Distribution Pattern, Emission Characteristics and Environmental Impact of Polycyclic Aromatic Hydrocarbons (PAHs) in Download Ash and Dust from Iron and Steel Enterprise.
Download ash and emission dust samples were collected from sintering, coking, ironmaking and steelmaking processes of iron and steel enterprises in Laiwu. Sixteen kinds of polycyclic aromatic hydrocarbons (PAHs) in the United States Environmental Protection Agency (USEPA) priority controlled lists were quantitatively analyzed using Gas Chromatography-Mass Spectrometer (GC-MS). Laser particle size analyzer was used to obtain the distribution pattern of download ash. It was found that the diameter distribution pattern from four production processes was quite different. The proportion of fine particulate (0-2.5 μm) was the highest (72.62%) in the steelmaking refining process, and was 28.962% in the ironmaking process. Moreover, the particle size in download ash from steelmaking refining is all less than 10 μm and that from the ironmaking process was 52.92%. The medium-sized particles (10-100 μm) were dominant in sinter and coking download ashes. The total PAHs (∑16PAHs) mass concentration ranged from 0.49 ± 0.06 to 69.63 ± 5.57 μg·g-1 in download ash samples, and varied from 2.815 ± 0.253 to 19.429 ± 2.545 μg·m-3 in emission dust samples. The ∑16PAHs values were both largest in download ash and dust emission from the coking process (69.63 ± 5.57 μg·g-1 and 19.429 ± 2.545 μg·m-3, respectively). The most abundant individual PAHs were benzo[b]fluoranthene, benzo[k]fluoranthene, phenanthrene, benzo[a]anthracene in ash samples, and benzo[a]anthracene, benzo[k]fluoranthene, benzo[b]fluoranthene and indeno[1,2,3-cd]pyrene in emission dust samples. Dominant compounds were high-molecular weight (four- to six-ring) PAHs in both ash and dust samples. The concentration order of individual compounds in PM10 and PM2.5 in ambient air around the steel plant was completely consistent with each other, and the concentration of ∑16PAHs was the highest in the steel plant and lowest in Daqin village because of upwind of the steel plant. The concentrations of benzo[b]fluoranthene and fluoranthene in ambient air were comparatively high, and were in accordance with the higher concentration of the two monomers in the download ash samples, which suggested that the effect of the emission flue gas from the steel plant on ambient air was necessary to concern.


Mortality by cause for eight regions of the world: Global Burden of Disease Study.
Reliable information on causes of death is essential to the development of national and international health policies for prevention and control of disease and injury. Medically certified information is available for less than 30% of the estimated 50.5 million deaths that occur each year worldwide. However, other data sources can be used to develop cause-of-death estimates for populations. To be useful, estimates must be internally consistent, plausible, and reflect epidemiological characteristics suggested by community-level data. The Global Burden of Disease Study (GBD) used various data sources and made corrections for miscoding of important diseases (eg, ischaemic heart disease) to estimate worldwide and regional cause-of-death.patterns in 1990 for 14 age-sex groups in eight regions, for 107 causes. Preliminary estimates were developed with available vital-registration data, sample-registration data for India and China, and small-scale population-study data sources. Registration data were corrected for miscoding, and Lorenz-curve analysis was used to estimate cause-of-death patterns in areas without registration. Preliminary estimates were modified to reflect the epidemiology of selected diseases and injuries. Final estimates were checked to ensure that numbers of deaths in specific age-sex groups did not exceed estimates suggested by independent demographic methods. 98% of all deaths in children younger than 15 years are in the developing world. 83% and 59% of deaths at 15-59 and 70 years, respectively, are in the developing world. The probability of death between birth and 15 years ranges from 22.0% in sub-Saharan Africa to 1.1% in the established market economies. Probabilities of death between 15 and 60 years range from 7.2% for women in established market economies to 39.1% for men in sub-Saharan Africa. The probability of a man or woman dying from a non-communicable disease is higher in sub-Saharan Africa and other developing regions than in established market economies. Worldwide in 1990, communicable, maternal, perinatal, and nutritional disorders accounted for 17.2 million deaths, non-communicable diseases for 28.1 million deaths and injuries for 5.1 million deaths. The leading causes of death in 1990 were ischaemic heart disease (6.3 million deaths), cerebrovascular accidents (4.4 million deaths), lower respiratory infections (4.3 million), diarrhoeal diseases (2.9 million), perinatal disorders (2.4 million), chronic obstructive pulmonary disease (2.2 million), tuberculosis (2.0 million), measles (1.1 million), road-traffic accidents (1.0 million), and lung cancer (0.9 million). Five of the ten leading killers are communicable, perinatal, and nutritional disorders largely affecting children. Non-communicable diseases are, however, already major public health challenges in all regions. Injuries, which account for 10% of global mortality, are often ignored as a major cause of death and may require innovative strategies to reduce their toll. The estimates by cause have wide Cls, but provide a foundation for a more informed debate on public-health priorities.


Spatial Organization of Slit-Confined Melts of Ring Polymers with Nonconserved Topology: A Lattice Monte Carlo Study.
We present Monte Carlo computer simulations for melts of semiflexible randomly knotted and randomly concatenated ring polymers on the fcc lattice and in slit confinement. Through systematic variation of the slit width at fixed melt density, we explore the influence of confinement on single-chain conformations and interchain interactions. We demonstrate that confinement makes chains globally larger and more elongated while enhancing both contacts and knottedness propensities. As for multichain properties, we show that ring-ring contacts decrease with the confinement, yet neighboring rings overlap more as confinement grows. These aspects are accompanied by a marked decrease in the links formed between pairs of neighboring rings. In connection with the quantitative relation between links and entanglements in polymer melts recently established by us [Ubertini M. A.; Rosa A.Macromolecules2023, 56, 3354-3362], we propose that confinement can be used to set polymer networks that act softer under mechanical stress and suggest a viable experimental setup to validate our results.


Metabolic and Behavioral Mechanisms of Indoxacarb Resistance in Sitophilus zeamais (Coleoptera: Curculionidae).
The control of the most important pest of stored maize, the weevil Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae), is mainly achieved with the use of pyrethroid insecticides. However, the intensive use of these compounds has led to the selection of resistant populations and has compromised the control efficacy of this insect pest. Here, the toxicity of indoxacarb for a potential use in the control of S. zeamais was assessed on 13 Brazilian populations. Concentration-mortality bioassays, in the presence of synergists (piperonyl butoxide, triphenyl phosphate, and diethyl maleate), were used to assess potential metabolic-based indoxacarb resistance mechanisms. We also assessed the behavioral (locomotory) responses of these populations to indoxacarb exposure. The results showed significant differences between the populations (LD50 values ranged from 0.06 to 13.99 mg a.i/kg of grains), resulting in resistance ratios of >200-fold between the least (Canarana-MT) and the most (Espirito Santo do Pinhal-SP) susceptible populations. The results obtained with synergized indoxacarb suggest the involvement of esterases and glutathione-S-transferases on indoxacarb action, and also suggest the involvement of cytochrome P450-dependent monooxygenases as a potential indoxacarb resistance mechanism in Brazilian populations of S. zeamais. Although indoxacarb-induced behavioral avoidance varied among populations, some resistant populations (e.g., Canarana-MT) were able to reduce exposure to indoxacarb by spending more time in the nontreated areas. Collectively, our findings indicate that the behavioral (locomotory) and physiological responses of these insects may compromise the control efficacy of oxadiazine insecticides (e.g., indoxacarb) in Brazilian populations of S. zeamais.


Mother and Adolescent Eating in the Context of Food Insecurity: Findings from Urban Public Housing.
Introduction Anecdotal evidence suggests that parents protect their children from food insecurity and its effects, but few studies have concurrently assessed food insecurity among youth and parents. The purpose of this study was to examine food insecurity and eating behaviors among an urban sample of mother-adolescent dyads. Methods Mother-adolescent dyads (n = 55) were from six public housing sites in Phoenix, Arizona who completed surveys during 2014. Multivariate mixed linear and logistic regression models assessed the relationship between mother and adolescent eating behaviors in the context of food insecurity. Results Food insecurity was prevalent with 65.4% of parents and 43.6% of adolescents reporting food insecurity; 34.5% of parents and 14.5% of adolescents reported very low food security. After adjusting for food insecurity status, parents' and adolescents' fruit, vegetable, and sugar-sweetened beverage consumption was not associated. However, significant associations were observed between mothers' and adolescents' fast food intake (β = 0.52; p < 0.001), family meal intake (β = 0.52; p = 0.001), mindful eating (β = 0.51; p = 0.032), and binge eating (OR 8.05; p = 0.011). Discussion Parents may protect their adolescent children against food insecurity given the lower prevalence of food insecurity observed among adolescents. Interventions addressing food insecurity among mothers and adolescents may want to capitalize on shared eating patterns and address issues related to binge eating and leverage site-based strengths of public housing.


Shorter Versus Longer Courses of Antibiotics for Infection in Hospitalized Patients: A Systematic Review and Meta-Analysis.
Infection is a leading cause of hospitalization with high morbidity and mortality, but there are limited data to guide the duration of antibiotic therapy. Systematic review to compare outcomes of shorter versus longer antibiotic courses among hospitalized adults and adolescents. MEDLINE and Embase databases, 1990-2017. Inclusion criteria were human randomized controlled trials (RCTs) in English comparing a prespecified short course of antibiotics to a longer course for treatment of infection in hospitalized adults and adolescents aged 12 years and older. Two authors independently extracted study characteristics, methods of statistical analysis, outcomes, and risk of bias. Of 5187 unique citations identified, 19 RCTs comprising 2867 patients met our inclusion criteria, including the following: 9 noninferiority trials, 1 superiority design trial, and 9 pilot studies. Across 13 studies evaluating 1727 patients, no significant difference in clinical efficacy was observed (d = 1.6% [95% confidence interval (CI), -1.0%-4.2%]). No significant difference was detected in microbiologic cure (8 studies, d = 1.2% [95% CI, -4.1%-6.4%]), short-term mortality (8 studies, d = 0.3% [95% CI, -1.2%-1.8%]), longer-term mortality (3 studies, d = -0.4% [95% CI, -6.3%-5.5%]), or recurrence (10 studies, d = 2.1% [95% CI, -1.2%-5.3%]). Heterogeneity across studies was not significant for any of the primary outcomes. Based on the available literature, shorter courses of antibiotics can be safely utilized in hospitalized patients with common infections, including pneumonia, urinary tract infection, and intra-abdominal infection, to achieve clinical and microbiologic resolution without adverse effects on mortality or recurrence.


