Ets-1 regulates fli-1 expression in endothelial cells. Identification of ETS binding sites in the fli-1 gene promoter.
To understand the role of the Ets-1 transcription factor during angiogenesis, we have overexpressed it in endothelial cells and analyzed the levels of expression of several candidate target genes involved in angiogenesis. The transcripts levels of the ETS transcription factor fli-1 are specifically up-regulated in endothelial cells, which overexpress Ets-1, but not in fibroblasts. Analysis of the promoter of the mouse fli-1 gene reveals that the 1-kb region that comprises the transcription starts and part of exon 1 is responsible for the response of the promoter to Ets-1. The -270/-41 fragment contains two known Spi-1-responding Ets binding sites (EBS), which are also necessary for the activation by Ets-1. In contrast to Spi-1, a third EBS is necessary for the full response of this promoter fragment to Ets-1. The rest of the promoter activity has been located in the -986/-505 region, where three active EBSs have been identified. Furthermore, endogenous Fli-1 was found to be bound to its own gene promoter and to be able to promote the transactivation of its gene. These results suggest that Ets-1 activates an auto-regulatory loop of expression of fli-1 in endothelial cells, a mechanism that could have significant implications for the endothelial cell fate.


Maternal regulation of infant reactivity from 2 to 6 months.
Previous research has investigated the effect of maternal soothing behaviors on reducing infant reactivity but not the differential effects of specific maternal behaviors on infant stress responses. The present study investigated maternal regulation of 2- and 6-month-olds' responses to an inoculation and found a significant decline with age in both the intensity and duration of infants' crying. Maternal affection and touching decreased from 2 to 6 months, whereas maternal vocalizing and distraction behaviors increased. At both ages, the combination of maternal holding/rocking and vocalizing was associated with decreases in all levels of infant reactivity. Neither strategy alone, however, was found to be effective. Feeding/ pacifying behaviors were effective only when initial distress was at a low or moderate level, which suggests that the effectiveness of maternal regulatory behaviors may depend on the intensity of infants' crying.


Path Planning in Localization Uncertaining Environment Based on Dijkstra Method.
Path planning obtains the trajectory from one point to another with the robot's kinematics model and environment understanding. However, as the localization uncertainty through the odometry sensors is inevitably affected, the position of the moving path will deviate further and further compared to the original path, which leads to path drift in GPS denied environments. This article proposes a novel path planning algorithm based on Dijkstra to address such issues. By combining statistical characteristics of localization error caused by dead-reckoning, the replanned path with minimum cumulative error is generated with uniforming distribution in the searching space. The simulation verifies the effectiveness of the proposed algorithm. In a real scenario with measurement noise, the results of the proposed algorithm effectively reduce cumulative error compared to the results of the conventional planning algorithm.


Nitrifying genera in activated sludge may influence nitrification rates.
Sequencing batch reactors were acclimated under aerobic and alternating anoxic/aerobic conditions. Greater nitrification rates in the alternating reactor were investigated by comparing environmental conditions. In the alternating reactor, pH, alkalinity, oxygen, and nitrite were higher at the onset of aerobic nitrification. Kinetic studies and batch tests, with biomass developed under aerobic and alternating conditions, revealed that these factors were insufficient to explain the divergent nitrification rates. Nitrifying genera vary in nitrification kinetics and sensitivity to environmental conditions. Nitrosospira and Nitrospira spp. could dominate in aerobic reactors, as they are adapted to low nitrite and oxygen conditions. Nitrosomonas and Nitrobacter spp. are better competitors with abundant substrates and have higher nitrite tolerance, so they could excel under alternating conditions. This theoretical explanation is consistent with the kinetics and environmental conditions in these reactors and argues for using alternating treatment, because the harsh conditions select for populations with inherently faster nitrification rates.


