which produces long-term synaptic facilitation (LTF), the response of the motoneuron to an excitatory amino acid agonist of the synaptic receptors is increased. General inhibition of protein synthesis with anisomycin blocks this enhancement. Inhibiton of protein synthesis limited to the postsynaptic neuron by intracellular injection of gelonin, a ribosome-inactivating toxin, also blocks the increase in the response to the agonist but fails to block 24 hr LTF. These results are compatible with a model of LTF that involves coordinate pre- and postsynaptic changes. The latter may include an upregulation of functional postsynaptic receptors. These may not be initially required for LTF measured at a 24 hr time point, but could become necessary for later stages of LTF. An increase in the number of functional postsynaptic receptors in a reserve pool may also prime the postsynaptic neuron for subsequent learning-associated plasticity.


Steady boundary layer slip flow along with heat and mass transfer over a flat porous plate embedded in a porous medium.
In this paper, a simplified model of an incompressible fluid flow along with heat and mass transfer past a porous flat plate embedded in a Darcy type porous medium is investigated. The velocity, thermal and mass slip conditions are utilized that has not been discussed in the literature before. The similarity transformations are used to transform the governing partial differential equations (PDEs) into a nonlinear ordinary differential equations (ODEs). The resulting system of ODEs is then reduced to a system of first order differential equations which was solved numerically by using Matlab bvp4c code. The effects of permeability, suction/injection parameter, velocity parameter and slip parameter on the structure of velocity, temperature and mass transfer rates are examined with the aid of several graphs. Moreover, observations based on Schmidt number and Soret number are also presented. The result shows, the increase in permeability of the porous medium increase the velocity and decrease the temperature profile. This happens due to a decrease in drag of the fluid flow. In the case of heat transfer, the increase in permeability and slip parameter causes an increase in heat transfer. However for the case of increase in thermal slip parameter there is a decrease in heat transfer. An increase in the mass slip parameter causes a decrease in the concentration field. The suction and injection parameter has similar effect on concentration profile as for the case of velocity profile.


The revised Approved Instructional Resources score: An improved quality evaluation tool for online educational resources.
Free Open-Access Medical education (FOAM) use among residents continues to rise. However, it often lacks quality assurance processes and residents receive little guidance on quality assessment. The Academic Life in Emergency Medicine Approved Instructional Resources tool (AAT) was created for FOAM appraisal by and for expert educators and has demonstrated validity in this context. It has yet to be evaluated in other populations. We assessed the AAT's usability in a diverse population of practicing emergency medicine (EM) physicians, residents, and medical students; solicited feedback; and developed a revised tool. As part of the Medical Education Translational Resources: Impact and Quality (METRIQ) study, we recruited medical students, EM residents, and EM attendings to evaluate five FOAM posts with the AAT and provide quantitative and qualitative feedback via an online survey. Two independent analysts performed a qualitative thematic analysis with discrepancies resolved through discussion and negotiated consensus. This analysis informed development of an initial revised AAT, which was then further refined after pilot testing among the author group. The final tool was reassessed for reliability. Of 330 recruited international participants, 309 completed all ratings. The Best Evidence in Emergency Medicine (BEEM) score was the component most frequently reported as difficult to use. Several themes emerged from the qualitative analysis: for ease of use-understandable, logically structured, concise, and aligned with educational value. Limitations include deviation from questionnaire best practices, validity concerns, and challenges assessing evidence-based medicine. Themes supporting its use include evaluative utility and usability. The author group pilot tested the initial revised AAT, revealing a total score average measure intraclass correlation coefficient (ICC) of moderate reliability (ICC = 0.68, 95% confidence interval [CI] = 0 to 0.962). The final AAT's average measure ICC was 0.88 (95% CI = 0.77 to 0.95). We developed the final revised AAT from usability feedback. The new score has significantly increased usability, but will need to be reassessed for reliability in a broad population.


Allergic bronchopulmonary aspergillosis: a case report and comment on reliability of testing sources.
A case of allergic bronchopulmonary aspergillosis (ABPA) is presented. Difficulty in establishing the diagnosis occurred because of a false-negative precipitin result obtained from a commercial laboratory. This would seem to support the contention that the paucity of ABPA cases reported in the United States is secondary to the low potency and variable composition of commercial antigens available for skin tests and immunodiffusion, resulting in false-negative skin and precipitin tests. Furthermore, positive tests to species of Aspergillus other than fumigatus heretofore considered non-pathogenic must now be considered as possible etiologic explanations.


Internet addiction in young people.
In our technology-savvy population, mental health professionals are seeing an increasing trend of excessive Internet use or Internet addiction. Researchers in China, Taiwan and Korea have done extensive research in the field of Internet addiction. Screening instruments are available to identify the presence of Internet addiction and its extent. Internet addiction is frequently associated with mental illnesses such as anxiety, depression, conduct disorder and attention deficit hyperactivity disorder (ADHD). Treatment modalities include individual and group therapies, cognitive behavioural therapy (CBT), family therapy and psychotropic medications. A significant proportion of Singapore adolescents engaging in excessive Internet use are also diagnosed to have concomitant Internet addiction. Despite the presence of a variety of treatment options, future research in this area is needed to address its growing trend and to minimise its negative psychological and social impact on the individuals and their families.


Causes of hyperglycemia and hypoglycemia in adult inpatients.
The underlying causes of hyperglycemia and hypoglycemia in adult medical and surgical inpatients were studied. Hyperglycemic and hypoglycemic events occurring in adult medical and surgical patients admitted between February and July 2003 to a tertiary care hospital were identified prospectively from automated daily printouts of abnormal blood glucose levels generated by the hospital laboratory. Information on the causes of a random sample of events was ascertained within 24 hours through chart review and provider and patient interviews. Narratives were presented to an expert committee to assess the causes of each event and preventability. Eighteen of 24 hypoglycemic events and 26 of 26 hyperglycemic episodes were considered preventable. Failure to adjust antidiabetic drugs in response to decreases in oral intake and unexpected deviation from normal hospital routine were the most common factors contributing to hypoglycemia. Hyperglycemia was most often associated with an unwillingness of providers to take responsibility for diabetes management and the exclusive use of sliding-scale insulin regimens. Hyperglycemia and hypoglycemia in medical and surgical inpatients were mostly related to inadequate prescribing, monitoring, and communication practices.