Concepts for Developing Physical Gels of Chitosan and of Chitosan Derivatives.
Chitosan macro- and micro/nano-gels have gained increasing attention in recent years, especially in the biomedical field, given the well-documented low toxicity, degradability, and non-immunogenicity of this unique biopolymer. In this review we aim at recapitulating the recent gelling concepts for developing chitosan-based physical gels. Specifically, we describe how nowadays it is relatively simple to prepare networks endowed with different sizes and shapes simply by exploiting physical interactions, namely (i) hydrophobic effects and hydrogen bonds-mostly governed by chitosan chemical composition-and (ii) electrostatic interactions, mainly ensured by physical/chemical chitosan features, such as the degree of acetylation and molecular weight, and external parameters, such as pH and ionic strength. Particular emphasis is dedicated to potential applications of this set of materials, especially in tissue engineering and drug delivery sectors. Lastly, we report on chitosan derivatives and their ability to form gels. Additionally, we discuss the recent findings on a lactose-modified chitosan named Chitlac, which has proved to form attractive gels both at the macro- and at the nano-scale.


Cytotoxic and Genotoxic Activities of Alkaloids from the Bulbs of Griffinia gardneriana and Habranthus itaobinus (Amaryllidaceae).
Amaryllidaceae plants are known to be a great source of alkaloids, which are considered an extensive group of compounds encompassing a wide range of biological activities. The remarkable cytotoxic activities observed in most of the Amaryllidaceae alkaloids derivatives have prompt the chemical and biological investigations in unexplored species from Brazil. To evaluate the cytotoxic and genotoxic properties of alkaloids of Griffinia gardneriana and Habranthus itaobinus bulbs and study the role of caspase-3 as a molecular apoptosis mediator. Methanolic crude extracts of Griffinia gardneriana and Habranthus itaobinus bulbs were submitted to acid-base extraction to obtain alkaloid-enriched fractions. The obtained fractions were fractionated using chromatographic techniques leading to isolation and identification of some alkaloids accomplished via HPLC and 1H-NMR, respectively. Molecular docking studies assessed the amount of free binding energy between the isolated alkaloids with the caspase-3 protein and also calculated the theoretical value of Ki. Studies have also been developed to evaluate in vitro cytotoxicity and genotoxicity in such alkaloids and apoptosis activation via the caspase pathway using both tumor and normal cell lines. Seven alkaloids were isolated and identified. Among these, 11-hydroxyvittatine and 2-α-7- dimethoxyhomolycorine were not cytotoxic, whereas tazettine, trisphaeridine, and sanguinine only showed activity against the fibroblast lineage. Lycorine and pretazettine were 10 to 30 folds more cytotoxic than the other alkaloids, including cancerous lines, and were genotoxic and capable of promoting apoptosis via the caspase-3 pathway. This result supports data obtained in docking studies wherein these two compounds exhibited the highest free energy values. The cytotoxicity assay revealed that, among the seven alkaloids isolated, only lycorine and pretazettine were active against different cell lines, exhibiting concentration- and time-dependent cytotoxic actions alongside genotoxic action and the ability to induce apoptosis by caspase-3, a result consistent with those obtained in docking studies.


Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates.
Gene-targeted disruption of Grg5, a mouse homologue of Drosophila groucho (gro), results in postnatal growth retardation in mice. The growth defect, most striking in approximately half of the Grg5 null mice, occurs during the first 4-5 weeks of age, but most mice recover retarded growth later. We used the nonlinear mixed-effects model to fit the growth data of wild-type, heterozygous, and Grg5 null mice. On the basis of preliminary evidence suggesting an interaction between Grg5 and the transcription factor Cbfa1/Runx2, critical for skeletal development, we further investigated the skeleton in the mice. A long bone growth plate defect was identified, which included shorter zones of proliferative and hypertrophic chondrocytes and decreased trabecular bone formation. This decreased trabecular bone formation is likely caused by a reduced recruitment of osteoblasts into the growth plate region of Grg5 null mice. Like the growth defect, the growth plate and trabecular bone abnormality improved as the mice grew older. The growth plate defect was associated with reduced Indian hedgehog expression and signaling. We suggest that Grg5, a transcriptional coregulator, modulates the activities of transcription factors, such as Cbfa1/Runx2 in vivo to affect Ihh expression and the function of long bone growth plates.


Stability analysis of spatiotemporal cnoidal waves in cubic nonlinear media.
We analyze numerically the modulational instability of spatiotemporal cnoidal waves of cn, dn, and sn types that are periodic along a single space coordinate and are uniform in time. The band of possible increments is calculated for all three types of cnoidal waves as a function of parameter describing the degree of localization of the wave field energy. It is shown that this band transforms into a set of discrete values for waves of cn and dn types in the limit of strong spatial localization. Simulation of perturbed cnoidal-wave propagation revealed suppression of collapse and multiple-wave filamentation on the developed stage of instability. Different instability scenarios are considered in detail.


A BAC-based contig map of the cynomolgus macaque (Macaca fascicularis) major histocompatibility complex genomic region.
The construction of a cynomolgus macaque (Macaca fascicularis, Mafa) BAC library for genomic comparison between rhesus and cynomolgus macaques is necessary to promote the cynomolgus macaque as one of the important experimental animals for future medical and biological research. In this paper, we constructed a cynomolgus macaque BAC library and a map of the MHC (Mafa) genomic region for comparison of the genomic organization and nucleotide similarities between the human, the chimpanzee, and the rhesus macaque. The BAC library consists of 221,184 clones with an average insert size of 83 kb, providing a sixfold coverage of the haploid genome. A total of 114 BAC clones and 54 PCR primer sets were used to construct a 4.3-Mb contig of the MHC region. Diversity analysis of genomic sequence from selected subregions of the MHC revealed that the cynomolgus sequence varied compared to rhesus macaque, human, and chimpanzee sequences by 0.48, 4.15, and 4.10%, respectively. From these findings, we conclude that the BAC library and Mafa genomic map are useful tools for genome analysis and will have important applications for comparative genomics and identifying regions of consequence in medical research.


Determining the pharmacological activity of Physalis peruviana fruit juice on rabbit eyes and fibroblast primary cultures.
The pharmacologic activity of compounds isolated from Physalis peruviana has been demonstrated. The use of this fruit juice for treating pterygium has been reported in Colombian traditional medicine. However, studies demonstrating the fruit juice's pharmacologic activity when used in this disease have not been published to date. In the present study the anti-inflammatory and cytostatic activities of P. peruviana fruit juice in a rabbit eye inflammatory model were investigated. A novel rabbit eye inflammation model was developed for studying the juice's anti-inflammatory activity (based on an adaptation of the Draize test). Cytostatic activity was evaluated by measuring and comparing growth rates of cultured fibroblasts exposed and not exposed to various fruit juice concentrations. P. peruviana fruit juice exhibited a mild anti-inflammatory activity compared with methylprednisolone, a known anti-inflammatory drug. An interesting dose-dependent cytostatic effect on cultured fibroblasts was also established. The data found suggest that the P. peruviana fruit juice anti-pterygium effect described in traditional medicine may be related to its inhibiting fibroblast growth. The present study contributes to the pharmacologic knowledge regarding a remedy commonly used in Colombian traditional medicine.


Activated protein C resistance: What have we learned now that the dust has settled?
Activated protein C resistance, most often caused by a single point mutation in the factor V gene, is the most common hereditary coagulation abnormality associated with venous thrombosis. Recent studies have established risk estimates of thrombosis in multiple clinical settings. The impact of activated protein C resistance on the absolute thrombotic risk of a given individual is significantly influenced by the presence or absence of other acquired or congenital risk factors. In this paper, the complex interplay between different risk factors for venous thrombosis is discussed. Additionally, the potential significance for arterial thrombosis of activated protein C resistance, that is not due to the genetic variant, Glutamine 506 factor V, is discussed.


Functional analysis of the promoters of the small GTPases RhoA and RhoB in embryonic stem cells.
Small GTPases of the Rho subfamily have been implicated in many physiological and pathological processes in various cell types including embryonic stem cells (ESCs). In the present study we performed a functional analysis of the promoters of the RhoA and the RhoB genes in order to identify regulatory elements that are important for their transcriptional control in ESCs. We show that RhoA mRNA levels were significantly higher compared with the RhoB mRNA levels in ESCs as well in various cancer cell lines and this difference could be accounted for by differences in the activities of the corresponding promoters. Deletion analysis of the RhoA and RhoB promoters in ESCs revealed that the proximal regions contain regulatory elements that are critical for their activity. Both proximal promoters contain CCAAT boxes and mutagenesis of these elements decreased significantly the activity of both promoters suggesting a coordinated regulation of the two genes by CCAAT box binding factors. Finally, we show that both genes are subjects to autoregulation in ESCs and in the case of RhoB, this autoregulation requires the GTPase activity of the Rho proteins. Understanding the mechanisms that control the transcription of Rho GTPases in ESCs may shed new light into the still unknown roles of these proteins in stem cell functions.


Image-guided lacrimal drainage surgery in congenital arhinia-microphthalmia syndrome.
The aim of this study was to illustrate the surgical techniques and utility of stereotactic or image-guided navigation in the management of lacrimal drainage obstruction in congenital arhinia-microphtalmia syndrome and review the relevant literature. Image-guided combined external and endoscopic dacryocystorhinostomy was performed in a female, aged 16 years with congenital partial arhinia and ipsilateral microphthalmus. The lacrimal sac was bypassed to the contra lateral nasal cavity through a septal window. The surgical procedure was performed using the intra-operative optical image-guided Nav 1 PicoTM ENT navigation system with real-time intra-operative instrument geometry. Different phases of the surgical technique, adjunctive endoscopic procedures, intra-operative anatomical guidance, and utility at crucial phases of surgery were noted. A review of the literature was performed pertinent to arhinia and navigation guided lacrimal surgeries. Lacrimal bypass into the contra lateral nasal cavity even through a malformed septum is possible in partial arhinia syndromes. Detailed preoperative evaluation including 3D imaging studies, navigation guided planning of risk structures with intra-operative distance control and construction of meticulous surgical roadmaps were found to be essential factors in successful outcomes. At six months follow up after surgery, there was a complete and contiguous healed mucosal anastomosis with lacrimal system patent on irrigation and resolution of epiphora. Combined external and endoscopic approach is useful in partial arhinia syndromes. Image guidance is a very useful adjunctive tool that facilitates safe and precise surgery in the management of such complex lacrimal surgeries.