Computational analysis of interactions of oxidative stress and tetrahydrobiopterin reveals instability in eNOS coupling.
In cardiovascular and neurovascular diseases, an increase in oxidative stress and endothelial dysfunction has been reported. There is a reduction in tetrahydrobiopterin (BH4), which is a cofactor for the endothelial nitric oxide synthase (eNOS), resulting in eNOS uncoupling. Studies of the enhancement of BH4 availability have reported mixed results for improvement in endothelial dysfunction. Our understanding of the complex interactions of eNOS uncoupling, oxidative stress and BH4 availability is not complete and a quantitative understanding of these interactions is required. In the present study, we developed a computational model for eNOS uncoupling that considers the temporal changes in biopterin ratio in the oxidative stress conditions. Using the model, we studied the effects of cellular oxidative stress (Qsupcell) representing the non-eNOS based oxidative stress sources and BH4 synthesis (QBH4) on eNOS NO production and biopterin ratio (BH4/total biopterins (TBP)). Model results showed that oxidative stress levels from 0.01 to 1nM·s-1 did not affect eNOS NO production and eNOS remained in coupled state. When the Qsupcell increased above 1nM·s-1, the eNOS coupling and NO production transitioned to an oscillatory state. Oxidative stress levels dynamically changed the biopterin ratio. When Qsupcell increased from 1 to 100nM·s-1, the endothelial cell NO production, TBP levels and biopterin ratio reduced significantly from 26.5 to 2nM·s-1, 3.75 to 0.002μM and 0.99 to 0.25, respectively. For an increase in BH4 synthesis, the improvement in NO production rate and BH4 levels were dependent on the extent of cellular oxidative stress. However, a 10-fold increase in QBH4 at higher oxidative stresses did not restore the NO-production rate and the biopterin ratio. Our mechanistic analysis reveals that a combination of enhancing tetrahydrobiopterin level with a reduction in cellular oxidative stress may result in significant improvement in endothelial dysfunction.


Sequence specific binding of tetraols of benzo[a]pyrene-diol-epoxide to DNA in neutral and acidic solutions.
Comparative binding studies of tetraols (anti- BPTs ) derived from trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetra- hydrobenzo [a]py rene (anti-BPDE) with native DNA in neutral and acidic solutions reveal that 4-5 times stronger intercalative binding occurs in the protonated duplex DNA than in the unprotonated one. Spectroscopic (absorption and circular dichroism) investigations with synthetic polynucleotides indicate that in neutral pH, anti- BPTs intercalate significantly in poly(dA-dT):poly(dA-dT), only slightly in guanine containing alternating polynucleotides poly(dG-dC): poly(dG-dC) and poly(dA-dC):poly(dG-dT), and hardly in homopolymers poly(dG):poly(dC) and poly(dA):poly(dT). In acidic solutions, on the other hand, all three alternating polynucleotides, poly(dG-dC):poly(dG-dC) in particular, exhibit strong intercalative binding to anti- BPTs although the homopolymers still lack such capability. These results are very similar to those of corresponding pyrene studies suggesting that pyrene can be a useful model compound for the DNA binding studies of benzo[a]pyrene metabolites. The observed enhanced binding of anti- BPTs in the acidic natural DNA solution is seen as the consequence of changes in base sequence preference upon base protonation.


FOUNDER EFFECTS AND THE RATE OF MITOCHONDRIAL DNA EVOLUTION IN HAWAIIAN DROSOPHILA.
The nearly-neutral-mutation theory predicts that populations with small effective sizes will undergo more rapid molecular evolution than populations with very large effective sizes. In particular, Ohta (1976) predicted that populations of Hawaiian Drosophila that are known to have small population sizes and to experience repeated population bottlenecks due to founder events should show a more rapid rate of molecular evolution relative to the rate of molecular evolution of species with large population sizes such as the continental Drosophila. In this paper we test this prediction by comparing the rate of molecular evolution in two closely related lineages of Hawaiian Drosophila that have experienced very different evolutionary histories. Both lineages belong to the planitibia subgroup of Hawaiian Drosophila. The beta lineage (which includes D. silvestris, D. planitibia, D. differens, and D. hemipeza) has undergone repeated founder events, as evidenced by their geographic distribution and behavioral biology. On the other hand, evidence on geographic distribution and behavior indicates that the alpha lineage (which includes D. melanocephala, D. cyrtaloma, and D. neoperkinsi) has arisen from large ancestral populations without founder effects. The mitochondrial DNA data reveal that, within a lineage, the rate of molecular evolution is rather uniform, while all comparisons between the two lineages show that the rate of molecular evolution in the beta lineage is three times that of the alpha lineage. This analysis strongly supports the predictions made by Ohta.