Dimerization capacities of FGF2 purified with or without heparin-affinity chromatography.
Fibroblast growth factor-2 (FGF2) is a pleiotropic growth factor exhibiting a variety of biological activities. In this article, we studied the capacity of FGF2 purified with or without heparin affinity chromatography to self-associate. Analyzing the NMR HSQC spectra for different FGF2 concentrations, heparin-affinity purified FGF2 showed perturbations that indicate dimerization and are a higher-order oligomerization state. HSQC perturbation observed with different FGF2 concentrations revealed a heparin-binding site and two dimer interfaces. Thus, with increasing protein concentrations, FGF2 monomers make contacts with each other and form dimers or higher order oligomers. On the contrary, FGF2 purified with ion-exchange chromatography did not show similar perturbation indicating that self-association of FGF2 is eliminated if purification is done without heparin-affinity chromatography. The HSQC spectra of heparin-affinity purified FGF2 can be reproduced to some extent by adding heparin tetra-saccharide to ion exchange chromatography purified FGF2. Heparin-affinity purified FGF2 bound to acceptor and donor beads in a tagged form using His-tagged or GST-tagged proteins, also dimerized in the AlphaScreen™ assay. This assay was further validated using different experimental conditions and competitors. The assay constitutes an interesting tool to study dimerization of other FGF forms as well.


Radionuclide detection of dialysate leakage in patients on continuous ambulatory peritoneal dialysis.
While continuous ambulatory peritoneal dialysis (CAPD) offers several advantages over haemodialysis in patients with end-stage renal disease, several complications have been recognised. The intraperitoneal instillation of dialysate increases intra-abdominal pressure and consequently predisposes to leaks and herniations through defects in the abdominal wall. This can lead to disruption of CAPD therapy. Peritoneal scintigraphy with Tc99m colloid has been used to identify such leaks of dialysate. This report analyses the clinical role of peritoneal scintigraphy in patients on the CAPD programme in the Singapore General Hospital. The results of 25 scans performed over a two-and-a-half year period were correlated with clinical and surgical findings. The clinical presentations of suspected dialysate leakage were varied, but can be broadly classified into three subsets for this analysis: (A) swellings confined to the inguinal and genital region, (B) peri-catheter, umbilical and incisional swellings, and (C) diffuse pattern of swellings in the abdominal wall, pelvic and genital region. In group A, the scan proved to be clearly helpful, correctly identifying 10/10 inguinal hernias, all of which resolved after herniorrhaphy. In group B, the scan correctly identified 7/9 leaks and hernias in the ventral abdominal wall. There was one false negative scan in a patient with a peri-catheter leak, and an equivocal result in another with fluid leakage in the lower anterior abdominal wall. In group C, which presented the greatest difficulty in clinical diagnosis, 2/3 cases were correctly diagnosed by scintigraphy. An equivocal result was seen in a patient who had had multiple operations for recurrent incisional hernias.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of the risk of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors with cultured intestinal stem cells originated from crypts in humans and monkeys.
Severe diarrhea is a common side effect of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We aimed to evaluate the risk of EGFR-TKI-induced diarrhea using spheroids of human and monkey crypt-derived intestinal stem cells. Intestinal spheroids exhibited higher toxic susceptibility to EGFR-TKIs than Caco-2 cells. As concentration of EGFR-TKIs increased, cellular ATP first decreased relative to the control condition, followed by an increase in LDH release, in contrast with their simultaneous changes with traditional cytotoxic anticancer drugs. The toxic sensitivity of spheroids to various EGFR-TKIs corresponded to clinical diarrhea incidence. Afatinib, a second-generation EGFR-TKI, exhibited higher toxic sensitivity compared with the first-generation ones, corresponding to the clinical evidence that afatinib-induced diarrhea is almost inevitable and severe. By contrast, the third-generation osimertinib, which reduces the risk of diarrhea, showed mitigated cytotoxicity compared with afatinib. For irreversible EGFR-TKIs, the decreased ATP level persisted or its recovery was delayed even after drug removal compared with reversible ones. Furthermore, the highest drug accumulation in spheroids (TKIspheroids) and inhibition potency against EGFR (TKIspheroids/Ki) were observed for afatinib. This system would be useful for predicting the risk of EGFR-TKI-induced diarrhea; moreover, on-target cytotoxicity against intestinal stem cells might contribute to clinically observed diarrhea.


VO2 response profiles in severe intensity exercise.
VO2peak can be achieved over the range of intensities that define the severe intensity domain. The purpose of this study was to help characterize the VO2 response during constant-load exercise in this domain. Twelve participants performed cycle ergometer tests at 267+/-52 W, 238+/-45 W, and 216+/-37 W, which were individually selected to elicit VO2peak and to cause fatigue in 3 min, 5 min, and 7 min, respectively. Times to fatigue were 201+/-16 s, 301+/-20 s, and 448+/-51 s, respectively. VO2 responded faster at higher work rates, with VO2peak reached after 154+/-25 s, 193+/-35 s, and 206+/-24 s, respectively. Extrapolation of the times to reach VO2peak revealed that 300 W was the highest power, and 151 s was the shortest time, for which VO2peak could be elicited. TheVO2 response was described using a three-component model. Exercise intensity did not affect the speed of the primary response, with time constants of 22+/-3 s, 23+/-4 s, and 23+/-4 s, respectively. However, the size of the primary phase was greater at higher intensities, with amplitudes of 1,798+/-200 mlxmin-1, 1,739+/-267 mlxmin-1, and 1,677+/-254 mlxmin-1, respectively. The amplitude of the slow component was correspondingly smaller at higher intensities. Extrapolation of the slow component amplitudes revealed that 299 W was the highest intensity, and 152(-1)53 s was the shortest time, for which a slow component would be engendered. VO2peak is attained faster at higher intensities because the amplitude of the primary response is greater, not because the response is faster. There is a slow component to the VO2 response at all intensities within the severe domain, but not at higher intensities, in the extreme domain, where fatigue occurs before VO2peak can be elicited.


Unravelling the mysteries of gout by multimodality imaging.
Gout is a common inflammatory arthritis that manifests as an aggregate of variably symptomatic monosodium urate crystals (MSU) in the joints and surrounding tissues in addition to multisystem involvement such as genitourinary and cardiovascular systems. In recent decades, there has been a documented increase in the prevalence and incidence of gout. Risk factors for gout include obesity, dietary influences, hypertension, renal impairment, and diuretic use. A prompt diagnosis followed by uric acid lowering treatment prior to the onset of bone destruction is the goal in any suspected case of gout. Advanced imaging modalities, such as dual energy computed tomography (DECT) and ultrasonography (US), employed for the diagnosis of gout are each accompanied by advantages and disadvantages. Conventional radiography (CR), although useful in visualizing joint erosions and mineralization, is limited in its ability to diagnose gout flare. Although synovial fluid aspiration remains the gold standard for MSU crystal visualization, less-invasive imaging modalities are preferred to avoid potential complications. DECT and US in particular are useful in the diagnosis of gout. In this review, we will discuss the current state and role of imaging in the detection of gout.


Relationship of leptin concentrations with feed intake, growth, and efficiency in finishing beef steers.
The objective of this experiment was to determine the association of serum leptin concentrations with production measures including DMI, ADG, and G:F as well as carcass characteristics in genetically diverse finishing beef steers. Three cohorts of steers ( = 473 total) were individually fed a finishing ration for 92, 64, and 84 d for cohort 1, 2, and 3, respectively. Serum was collected on d 42, 22, and 19 of the experiment for cohort 1, 2, and 3, respectively. Leptin concentrations were positively correlated to DMI ( = 0.21, < 0.01) but negatively correlated to grams DMI per kilogram initial BW ( = -0.21, < 0.01). Leptin concentrations were also negatively correlated to ADG and G:F ( < 0.01). Leptin concentrations were positively correlated to 12th-rib fat thickness, yield grade, and marbling score ( < 0.01) and negatively correlated to LM area ( < 0.01). Using a mixed model analysis (SAS 9.3; SAS Inst. Inc., Cary, NC) to account for breed effects, leptin concentrations were positively associated with DMI ( = 0.01) and accounted for 1.10% of the variance. However, if initial BW and yield grade were included as covariates to account for body size and fatness, leptin was negatively associated with DMI ( = 0.02) and accounted for 0.54% of the variance. Regardless of covariates included in the model, leptin was negatively associated with ADG ( < 0.01) and G:F ( < 0.01) and accounted for 2.62 and 7.87% of the variance for ADG and G:F, respectively. Leptin concentrations were also positively associated with 12th-rib fat thickness, yield grade, and marbling score ( < 0.01) and accounted for 14.74, 12.74, and 6.99% of the variance for 12th-rib fat, yield grade, and marbling score, respectively. Leptin concentrations could be a useful physiological marker for growth and feed efficiency of finishing beef cattle. Genetic influences on the biology of leptin also need to be considered when using leptin as physiological marker for production measures.


The efficacy of combined therapy with metronidazole and broad-spectrum antibiotics on postoperative outcomes for pediatric patients with perforated appendicitis.
The aim of this study was to evaluate the efficacy of combined therapy with metronidazole and broad-spectrum antibiotics for patients with perforated appendicitis who underwent surgical intervention.Broad-spectrum antibiotic therapy is warranted in the treatment of perforated appendicitis. Metronidazole has been used as anaerobic antimicrobial therapy. However, few studies about the use of metronidazole in perforated appendicitis have been reported.The medical records of 249 patients treated with metronidazole combined with broad-spectrum antibiotics following perforated appendicitis surgery were reviewed retrospectively and compared with the medical records of 149 patients treated only with broad-spectrum antibiotics. Propensity score matching was performed to adjust for selected baseline variables. Clinical outcomes, including postoperative complications and length of hospital stay, were compared between the 2 groups.No differences were found between the use of combined therapy with metronidazole and the use of solely broad-spectrum antibiotic agents with regard to postoperative duration of intravenous antibiotic treatment (6.8 ± 1.3 vs 7.9 ± 2.1 days, respectively, P = .18), inflammation variables at POD 5 (white blood cell [WBC] [risk ratio [RR], 1.06; 95% confidence interval [CI], 0.67-1.93, P = .15] and C-reactive protein [CRP] [RR, 1.18; 95% CI, 0.73-2.25, P = .36]) (Table 2), and the mean postoperative length of hospital stay (LOS) (RR, 0.68, 95% CI, 0.41-0.94, P = .41). There were also no differences in the incidence of postoperative complications, including the intra-abdominal or pelvic abscess rate (7[7.1%] vs 9[9.2%], respectively, P = .40), the incidence of wound infection (14[14.3%] vs 15[15.3%], respectively, P = .50), and the 30-day readmission rate (9[9.2%] vs 12[12.2%], respectively, P = .32).Regarding overall postoperative outcomes and complications, our study demonstrated no beneficial clinical effects of metronidazole administration in patients with perforated appendicitis who underwent surgical intervention. Therefore, metronidazole is not indicated when broad-spectrum antibiotics such as aminopenicillins with β-lactam inhibitors or carbapenems and select cephalosporins are used.


Double Imaging Photoelectron Photoion Coincidence Sheds New Light on the Dissociation of State-Selected CH3F+ Ions.
The vacuum ultraviolet (VUV) photoionization and dissociative photoionization of methyl fluoride (CH3F) in the 12.2-19.8 eV energy range were investigated by using synchrotron radiation coupled to a double imaging photoelectron photoion coincidence (i2PEPICO) spectrometer. The production of several fragment ions including CH2F+, CHF+, CH3+, and CH2+ as a function of state and internal energy of CH3F+ ions was identified and analyzed, with their individual appearance energies measured through threshold photoelectron spectroscopy. Dynamical information was inferred from electron and ion kinetic energy correlation diagrams measured at chosen fixed photon energies. The detailed mechanisms governing the dissociation of state-selected CH3F+ ions prepared in the X2E, A2A1, and B2E low-lying electronic states as well as outside the Franck-Condon region have been inferred based on the present experimental results and existing theoretical calculations. Both the CH2F+ and CH3+ primary fragment ions have three different channels of production from different electronic states of CH3F+. The spin-orbit splitting states of the F fragment, 2P3/2 and 2P1/2, in the CH3+ + F dissociation channels were assigned and adiabatically correlate to the X2E ground state and the A2A1 electronic state, respectively, with the aid of previous theoretical results. The CH3F+ ions in the high energy part of the X2E ground state are unstable and statistically dissociate to the CH2F+(11A1) and H(2S) fragments along the potential energy curve of the X2E state. The A2A1 electronic state is a repulsive state and exclusively dissociates to the CH3+(11A1') and F(2P1/2) fragments. In addition, the CH2F+, CHF+, CH3+, and CH2+ fragment ions are also produced in the B2E state and in the Franck-Condon gap by indirect processes, such as internal conversion or dissociative autoionization.


Experimental studies of the NaCs 12(0+) [71Σ+] state: Spin-orbit and non-adiabatic interactions and quantum interference in the 12(0+) [71Σ+] and 11(0+) [53Π0] emission spectra.
We present results from experimental studies of the 11(0+) and 12(0+) electronic states of the NaCs molecule. An optical-optical double resonance method is used to obtain Doppler-free excitation spectra. Selected data from the 11(0+) and 12(0+) high-lying electronic states are used to obtain Rydberg-Klein-Rees and Inverse Perturbation Approach potential energy curves. Interactions between these two electronic states are evident in the patterns observed in the bound-bound and bound-free fluorescence spectra. A model, based on two separate interaction mechanisms, is presented to describe how the wavefunctions of the two states mix. The electronic parts of the wavefunctions interact via spin-orbit coupling, while the individual rotation-vibration levels interact via a second mechanism, which is likely to be non-adiabatic coupling. A modified version of the BCONT program was used to simulate resolved fluorescence from both upper states. Parameters of the model that describe the two interaction mechanisms were varied until simulations were able to adequately reproduce experimental spectra.


Construction of a 2D Layered Phosphorus-doped Graphitic Carbon Nitride/BiOBr Heterojunction for Highly Efficient Photocatalytic Disinfection.
Infectious diseases caused by bacteria intimidate the health of human beings all over the world. Although many avenues have been tried, various operating conditions limit their actual applications. Photocatalytic nanomaterials are becoming candidates to be competent for water purification. Here, a novel and more efficient S-scheme has been engineered between two dimensional (2D) layered phosphorus-doped graphitic carbon nitride (P-g-C3 N4 ) and BiOBr via hydrothermal polymerization to inhibit the recombination of charge and broaden light absorption. The as-prepared P-g-C3 N4 /BiOBr hybrids exhibits significantly improved photocatalytic disinfection contrast to g-C3 N4 /BiOBr in visible wavelengths, suggesting phosphorus doping which adjusts the band structure plays a significant role in the S-scheme system. And the sterilization rate of multidrug-resistant Acinetobacter baumannii 28 (AB 28) was 99.9999% within 80 min and Staphylococcus aureus (S. aureus) was 99.9%.


Human behavioural discrimination of human, chimpanzee and macaque affective vocalisations is reflected by the neural response in the superior temporal sulcus.
Accurate perception of the emotional content of vocalisations is essential for successful social communication and interaction. However, it is not clear whether our ability to perceive emotional cues from vocal signals is specific to human signals, or can be applied to other species' vocalisations. Here, we address this issue by evaluating the perception and neural response to affective vocalisations from different primate species (humans, chimpanzees and macaques). We found that the ability of human participants to discriminate emotional valence varied as a function of phylogenetic distance between species. Participants were most accurate at discriminating the emotional valence of human vocalisations, followed by chimpanzee vocalisations. They were, however, unable to accurately discriminate the valence of macaque vocalisations. Next, we used fMRI to compare human brain responses to human, chimpanzee and macaque vocalisations. We found that regions in the superior temporal lobe that are closely associated with the perception of complex auditory signals, showed a graded response to affective vocalisations from different species with the largest response to human vocalisations, an intermediate response to chimpanzees, and the smallest response to macaques. Together, these results suggest that neural correlates of differences in the perception of different primate affective vocalisations are found in auditory regions of the human brain and correspond to the phylogenetic distances between the species.


Antimicrobial peptides modulate long-term memory.
Antimicrobial peptides act as a host defense mechanism and regulate the commensal microbiome. To obtain a comprehensive view of genes contributing to long-term memory we performed mRNA sequencing from single Drosophila heads following behavioral training that produces long-lasting memory. Surprisingly, we found that Diptericin B, an immune peptide with antimicrobial activity, is upregulated following behavioral training. Deletion and knock down experiments revealed that Diptericin B and another immune peptide, Gram-Negative Bacteria Binding Protein like 3, regulate long-term but not short-term memory or instinctive behavior in Drosophila. Interestingly, removal of DptB in the head fat body and GNBP-like3 in neurons results in memory deficit. That putative antimicrobial peptides influence memory provides an example of how some immune peptides may have been repurposed to influence the function of nervous system.


Crystal structure analysis, covalent docking, and molecular dynamics calculations reveal a conformational switch in PhaZ7 PHB depolymerase.
An open and a closed conformation of a surface loop in PhaZ7 extracellular poly(3-hydroxybutyrate) depolymerase were identified in two high-resolution crystal structures of a PhaZ7 Y105E mutant. Molecular dynamics (MD) simulations revealed high root mean square fluctuations (RMSF) of the 281-295 loop, in particular at residue Asp289 (RMSF 7.62 Å). Covalent docking between a 3-hydroxybutyric acid trimer and the catalytic residue Ser136 showed that the binding energy of the substrate is significantly more favorable in the open loop conformation compared to that in the closed loop conformation. MD simulations with the substrate covalently bound depicted 1 Å RMSF higher values for the residues 281-295 in comparison to the apo (substrate-free) form. In addition, the presence of the substrate in the active site enhanced the ability of the loop to adopt a closed form. Taken together, the analysis suggests that the flexible loop 281-295 of PhaZ7 depolymerase can act as a lid domain to control substrate access to the active site of the enzyme. Proteins 2017; 85:1351-1361. © 2017 Wiley Periodicals, Inc.


Social inclusion for children with hearing loss in listening and spoken Language early intervention: an exploratory study.
Social inclusion is a common focus of listening and spoken language (LSL) early intervention for children with hearing loss. This exploratory study compared the social inclusion of young children with hearing loss educated using a listening and spoken language approach with population data. A framework for understanding the scope of social inclusion is presented in the Background. This framework guided the use of a shortened, modified version of the Longitudinal Study of Australian Children (LSAC) to measure two of the five facets of social inclusion ('education' and 'interacting with society and fulfilling social goals'). The survey was completed by parents of children with hearing loss aged 4-5 years who were educated using a LSL approach (n = 78; 37% who responded). These responses were compared to those obtained for typical hearing children in the LSAC dataset (n = 3265). Analyses revealed that most children with hearing loss had comparable outcomes to those with typical hearing on the 'education' and 'interacting with society and fulfilling social roles' facets of social inclusion. These exploratory findings are positive and warrant further investigation across all five facets of the framework to identify which factors influence social inclusion.


Efficient solid-phase synthesis of symmetric norbinaltorphimine derivatives.
[reaction: see text] We describe an efficient solid-phase synthesis of symmetric norbinaltorphimine (norBNI) derivatives 2. Pyrrole formation involving the homocoupling of two solid-supported ketones 6, followed by chemoselective and sequential N-alkylation, provided N-substituted norBNI derivatives 2. Use of this methodology led to the combinatorial synthesis of 120 norBNI derivatives.


GRID-ENABLED TREATMENT PLANNING FOR PROTON THERAPY USING MONTE CARLO SIMULATIONS.
Grid computing is an emerging technology that enables computational tasks to be accomplished in a collaborative approach by using a distributed network of computers. The grid approach is especially important for computationally intensive problems that are not tractable with a single computer or even with a small cluster of computers, e.g., radiation transport calculations for cancer therapy. The objective of this work was to extend a Monte Carlo (MC) transport code used for proton radiotherapy to utilize grid computing techniques and demonstrate its promise in reducing runtime from days to minutes. As proof of concept we created the Medical Grid between Texas Tech University and Rice University. Preliminary computational experiments were carried out in the GEANT4 simulation environment for transport of 25 ×106 200 MeV protons in a prostate cancer treatment plan. The simulation speedup was approximately linear; deviations were attributed to the spectrum of parallel runtimes and communication overhead due to Medical Grid computing. The results indicate that ~3 × 105 to 5 × 105 proton events with processor core would result in 65 to 83% efficiency. Extrapolation of our results indicates that about 103 processor cores of the class used here would reduce the MC simulation runtime from 18.3 days to ~1 h.