Adaptive Designs with Discrete Test Statistics and Consideration of Overrunning.
Interim analyses are used in clinical trials in order to enable early decisions for medical, ethical, and economic reasons. However, it appears unfeasible to stop a trial during such an interim analysis. New patients will thus enter the trial while the interim analysis is ongoing. Moreover, depending on the event kinetics of the specific disease, the trial design, and the corresponding endpoints, some patients might still be unevaluable at the interim analysis due to not yet completed follow-up. Occurrence of these types of patients is characteristic for sequentially analyzed trials. Such patients are referred to as interim patients. In trials with multiple primary endpoints, another type of interim patients occurs. If some but not all null hypotheses can be rejected at the interim analysis, the trial might be continued to a second stage in order to answer the remaining questions. These second stage patients, however, provide new data to all trial questions including the already rejected ones and thus formally act as interim patients regarding the already rejected null hypotheses. Although all kinds of interim patients are not part of the interim analysis, the data collected on those patients have to be sent to the office of regulatory affairs and will be analyzed. If a smaller or contrasting treatment effect is observed in interim patients, this might lead to a withdrawal of an earlier superiority proof. Presently, interim patients and their data are usually not considered in the confirmatory test. We offer a strategy to deal with interim patients in sequentially analyzed trials with discrete test statistics. The method covers sequentially analyzed single- and multi-arm trials with one or multiple primary endpoints. When planning adaptive designs, it is common practice to assume that the stage-wise p-values are independent and standard uniformly distributed under the null hypothesis. In the context of discrete test statistics, this implies conservative tests. We provide an algorithm which iteratively optimizes an initially given design while adjusting for both discreteness of test statistics and interim patients. The algorithm is described verbally, graphically and formally to facilitate immediate implementation in computer software. The optimized design exploits the aspired significance level better and is more powerful than the initial one. The algorithm applies to fixed sample and planned flexible adaptive designs for single- and multi-arm trials with one or multiple primary endpoints. The benefit increases with the number of interim patients. When planning a trial with interim analyses, the rules for decisions must be adjusted to interim patients. Otherwise, the test procedure is conservative resulting in loss of power. This is essential in situations where the number of interim patients is important compared to the first stage, particularly in trials with multiple primary endpoints.


[A long-survival case of unresectable liver metastasis of colon cancer by hepatic arterial intermittent multidrug infusion chemotherapy].
We experienced a long-survival case with unresectable liver metastasis of sigmoid cancer by hepatic arterial intermittent multidrug infusion chemotherapy. The patient was a 65-year-old man. A movable tumor was palpable at the left lower abdomen. The serum CEA value was 15.6 ng/ml. Abdominal CT scan showed a 3 cm-sized low-density area near the root of the right and middle hepatic vein in segment 4. He had undergone sigmoidectomy, cholecystectomy and cannulation into the proper hepatic artery. Chemotherapy was performed by using 5-FU (250 mg), Adriacin (5 mg) and mitomycin C (4 mg) every second week from 4 months after surgery as an outpatient. In the CT scan image, the low-density area completely disappeared at 10 months after treatment, and the CR interval was 14 months. The patient has been alive for 5 years after surgery.