Values of ultrasound for diagnosis and management of insulin-induced lipohypertrophy: A prospective cohort study in China.
The aim of this study was to explore the values of ultrasound for diagnosis and management of insulin-induced lipohypertrophy and further analyzing the impact of body mass index and subcutaneous fat thickness on ultrasound manifestations of lipohypertrophy.In this 3-month, prospective cohort study, a total of 162 patients with diabetes who used insulin therapy more than 1 year with unknown lipohypertrophy status were enrolled into this study. Demographic information, assessment of glycemic control and insulin injection technique were evaluated. Physical and ultrasound examination were separately performed to detect lipohypertrophy by a team of diabetes educator nurses or ultrasonographer in a blinded fashion. Patients with lipohypertrophy received insulin injection technique education based on ultrasound examination and Chinese guideline.Ultrasound examination detected 41.1% more patients (74.1% vs 52.5%; P < .001) with lipohypertrophy and 61.2% more lesions (216 vs 134; P < .001) than physical examination. Glycosylated hemoglobin A1c and fasting blood glucose were significantly decreased in patients with lipohypertrophy or subclinical lipohypertrophy (lipohypertrophy without visual and palpation changes) after receiving insulin injection technique education based on ultrasound examination and Chinese guideline than baseline at 3 months (P < .001). The proportion of lesions with ultrasound manifestation 2 (distortion of surrounding connective tissue) in obese and STF (>15 mm) groups were no more than 50% and showed a decreased trend with increased subcutaneous fat thickness and body mass index (P < .001).Lipohypertrophy has characteristic ultrasound manifestations which can detect more accurate results than palpation alone and provide detailed information to promote effective education on lipohypertrophy management, thereby improving glycemic control.


Factors that influence cancer patients' and relatives' anxiety following a three-person medical consultation: impact of a communication skills training program for physicians.
No study has yet assessed the impact of physicians' skills acquisition after a communication skills training program on changes in patients' and relatives' anxiety following a three-person medical consultation. This study aimed at comparing, in a randomized study, the impact, on patients' and relatives' anxiety, of a basic communication skills training program and the same program consolidated by consolidation workshops and at investigating physicians' communication variables associated with patients' and relatives' anxiety. Consultations with a cancer patient and a relative were recorded and analyzed by the Cancer Research Campaign Workshop Evaluation Manual. Patients' and relatives' anxiety were assessed with the State-Trait Anxiety Inventory-State. No statistically significant change over time and between groups was observed. Mixed-effects modeling of changes in patients' and relatives' anxiety showed that decreases in both patients' and relatives' anxiety were linked with patients' and relatives' self-reported distress (p = 0.031 and 0.005), and that increases in both patients' and relatives' anxiety were linked with physicians' breaking bad news (p = 0.028 and 0.005). No impact of the training program was observed. Results indicate the need to further study communication skills which may help reduce patients' and relatives' anxiety especially when breaking bad news.


Development of a Clinical-Radiomics Nomogram That Used Contrast-Enhanced Ultrasound Images to Anticipate the Occurrence of Preoperative Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma Patients.
Papillary thyroid carcinoma (PTC) is a prevalent histological type of thyroid cancer; however, noninvasive assessment of cervical lymph node metastasis (LNM) poses a challenge. This study aims to develop a novel clinical-radiomics nomogram that utilizes ultrasound (US) images to predict the presence of cervical LNM metastasis in patients with PTC. A total of 423 patients with PTC were recruited to participate in this study between January 2020 and December 2022, of which 282 were classified into the training group and 141 patients were classified into the validation set. Contrast-enhanced ultrasound (CEUS) and B-mode ultrasound (BMUS) images were subjected to radiomic analysis, leading to the extraction of 912 radiomic features. Thereafter, a radiomics score (Radscore) was developed to effectively integrate the information derived from BMUS and CEUS modalities. Univariate and multivariate backward stepwise logistic regression analysis techniques were used to construct the clinical and clinical-radiomics models, respectively. The findings revealed that the clinical-radiomics nomogram incorporated age, sex, CEUS Radscore, and US-reported LNM as risk factors. The nomogram demonstrated good performance using data from the training (AUC = 0.891) and validation (AUC = 0.870) sets. The decision curve analysis implied that this nomogram exhibited good clinical utility, which was further supported by the results of the calibration curves and Hosmer-Lemeshow test. The CEUS Radscore-based clinical radiomics nomogram could serve as a valuable tool for predicting cervical LNM metastasis in patients with PTC, thereby tailoring individualized treatment strategies for them.


Bacillus licheniformis escapes from Myxococcus xanthus predation by deactivating myxovirescin A through enzymatic glucosylation.
Myxococcus xanthus kills susceptible bacteria using myxovirescin A (TA) during predation. However, whether prey cells in nature can escape M. xanthus by developing resistance to TA is unknown. We observed that many field-isolated Bacillus licheniformis strains could survive encounters with M. xanthus, which was correlated to their TA resistance. A TA glycoside was identified in the broth of predation-resistant B. licheniformis J32 co-cultured with M. xanthus, and a glycosyltransferase gene (yjiC) was up-regulated in J32 after the addition of TA. Hetero-expressed YjiC-modified TA to a TA glucoside (TA-Gluc) by conjugating a glucose moiety to the C-21 hydroxyl group, and the resulting compound was identical to the TA glycoside present in the co-culture broth. TA-Gluc exhibited diminished bactericidal activity due to its weaker binding with LspA, as suggested by in silico docking data. Heterologous expression of the yjiC gene conferred both TA and M. xanthus-predation resistance to the host Escherichia coli cells. Furthermore, under predatory pressure, B. licheniformis Y071 rapidly developed predation resistance by acquiring TA resistance through the overexpression of yjiC and lspA genes. These results suggest that M. xanthus predation resistance in B. licheniformis is due to the TA deactivation by glucosylation, which is induced in a predator-mediated manner.


The court medical expert in France: changes in status.
In France the status of the court expert has undergone a significant change with the adoption of statute no. 2004-130 of 11 February 2004 and its implementing regulations no. 2004-1463 of 23 December 2004. This article looks at the two most outstanding aspects of this change in status: (i) the conditions for registering on a court of appeal list and, (ii) the practical details of the quality control of the court expert's work as exercised by the judge. The article concludes with a brief comparison with the expert witness situation in England and Wales.


[Survival is not enough: remarks on article 32 of the Italian Constitution].
Article No. 32 of the Italian Constitution describes health as a fundamental human right in the interest of the community and guarantees free health care to the poor. It states that no one can be obliged to undergo any kind of treatment against his will, with the exception of cases where this is required by law. Supporting health includes also support for the quality of life. There are moral and economic reasons for granting health care. It is necessary to help those who suffer to live their lives with dignity.


Children's moral emotions, narratives, and aggression: relations with maternal discipline and support.
Children who attribute more positive emotions to hypothetical moral victimizers are typically more aggressive and have more behavior problems. Little is known, however, about when individual differences in these moral emotion attributions first emerge or about maternal correlates of these differences. In this study, 63 4-6-year-olds judged how they would feel after victimizing peers for gain and enacted event conclusions using narrative methods adapted from the MacArthur Story Stem Battery. In addition, children's mothers completed assessments of their disciplinary styles and social support, and children's aggressive tendencies were assessed based on ratings from mothers and a second familiar adult. Results revealed that most preschoolers expected to feel happy after their victimizing acts, but variations in happy victimization were unrelated to children's aggression. Several of children's narrative themes, including making amends (e.g., apologizing, reparations), aggressive acts, and mentions of death/killing, however, were related to children's aggression. Moreover, two maternal disciplinary dimensions, higher warmth and reasoning, as well as greater social support were also related to lower child aggression. Children's emotion attributions and moral narratives, however, were unrelated to maternal disciplinary practices or social support.


The blood-brain barrier in the cerebrum is the initial site for the Japanese encephalitis virus entering the central nervous system.
Japanese encephalitis (JE) virus is a member of the encephalitic flaviviruses and frequently causes neurological sequelae in a proportion of patients who survive the acute phase of the infection. In the present study, we molecularly identified viral infection in the brain of mice with rigidity of hindlimbs and/or abnormal gait, in which JE virus particles appeared within membrane-bound vacuoles of neurons throughout the central nervous system. Deformation of tight junctions (TJs) shown as dissociation of endothelial cells in capillaries, implying that the integrity of the blood-brain barrier (BBB) has been compromised by JE virus infection. BBB permeability evidently increased in the cerebrum, but not in the cerebellum, of JE virus-infected mice intravenously injected with the tracer of Evans blue dye. This suggests that the permeability of the BBB differentially changed in response to viral infection, leading to the entry of JE virions and/or putatively infected leukocytes from the periphery to the cerebrum as the initial site of infection in the central nervous system (CNS). Theoretically, the virus spread to the cerebellum soon after the cerebrum became infected.


Synthetic Methods for Various Chromeno-fused Heterocycles and their Potential as Antimicrobial Agents.
Chromenes are a significant family of heterocyclic chemicals that have a wide range of biological applications, a simple chemical structure, and only mildly undesirable side effects. The synthesis of a wide range of chromene analogs that displayed unexpected behaviors via numerous mechanisms was investigated by a number of different research teams, which led to the discovery of multiple pathways for their synthesis. In addition, different chromene-fused heterocycles exhibit a wide variety of fascinating biological actions, including those that are anticancer, anticonvulsant, antibacterial, anticholinesterase, antituberculosis, and anti-diabetic. In light of this, the purpose of this study is to highlight the many synthesis techniques and antibacterial activity associated with chromene-fused heterocyclic compounds. Moreover, such research can open avenues for exploring other therapeutic applications of these compounds in various disease areas, as their biological activities extend beyond antibacterial effects.


A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency.
Biotinidase deficiency is characterized by severe neurological manifestations as hypotonia, lethargy, ataxia, hearing loss, seizures and developmental retardation in its classical form. Late-onset biotinidase deficiency presents distinctly from the classical form such as limb weakness and vision problems. A 14-year-old boy presented with progressive vision loss and upper limb weakness. The patient was initiated steroid therapy with a preliminary diagnosis of neuromyelitis optica spectrum disorder due to the craniospinal imaging findings demonstrating optic nerve, brainstem and longitudinally extensive spinal cord involvement. Although the patient exhibited partial clinical improvement after pulse steroid therapy, craniocervical imaging performed one month after the initiation of steroid therapy did not show any regression. The CSF IgG index was <0.8 (normal: <0.8), oligoclonal band and aquaporin-4 antibodies were negative. Metabolic investigations revealed a low biotinidase enzyme activity 8% (0.58 nmoL/min/mL; normal range: 4.4 to 12). Genetic testing showed c.98-104delinsTCC and p.V457 M mutations in biotinidase (BTD) gene. At the third month of biotin replacement therapy, control craniospinal MRI demonstrated a complete regression of the lesions. The muscle strength of the case returned to normal. His visual acuity was 7/10 in the left eye and 9/10 in the right. The late-onset form of the biotinidase deficiency should be kept in mind in all patients with myelopathy with or without vision loss, particularly in those with inadequate response to steroid therapy. The family screening is important to identify asymptomatic individuals and timely treatment.


Reader Profiles for Adults with Low Literacy Skills: A Quest to Find Resilient Readers.
Resilient readers are those who, despite their poor phonological decoding skills, have good comprehension abilities (Jackson & Doellinger, 2002). Thus far, these readers have been identified in college settings. The purpose of this study was to a) determine if this reader profile was present in a sample taken from an Adult Basic Education (ABE) population, and b) identify compensatory mechanisms these readers might use to better their reading comprehension. We administered a battery of tasks consisting of non-word reading, comprehension, fluency, and orthographic processing to a diverse sample of adults in ABE classes. Not only did we identify a group of resilient readers in this sample, we identified three other sub-groups: unskilled readers who had poor decoding and comprehension abilities, skilled readers who possessed good decoding and comprehension abilities, and a group of individuals who had good decoding skills but poor comprehension abilities. We found that the resilient readers and good decoders/poor comprehenders had better orthographic and fluency skills compared to the unskilled readers. However, these last two groups produced different error patterns on the orthographic and fluency tasks. We discuss the implications that these very different reader profiles have for ABE programs.


MeCP2 in neurons: closing in on the causes of Rett syndrome.
The discovery in 1999 that Rett syndrome (RTT) is caused by mutations in a gene encoding the methyl-CpG-binding repressor protein MECP2 provided a significant breakthrough in the understanding of this devastating disease. The subsequent production of Mecp2 knockout mice 2 years later provided an experimental resource to better understand how mutations in the MECP2 gene result in RTT. This paper reviews the recent progress in understanding when and where MeCP2 function becomes important in the developing brain, why MeCP2 protein levels are crucial, which genes are normally silenced by MeCP2, and how misexpression of these targets might lead to the clinical manifestations of RTT.


Emollient treatment for childhood eczema: involving children and parents.
Emollients are the mainstay of managing eczema but many children find them tedious and unpleasant to apply and they are thought to be under-prescribed and underused. This paper discusses the advantages of involving children and parents in treatment, and of giving them a choice of emollients and the chance to try out different ones at different times of day and at night. The author suggests practical ways of making emollient therapy more fun for children, for example by decorating tubs and other containers and applying creams to dolls and other suitable toys. Children, as well as adults, can become"expert patients" and any good ideas that they have can be shared with other children with eczema. Experience suggests that getting them more involved will improve concordance with treatment. It should be acknowledged that managing chronic eczema in children and young people is hard and it is important to praise and encourage the efforts that children and their parents are making.


Activation of the phagocyte NADPH oxidase by Rac Guanine nucleotide exchange factors in conjunction with ATP and nucleoside diphosphate kinase.
Activation of the phagocyte NADPH oxidase is the consequence of the assembly of membranal cytochrome b559 with the cytosolic components p47phox, p67phox, and the GTPase Rac and is mimicked by a cell-free system comprising these components and an activator. We designed a variant of this system, consisting of membranes, p67phox) prenylated Rac1-GDP, and the Rac-specific guanine nucleotide exchange factor (GEF) Trio, in which oxidase activation is induced in the absence of an activator and p47phox. We now show that: 1) Trio and another Rac GEF (Tiam1) act by inducing GDP to GTP exchange on prenylated Rac1-GDP and that our earlier assertion that activation is GTP-independent is explained by contamination of p67phox preparations with GTP and/or ATP. 2) Oxidase activation by Rac GEFs is supported not only by GTP but also by ATP. 3) Non-hydrolysable GTP analogs are active, whereas ATP analogs, incapable of gamma-phosphoryl transfer, are inactive. 4) The ability of ATP to support GEF-induced oxidase activation is explained by ATP serving as a gamma-phosphoryl donor for a membrane-localized nucleoside diphosphate kinase (NDPK), converting GDP to GTP. 5) The existence of a NDPK in macrophage membranes is proven by functional, enzymatic, and immunologic criteria. 6) NDPK acts on free GDP, and the newly formed GTP is bound again to Rac. 7) Free GDP is derived exclusively by dissociation from prenylated Rac1-GDP, mediated by GEF. NDPK and GEF appear to be functionally linked in the sense that the availability of GDP, serving as substrate for NDPK, is dependent on the level of activity of GEF.


[Clinical and genetic analysis of Noonan syndrome in 20 children].
Objective: To explore the clinical and genetic characteristics of Noonan syndrome in children. Methods: The clinical characteristics,genetic analysis and follow-up data of 20 children diagnosed with Noonan syndrome who were admitted to Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University from March 2016 to December 2020 were retrospectively analyzed. Results: Among 20 children with Noonan syndrome, 13 were males and 7 were females. The age at diagnosis was 5.9 years (1.1 years to 12.2 years). The most common clinical complaints were delayed height growth, followed by hypospadias or cryptorchidism in 2 cases, and special facial appearance in 1 case. Physical examination revealed 12 cases of Noonan syndrome with facial features, 9 cases with cryptorchidism and hypospadias, 10 cases with abnormal cardiac structure, and 10 cases with mental retardation; Twelve patients were detected with PTPN11 variations, 4 patients carried SOS2 variations, 2 cases were confirmed with variations in SHOC2 and SOS1. Six children received recombinant human growth hormone treatment, and their height increased by 4.0 (2.5-6.0) cm to varying degrees at 9 months. No adverse events occurred. Conclusions: Male Noonan syndrome is more frequently found with external genitalia. In addition to the high frequency of PTPN11 variation, the frequency of gene variation in SOS2 gene is higher than previously reported. All of the SOS2 variations are de novo. The syndrome phenotype profiles could vary with the admitted clinical departments. To understand the full picture of the syndrome, it is necessary to collect medical information from different departments.


Efficacy and safety of adeno-associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy.
Adeno-associated viral (AAV) and lentiviral vectors are promising vectors for gene therapy for hemophilia because they are devoid of viral genes and have the potential for long-term gene expression. To compare the performance of different AAV serotypes (AAV8 and AAV9) vs. lentiviral vectors expressing factor (F) IX. AAV-based and lentiviral vectors were generated that express FIX from the same hepatocyte-specific expression cassette. AAV9 transduced the liver as efficiently as AAV8 and resulted in supra-physiological FIX levels (3000-6000% of normal) stably correcting the bleeding diathesis. Surprisingly, AAV9 resulted in unprecedented and widespread cardiac gene transfer, which was more efficient than with AAV8. AAV8 and AAV9 were not associated with any proinflammatory cytokine induction, in accordance with their minimal interactions with innate immune effectors. In contrast, lentiviral transduction resulted in modest and stable FIX levels near the therapeutic threshold (1%) and triggered a rapid self-limiting proinflammatory response (interleukin-6), which probably reflected their ability to efficiently interact with the innate immune system. AAV8 and 9 result in significantly higher FIX expression levels and have a reduced proinflammatory risk in comparison with lentiviral vectors. The unexpected cardiotropic properties of AAV9 have implications for gene therapy for heart disease.


Supportive care needs of women with gynecologic cancer.
Gynecologic cancers often place a heavy emotional and physical burden on patients. However, there is a lack of information about the types of supportive care needs that these patients have, the services that are available, and whether patients want help with their needs. The aims of this cross-sectional, descriptive study were to (1) identify the supportive care needs (physical, emotional, social, spiritual, psychological, informational, and practical) of women with gynecologic cancer who attended a comprehensive, outpatient cancer center in Ontario, Canada, and (2) determine if patients wanted assistance in meeting those needs. A total of 103 patients participated in this study by completing a self-report questionnaire. Sixty-five of the women were no longer on treatment at the time of completing the survey. Eight of the top 10 most frequently reported needs were non physical, such as fears about the cancer returning or spreading. The data indicated that a range of needs remained unmet for this patient group. However, identifying the presence of a need did not necessarily mean that a patient wanted to have assistance with the need. Suggestions for practice and future research are offered to assist healthcare professionals in providing care to these patients.


An Esophagogram or Tracheobronchogram? A Review of Barium Sulfate Aspiration.
The barium swallow is an important radiological investigation used for the diagnosis of upper gastrointestinal anatomical disorders like esophageal cancer, diverticulum, achalasia, foreign body, among others. Generally, it is believed to be a safe technique with rare complications, but few cases of barium sulfate aspiration have been reported in the literature with multiple complications. We are reporting a case of an elderly male who underwent esophagogram for the workup of chronic dysphagia, aspirated barium sulfate, and went into respiratory failure and circulatory shock several hours later. Moreover, we also did a systematic literature search and reviewed all available articles on aspiration of barium sulfate and its potential complications. We focused on predisposing factors for aspiration, clinical presentation, complications after aspiration, and prognosis with the aim to better understand and manage this condition.


Superior mesenteric arterial occlusion from a leiomyoma.
We report a solitary leiomyoma of the superior mesenteric artery resulting in arterial occlusion and gangrenous bowel. On histologic evaluation the lesion extended into the vessel lumen off its stalk and showed immunostaining for smooth muscle antigen and desmin. Leiomyomas can arise anywhere there is smooth muscle and occur most commonly in the uterus followed by the skin and gastrointestinal tract. We could not identify any previous case in the literature of a leiomyoma arising from within the wall of a mesenteric vessel.