Clinical relevance of E2F family members in ovarian cancer--an evaluation in a training set of 77 patients.
The major obstacle in treating ovarian cancer is the rapid development of platinum resistance during therapy. Deregulation of members of the E2F family of transcription factors is crucially involved in carcinogenesis and probably in mechanisms underlying platinum resistance. We therefore investigated the relevance of the whole set of E2F family members in predicting clinical outcome and their significance in predicting platinum resistance. Real-time PCR of all E2F family members was done from 77 ovarian carcinomas, defined as our training set, and 8 healthy control samples. The correlation with clinicopathologic characteristics, platinum resistance, and survival was investigated. Furthermore, the cross-talk of E2F family members was assessed for its value in predicting survival and platinum resistance. The proliferation-promoting E2F1 and E2F2 were associated with grade 3 tumors and residual disease >2 cm in diameter after initial surgery. Survival analyses showed low expression of E2F1 or E2F2 to be significantly associated with favorable disease-free and overall survival (E2F1, P = 0.039 and 0.047, respectively; E2F2, P = 0.009 and 0.006, respectively). In contrast, high expression of inhibiting E2F4 or E2F7 predicted favorable disease-free and overall survival (E2F4, P = 0.047 and 0.042, respectively; E2F7, P = 0.048 and 0.042, respectively). A high E2F2 to E2F4 ratio was the most valuable prognostic variable for disease-free survival in multivariate analysis (hazard ratio, 6.494; P = 0.002). Tumors considered platinum resistant were associated with lower E2F4 and E2F7 expression (P = 0.012 and 0.009, respectively) compared with platinum-sensitive tumors. Again, ratios of E2F1 or E2F2 to E2F7 were the most favorable variables in predicting platinum resistance. We here show that deregulation of both proliferation-promoting and proliferation-inhibiting E2F transcription factors and their cross-talk is crucially involved in the tumor biology of ovarian cancer and influences clinical outcome. Furthermore, down-regulation of E2F7 may contribute to mechanisms underlying platinum resistance, and calculation of ratios of proliferation-promoting E2F1 to E2F7 could serve as a putative predictor of platinum resistance.


A Rare but Life-Threatening Case of Fournier's Gangrene Caused by Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor, Empagliflozin.
Fournier's gangrene (FG) is a rare but severe infection in the soft tissue, leading to necrosis in the perineum, perianal and genitourinary area. This infection can spread rapidly in the body and lead to multi-organ failure, septic shock, and death. This life-threatening infection is usually caused by polymicrobial agents like Group A - Beta Hemolytic Streptococcus- Streptococcus pyogenes, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Proteus, and anaerobes like Bacteroides and Clostridium perfringes. Risk factors related to the development of FG are obesity, uncontrolled diabetes, lack of education, poor personal hygiene, especially in the genital region, history of fungal infection, recurrent urinary tract infection, smoking, immunosuppression, and medication. In 2018, a safety warning was issued by The U.S. Food and Drug Administration (FDA) on sodium-glucose cotransporter-2 (SGLT2) inhibitors, causing a rare but serious adverse outcome of FG in patients with type 2 diabetes mellitus. It is established that the increased urinary glucose concentration caused by SGLT-2 inhibitors creates a suitable environment for the growth of the infection in the urinary and genital area, leading to the development of FG. Here we present a case of life-threatening FG in an obese female with a past medical history of type 2 diabetes mellitus with recurrent history of genital yeast infection four months after starting an SGLT2 inhibitor, empagliflozin. This study aims to understand the relationship between the FG and SGLT-2 inhibitor, overall the benefits of SGLT2 inhibitors outweighs the risk manyfold, therefore, raising awareness among clinician to be vigilant, keep a high index of suspicion and focus on the safe use of SGLT2 inhibitors, especially before and after prescribing SGLT-2 inhibitor with a close follow-up to prevent its serious and life-threatening emergency like Fournier's gangrene and necrotizing fasciitis.