Design and Discovery of Novel Cyclic Peptides as EDPs-EBP Interaction Inhibitors for the Treatment of Liver Fibrosis.
Liver fibrosis is the undesirable result of excessive deposition of the extracellular matrix (ECM), and elastin is known as one of the key ECM components. Under specific pathological conditions, elastin undergoes degradation to produce elastin-derived peptides (EDPs), which bind to elastin-binding protein (EBP) to activate corresponding signal pathways, thus accelerating fibrosis progression. Herein, we describe the discovery of novel cyclic peptides that function as potent and stable inhibitors to interfere with the peptide-protein interaction between EDPs and EBP. Remarkably, CXJ-2 exhibited potent activities to inhibit the PI3K/ERK pathway and decrease hepatic stellate cell proliferation and migration. The subsequent in vivo study demonstrated that CXJ-2 possessed potent antifibrotic efficacy in ameliorating CCl4-induced liver fibrosis. This work provides a successful pharmacological strategy for the development of novel inhibitors of EDPs-EBP interaction, which sheds new light on how cyclic peptides disrupt peptide-protein interaction and may also provide new structure-oriented therapeutic candidates in liver fibrosis.


Antimicrobial effects of mechanical debridement.
Self-performed plaque removal using manual or powered toothbrushes and interdental cleaning devices is improved in subjects that have received oral hygiene instructions. Personal oral hygiene coupled with regular professional supragingival debridement may further improve the level of plaque control but still fails to achieve a completely plaque-free dentition. Both patient-performed and professional supragingival plaque removal has an effect on subgingival microbiota that is limited to the marginal 3 mm of the periodontal pocket. At sites with 4 mm or more of probing depth, only subgingival scaling leads to a significant reduction of the bacterial load. The subgingival microflora can be further reduced by pocket elimination surgery. Due to the sequence of bacterial recolonization that occurs following mechanical debridement, the level of periodontal pathogens such as B. forsythus, P. gingivalis and T. denticola may be reduced for several months. Mechanical debridement also influences the patient's immune system response, resulting in antibody titers and avidity against periodontal pathogens. As a basis for the restoration and maintenance of periodontal health, repeated subgingival debridement, as performed in supportive periodontal therapy, can reduce the number and proportions of periodontopathogenic bacteria in subgingival plaque. However, intensive subgingival scaling and root planing should be avoided in sites that probe less than 3 mm, as this is likely to traumatize the periodontium and cause attachment loss.


Activity-Induced MeCP2 Phosphorylation Regulates Retinogeniculate Synapse Refinement.
Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brain's capacity to respond to changes in neuronal activity and sensory experience. Here we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from that previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period. Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that predominantly affects girls. RTT is caused by loss of function mutations in a single gene MeCP2. Girls with RTT develop normally during their first year of life, but then experience neurological abnormalities including breathing and movement difficulties, loss of speech, and seizures. This study investigates the function of the MeCP2 protein in the brain, and how MeCP2 activity is modulated by sensory experience in early life. Evidence is presented that sensory experience affects MeCP2 function, and that this is required for synaptic pruning in the brain. These findings provide insight into MeCP2 function, and clues as to what goes awry in the brain when the function of MeCP2 is disrupted.


Assessment of Mexican Arnica (Heterotheca inuloides Cass) and Rosemary (Rosmarinus officinalis) Extracts on Dopamine and Selected Biomarkers of Oxidative Stress in Stomach and Brain of Salmonella typhimurium Infected rats.
The effects of some natural products on dopamine (DA) and 5-hydroxyindole acetic acid (5-HIAA) in brain of infected models are still unclear. The purpose of this study was to measure the effect of Mexican arnica/rosemary (MAR) water extract and oseltamivir on both biogenic amines and some oxidative biomarkers in the brain and stomach of young rats under infection condition. Female Wistar rats (weight 80 g) in the presence of MAR or absence (no-MAR) were treated as follows: group 1, buffer solution (controls); oseltamivir (100 mg/kg), group 2; culture of Salmonella typhimurium (S.Typh) (1 × 106 colony-forming units/rat) group 3; oseltamivir (100 mg/kg) + S.Typh (same dose) group 4. Drug and extracts were administered intraperitoneally every 24 h for 5 days, and S.Typh was given orally on days 1 and 3. On the fifth day, blood was collected to measure glucose and hemoglobin. The brains and stomachs were obtained to measure levels of DA, 5-HIAA, glutathione (GSH), TBARS, H2O2, and total ATPase activity using validated methods. DA levels increased in MAR group treated with oseltamivir alone but decreased in no-MAR group treated with oseltamivir plus S.Typh. 5-HIAA, GSH, and H2O2 decreased in this last group, and ATPase activity increased in MAR group treated with oseltamivir plus S.Typh. TBARS (lipid peroxidation) increased in MAR group that received oseltamivir alone. Most of the biomarkers were not altered significantly in the stomach. MAR extract alters DA and metabolism of 5-HIAA in the brain of young animals infected. Antioxidant capacity may be involved in these effects. The purpose of this study was to measure the effect of Mexican arnica/rosemary water extract and oseltamivir on both biogenic amines and some oxidative biomarkers in the brain and stomach of young rats under infection condition. Results: Mexican arnica and rosemary extract alter dopamine and metabolism of 5-HIAA in the brain of young animals infected. Antioxidant capacity may be involved in these effects. Abbreviations used: AS: Automated system, ATP: Adenosine triphosphate, CNS: Central nervous system, CFU: Colony-forming unit, DA: Dopamine EDTA: Ethylenediaminetetraacetic acid, 5-HIAA: Äcido 5-hidroxindolacético (serotonina), GABA: γ-aminobutyric acid, GSH: Glutathione, H2O2: Hidrogen peroxide, HCLO4: Perchloric acid, iNOS: Inducible nitric oxide synthase, LPS: Lipopolysaccharides, MAR: Arnica/Rosemary, NaCl: Sodium Chloride, NOGSH: nitrosoglutathione, NOS: Nitric oxide, OPT: Ortho-phtaldialdehyde, Pbs: Phosphate buffered saline, pH: potential of Hydrogen, Pi: Inorganic phosphate, ROS: Reactive oxygen species, RNSs: Reactive nitrogen species Tba: Thiobarbaturic acid, TBARS: Thiobarbituric aid reactive, Tca: Trichloroacetic, Tris-HCL: Tris hydrochloride, TSA: Trypticasein Soya Agar.


Effect of Hatakeshimeji (Lyophyllum decastes Sing.) Mushroom on serum lipid levels in rats.
The effect of Hatakeshimeji (Lyophyllum decastes Sing.) mushroom on serum lipid levels was investigated in rats. When the mushroom (fruit body) powder or its hotwater extract was added at a level of 10% to a cholesterol-containing diet, the serum total cholesterol levels of rats fed the fruit body or the hot-water extract were markedly lower than that of controls, though there was no significant difference in serum HDL-cholesterol among the three groups. On a cholesterol-free diet, the addition of fruit body powder at a level of 5% significantly decreased serum total cholesterol. Serum triglycerides and phospholipids were significantly decreased in both the fruit body and hot-water extract groups. Furthermore, Hatakeshimeji in the diet significantly increased the activity of cholesterol 7a-hydroxylase, which converts cellular cholesterol to bile acids, as well as the fecal excretion of bile acids.


Kinetics of copper nanoparticle precipitation in phosphate glass: an isothermal plasmonic approach.
The kinetics of copper nanoparticle (NP) precipitation in melt-quenched barium-phosphate glass has been studied by in situ isothermal optical micro-spectroscopy. A spectroscopically based approximation technique is proposed to obtain information about the activation energies of nucleation and growth in a narrow temperature range (530-570 °C). Pre-plasmonic and plasmonic NP precipitation stages are identified separated in time. The process as a whole is discussed employing classical nucleation/growth theory and the Kolmogorov-Johnson-Mehl-Avrami phase change model. Activation energies of 3.9(7) eV and 2.6(5) eV have been estimated for the pre-plasmonic and plasmonic spectroscopically assessed stages, respectively. High resolution transmission electron microscopy, differential scanning calorimetry, and Raman spectroscopy were used as complementary techniques for studying the nanoparticulate phase and glass host structure. An empirical linear dependence of the diffusion activation energy on the glass transition temperature with broad applicability is suggested.


[Follicular dendritic cell sarcoma: a clinicopathologic study of 8 cases].
To investigate clinicopathologic features, immunophenotypes and differential diagnoses of follicular dendritic cell sarcoma/tumor (FDCS). Eight cases of FDCS were studied using histological and immunohistochemical examinations and EBER in situ hybridization, with a review of the related literatures. There were 5 male and 3 female patients with a median age of 50 years. The sites of involvement included lymph node (4 cases), tonsil, nasopharynx, liver, and spleen (1 case each, respectively). The predominant microscopic features histologically included storiform, fascicular, diffuse, whorled and nodular in patterns. The neoplastic cells, dispersed by the infiltrated small lymphocytes, were characterized by abundant eosinophilic or fine granular cytoplasm with indistinct cell borders, and syncytial in appearance. The nuclei of the tumors were ovoid, round to spindled in shape with vesicular or stippled chromatin and small distinct nucleoli. Mitotic figures varied among cases. Pseudovascular spaces and perivascular cuffing were observed in some cases. One case of FDCS involving lesion in liver showed a background of abundant lymphocytes mixing with dispersed spindle or ovoid neoplastic cells having delicate chromatin, mild nuclear atypia, irregular/vesicular nuclei and distinct nucleoli. The neoplastic cells were positive for CD21, CD35, clusterin, and weakly positive for CD68, EMA, S-100 and EGFR. Ki-67 stain showed a variable expression among cases. EBER was positive in 2 cases. FDCS is a rare malignant tumor with a tendency to relapse and metastasis. Combined morphological and immunophenotypical analysis is necessary to reach a correct diagnosis.


Purification and characterization of a soybean hull allergen responsible for the Barcelona asthma outbreaks. II. Purification and sequencing of the Gly m 2 allergen.
A low MW allergen from soybean hull, Gly m 1, with two isoallergens, Gly m 1 A and Gly m 1 B, was associated with the asthma outbreaks that occurred in Cartagena, Spain. Using sera of asthmatic epidemic patients (AEP) from Barcelona, three main soybean hull allergens, two of them with MWs and pIs identical to those reported for Gly m 1 A and Gly m 1 B, were identified. The purpose of this study was to purify and to study the N-terminal amino acid sequence of the third allergen, which has a MW of 8 kDa. The purification procedure combined the double dialysis method and preparative isoelectofocusing (IEF). Specific IgE determination to the fractions obtained demonstrated three peaks, one of them corresponding to the 8 kDa allergen. The pooled fractions containing this allergen were studied by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE), SDS-PAGE/Western blot and IEF/Western blot. Only a band with a MW of 8 kDa and a pI of 6 was obtained. Its allergenic activity was measured and it was demonstrated that the allergenicity of soybean hull correlates with the presence of the 8 kDa allergen. The N-terminal amino acid sequence of the first 20 amino acids, which was registered at the PIR Data Submission as the N-terminal partial sequence of Gly m 2, was determined according the Edman degradation method. Gly m 2 N-terminal amino acid sequence lacks homology with that reported for the allergen Gly m 1 but has a homology of 71% with a storage protein from cotyledon of Vigna radiata (cow pea) and 64% with a "disease response protein' from Pisum sativum (green pea). These results suggest that Gly m 2 in soybeans could protect against diseases which affect soybean plants. This study demonstrates the existence of another soybean hull allergen, Gly m 2, partially responsible for the soybean asthma outbreaks that occurred in Barcelona, Spain.


Analysis of ras gene mutations in gastrointestinal cancers.
Point mutations of c-Ki-ras genes were analyzed in 33 samples of human gastrointestinal malignancy. DNA extracted from the frozen tissue was amplified by polymerase chain reaction (PCR) and analyzed by direct sequencing and slot-blot hybridization at codons 12, 13 and 61 of c-Ki-ras. In 7 cases out of 19 colorectal cancers, point mutations were found: 3 cases at codon 12, 1 at codon 13, 2 at codon 61 of c-Ki-ras and one case had double mutations at codon 12 and codon 13. In 11 cases of gastric cancer, 4 showed point mutations: 1 at codon 12 and 3 at codon 13 of c-Ki-ras. In 3 pancreatic carcinomas, 2 had point mutations: one at codon 12 and the other at codon 13 of c-Ki-ras. The results indicate that c-Ki-ras gene point mutations are involved in the tumorigenesis of the human gastrointestinal system.


Ultrasonic computed tomography of the breast. Improvement of image quality by use of cross-correlation time-of-flight and phase-insensitive attenuation measurements.
The authors present two methods of reducing refraction artifacts in ultrasonic computed tomography of the breast. Measuring the time of flight of sonic pulses by cross-correlation instead of leading-edge detection significantly reduces distortion and improves resolution in speed-of-sound images. Phase-insensitive reception of pulse energy across a large aperture array is shown to be superior to a conventional single-element transducer for attenuation imaging.


Safety of Catheter Ablation Therapy for Atrial Fibrillation in Cardiac Amyloidosis.
Background Despite the high burden of atrial fibrillation in cardiac amyloidosis (CA), the safety of catheter ablation therapy in CA is not well established. We sought to examine short-term safety outcomes following atrial fibrillation ablation in patients with CA compared with matched patients with dilated cardiomyopathy (DCM). Methods and Results Using data from the National Inpatient Sample, we identified all hospitalizations for atrial fibrillation ablation from the fourth quarter of 2015 through 2019. Admissions for CA and DCM were matched in a 1:5 ratio using propensity scores based on the following sociodemographics: age, sex, race or ethnicity, payor, median income, comorbidities, and hospital characteristics. We compared in-hospital outcomes between both cardiomyopathies. We identified 1395 unweighted hospitalizations (representing 6750 national hospitalizations) for atrial fibrillation ablation, out of which 45 (3.2%) were admissions for CA. Compared with DCM, patients with CA were older (72.9 versus 65.1 years), had a higher burden of prior stroke (20.0% versus 8.6%) and chronic kidney disease (53.3% versus 33.6%), and were less likely to have a prior implantable cardioverter-defibrillator (4.4% versus 23.0%). We successfully matched 42 CAs to 210 DCM hospitalizations. After matching, there was no difference in total complications (14.3% versus 10.5%, P=0.60), length-of-stay (3.1 versus 2.1 days, P=0.23), home disposition (97.6% versus 96.2%, P=0.65), and total charges ($137 250 versus $133 910, P=0.24). Conclusions In this nationally representative study of atrial fibrillation catheter ablation in CA, short-term safety outcomes and complication rates were similar to a propensity score-matched cohort of DCM. Further studies exploring long-term safety outcomes are needed.


Left Ventricular Mechanics in Untrained and Trained Males with Tetraplegia.
Reduced left ventricular (LV) function is common in tetraplegia, yet it is unknown whether intrinsic myocardial function is attenuated. This study examined the effect of SCI and exercise-training status on LV mechanics (intrinsic function) and LV systolic/diastolic function by comparing untrained (UT) and trained (TT) individuals with tetraplegia and able-bodied (AB) individuals. Individuals with tetraplegia had a traumatic, chronic, motor-complete cervical spinal cord injury. Nine UT males (40 ± 10 years), 8 TT males (30 ± 5 years), and nine AB males (37 ± 9 years) participated in the study. LV indices were assessed using two-dimensional transthoracic echocardiography, with speckle-tracking analysis for the determination of LV mechanics. For systolic function, stroke volumes were lower in both UT (59 ± 9 mL; p < 0.001) and TT (63 ± 9 mL; p < 0.001) relative to AB (82 ± 11 mL), whereas systolic mechanics were similar across groups. Diastolic function was only reduced in UT, including a lower ratio of early-to-late transmitral filling velocity (1.55 ± 0.28) relative to TT (2.07 ± 0.42; p < 0.05) and AB (2.44 ± 0.61; p < 0.01) and longer isovolumetric relaxation times in UT (101 ± 7 ms) relative to TT (88 ± 11 ms; p < 0.05) and AB (85 ± 6 ms; p < 0.01). Diastolic mechanics (apical circumferential strain rate) were significantly enhanced in TT (3.03 ± 0.83 s-1) compared to AB (1.85 ± 0.65 s-1; p < 0.05). There was a trend (p = 0.062) for a between-group difference in apical radial diastolic strain rate (UT: -2.51 ± 0.83 s-1; TT: -3.92 ± 1.96 s-1; AB: -1.84 ± 0.46 s-1). In tetraplegia, attenuated LV systolic function is not attributed to intrinsic dysfunction, whereas exercise-training status appears to improve both global LV diastolic function and LV mechanics.


[Contributions to the Establishment and Promotion of Pharmacy Education Reform].
In 2006, four-year pharmacist training courses in Japanese pharmacy schools were extended to a six-year course. Around that time, I participated in a committee related to pharmacy education reform within the Ministry of Education, Culture, Sports, Science and Technology. I also joined the pharmacist division of the medical council of the Ministry of Health, Labour and Welfare, to reform the national pharmacist examination system. In addition, I was part of the Pharmacy Education Council responsible for developing the contents of the new six-year curriculum, especially for clinical training. In the process, I had the opportunity to interact with many pharmacists and pharmacy educators. Following my transfer from the Pharmaceutical University Division to the Hospital Pharmacy Division in 2007, I participated in multidisciplinary collaborative education [inter professional work (IPW)/inter professional education (IPE)] for students in the disciplines of medicine, nursing, clinical laboratory examination, physiotherapy, occupational therapy, and pharmacy. This gave me an opportunity to apply this multidisciplinary experience to pharmacy education. "IPW", beyond the so-called "team medical care", is becoming an increasingly important concept in the medical field. Since all pharmacists are members of a team dedicated to patient-centered care, it is necessary to strengthen collaborative education, which will lead to an overall improvement in medical care. I believe that education is fundamental in all fields, and especially so in medical care. Pharmacy education needs radical reforms to increase its potency and to augment the value of pharmacists in the medical field.


Single mutations in BraRS confer high resistance against nisin A in Staphylococcus aureus.
Nisin A is a lantibiotic produced by Lactococcus lactis that is widely used as a food preservative. In Staphylococcus aureus, the BraRS two-component system (TCS) senses nisin A and regulates the expression of the ABC transporter VraDE, which is responsible for nisin A resistance. In this study, we exposed S. aureus to a sub-minimum inhibition concentration of nisin A and obtained three spontaneous mutants that were highly resistant to this lantibiotic, designated as SAN (S. aureus nisin resistant) 1, SAN8, and SAN87. In the wild-type S. aureus strain, VraDE expression was induced by nisin A. In contrast, SAN8 and SAN87 showed constitutively high VraDE expression, even in the absence of nisin A, while SAN1 showed higher BraRS expression, which resulted in high VraDE expression in the presence of nisin A. We identified a single mutation in the promoter region of braXRS in SAN1, whereas SAN8 and SAN87 had single mutations in braR and braS, respectively. Interestingly, even the unphosphorylated form of the mutant BraR protein induced VraDE expression. These results indicate that conformational changes in BraS or BraR resulting from the point mutations may result in the constitutive expression of VraDE, allowing S. aureus to adapt to high concentrations of nisin A.


Novel mutation in the PYGM gene resulting in McArdle disease.
McArdle disease is a common metabolic disorder characterized by marked exercise intolerance, premature fatigue during exertion, myalgia, and cramps. Despite the wide knowledge of the molecular basis of McArdle disease, few studies have used a physiological approach or explored the possibility of improving the exercise capacity of these patients. To describe 3 unrelated patients with McArdle disease with a novel mutation in the PYGM gene and to assess the physical capacity in 1 of them. Using molecular genetic approaches, we identified the underlying molecular defect in 3 patients with McArdle disease. Physical performance was evaluated in 1 patient by means of an exercise tolerance test on a bicycle ergometer. Two university hospitals. Exercise physiology studies were performed in a university department. Patients The 3 patients showed common features of McArdle disease. They were definitively diagnosed by histochemistry, biochemistry, or molecular genetic analysis. All of the 3 patients were genetic compounds for the common Arg50Stop mutation and a novel c.13_14delCT mutation in the PYGM gene. The peak oxygen uptake (VO(2peak)) of the patient who performed the exercise test was only 20.2 mL x kg(-1) x min(-1). Together with the novel mutation, there is a markedly decreased exercise capacity in a patient with McArdle disease, which could account for the profound alteration in the capacity for performing normal activities of daily living in this subpopulation.