Early inoculation of an endophyte alters the assembly of bacterial communities across rice plant growth stages.
The core endophytes of plants are regarded as promising resources in future agroecosystems. How they affect the assembly of rice-related bacterial communities after early inoculation remains unclear. Here, we examined bacterial communities across 148 samples, including bulk and rhizosphere soils, sterilized roots, stems, and seeds at the seedling, tillering, booting, and maturity stages. Tissue cultured rice seedlings were inoculated with Xathomonas sacchari JR3-14, a core endophytic bacterium of rice seeds, before transplanting. The results revealed that α-diversity indices were significantly enhanced in the root and stem endosphere at the seedling stage. β-diversity was altered at most plant developmental stages, except for the root and stem at the booting stage. Network complexity consequently increased in the root and stem across rice growth stages, other than the stem endosphere at the booting stage. Four abundant beneficial bacterial taxa, Bacillus, Azospira, Azospirillum, and Arthrobacter, were co-enriched during the early growth stage. Infer Community Assembly Mechanisms by Phylogenetic-bin-based null model analysis revealed a higher relative contribution of drift and other eco-evolutionary processes mainly in root compartments across all growth stages, but the opposite pattern was observed in stem compartments. IMPORTANCE Endophytic bacteria are regarded as promising environmentally friendly resources to promote plant growth and plant health. Some of microbes from the seed are able to be carried over to next generation, and contribute to the plant's ability to adapt to new environments. However, the effects of early inoculation with core microbes on the assembly of the plant microbiome are still unclear. In our study, we demonstrate that early inoculation of the rice seed core endophytic bacterium Xanthomonas sacchari could alter community diversity, enhance complexity degree of network structure at most the growth stages, and enrich beneficial bacteria at the seedling stage of rice. We further analyzed the evolutionary processes caused by the early inoculation. Our results highlight the new possibilities for research and application of sustainable agriculture by considering the contribution of seed endophytes in crop production and breeding.


The Activity of Special Continuity Care Units in the City of Florence During the COVID-19 Pandemic.
Objectives: Worldwide, countries adopted different strategies in primary care (PC) to cope with the COVID-19 pandemic. This study aims to describe and evaluate the functions and activity load of a specific PC organizational model called "Special Continuity Care Units" (SCCU) in Florence, Italy, and to investigate the characteristics of the COVID-19 patients assisted by the service. Methods: The retrospective cross-sectional design used daily updated reports by SCCU team members to evaluate the activity load. The retrospective cohort study analyzed data of the demographics, clinical characteristics, and process outcomes of patients assisted during the second pandemic wave. Results: The analysis shows how the service activity load changed along with the epidemiological trend. Regarding people assisted by the SCCU, the median follow-up duration of symptoms was 6 days; male gender and being symptomatic were predictors of hospitalization. Conclusion: Some key characteristics can be described as indispensable in PC services facing health emergencies: model flexibility, the availability of resources, networking among services to enhance coordination and resource optimization, and close collaboration with general practitioners.


Functionalized Cobalt Triarylcorrole Covalently Bonded with Graphene Oxide: A Selective Catalyst for the Two- or Four-Electron Reduction of Oxygen.
A cobalt triphenylcorrole (CorCo) was covalently bonded to graphene oxide (GO), and the resulting product, represented as GO-CorCo, was characterized by UV-vis, FT-IR, and micro-Raman spectroscopy as well as by HRTEM, TGA, XRD, XPS, and AFM. The electrocatalytic activity of GO-CorCo toward the oxygen reduction reaction (ORR) was then examined in air-saturated 0.1 M KOH and 0.5 M H2SO4 solutions by cyclic voltammetry and linear sweep voltammetry using a rotating disk electrode and/or a rotating ring-disk electrode. An overall 4-electron reduction of O2 is obtained in alkaline media while under acidic conditions a 2-electron process is seen. The ORR results thus indicate that covalently bonded GO-CoCor can be used as a selective catalyst for either the 2- or 4-electron reduction of oxygen, the prevailing reaction depending upon the acidity of the solution.


Cloning and expression in Escherichia coli of genes encoding a multiprotein complex involved in secretion of proteins from Staphylococcus aureus.
The genes encoding the multiprotein membrane-bound ribosomal protein (MBRP) complex (mrp genes), associated with membrane-bound ribosomes in Staphylococcus aureus, were cloned in Escherichia coli. All four components (molecular sizes 71, 60, 46, and 41 kilodaltons) of the MBRP complex were expressed from an 8.5-kilobase DNA fragment as judged by Western blot (immunoblot) analysis. The order of the individual genes within the cloned DNA fragment was determined by deletion mutagenesis and subcloning of various restriction fragments. Three RNAs, transcribed from the same DNA strand, were identified within the MBRP-coding region: one large RNA of approximately 5.9 kilobases, presumably coding for all four MBRP components, and two minor RNAs, coding for MBRP-71 and MBRP-60. The two minor RNAs seemed to be transcribed from promoters within the large transcription unit. Attempts to make insertional inactivations of the mrp genes with an internal 600-base-pair DNA fragment of the MBRP-coding region as a target were unsuccessful, presumably because such insertions are lethal.


Nucleotide sequences important in DNA replication are responsible for differences in the capacity of two herpes simplex virus strains to spread from cornea to central nervous system.
Two herpes simplex virus (HSV) intertypic recombinants were isolated with genomes composed entirely of HSV-2(186) nucleotide sequences except for a 6.0 kb segment of HSV-1(17) DNA positioned between 0.40 and 0.44 map units. Following corneal infection of mice, HSV-1(17) and the two intertypic recombinants spread from infected eyes into the central nervous system and induced a fatal encephalitis. Ocular infection with the HSV-2(186) parent did not lead to detectable amounts of virus in the brain, and none of the mice developed encephalitis. The 6.0 kb HSV-1(17) DNA inserted within the genome of the two intertypic recombinants contained nucleotide sequences involved in DNA replication. These include the HSV-1(17) oriL, the HSV-1(17) gene for DNA polymerase and portions of the HSV-1(17) gene coding for DNA-binding protein ICP8. Thus, our results indicate that the difference in the capacity of HSV-1(17) and HSV-2(186) to spread from the cornea into the CNS is determined solely by nucleotide sequences associated with DNA replication.


Characterisation of the MutS and MutL Proteins from the Pseudomonas avellanae Mismatch Repair (MMR) System.
The identification and analysis of the Pseudomonas avellanae mismatch repair system (MMR) were performed via sequencing and cloning the mutS and mutL genes and then analyzing the characteristics of the corresponding proteins studying their function and biological role in an E. coli heterologous system. In these studies, the P. avellanae MutS and MutL proteins were shown to localise at the nucleoid level, in a MutS-dependent manner as far as MutL is concerned, and were also able to complement the defect observed in both the mutS and mutL knockout strains of E. coli. In addition, their ability to form both homo and heterodimers between each other was shown by using the prokaryotic two-hybrid assay. Our results represent a first step to elucidate the MMR mechanism in plant pathogenic pseudomonads since the MMR genes were identified in P. syringae pathovars but there was no evidence on their action as effective repair products.


hPEBP4 resists TRAIL-induced apoptosis of human prostate cancer cells by activating Akt and deactivating ERK1/2 pathways.
The treatment options available for prostate cancer are limited because of its resistance to therapeutic agents. Thus, a better understanding of the underlying mechanisms of the resistance of prostate cancer will facilitate the discovery of more efficient treatment protocols. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is recently identified by us as an anti-apoptotic molecule and a potential candidate target for breast cancer treatment. Here we found the expression levels of hPEBP4 were positively correlated with the severity of clinical prostate cancer. Furthermore, hPEBP4 was not expressed in TRAIL-sensitive DU145 prostate cancer cells, but was highly expressed in TRAIL-resistant LNCaP cells, which show highly activated Akt. Interestingly, hPEBP4 overexpression in TRAIL-sensitive DU145 cells promoted Akt activation but inhibited ERK1/2 activation. The hPEBP4-overexpressing DU145 cells became resistant to TRAIL-induced apoptosis consequently, which could be reversed by PI3K inhibitors. In contrast, silencing of hPEBP4 in TRAIL-resistant LNCaP cells inhibited Akt activation but increased ERK1/2 activation, resulting in their sensitivity to TRAIL-induced apoptosis that was restored by the MEK1 inhibitor. Therefore, hPEBP4 expression in prostate cancer can activate Akt and deactivate ERK1/2 signaling, leading to TRAIL resistance. We also demonstrated that hPEBP4-mediated resistance to TRAIL-induced apoptosis occurred downstream of caspase-8 and at the level of BID cleavage via the regulation of Akt and ERK pathways, and that hPEBP4-regulated ERK deactivation was upstream of Akt activation in prostate cancer cells. Considering that hPEBP4 confers cellular resistance to TRAIL-induced apoptosis and is abundantly expressed in poorly differentiated prostate cancer, silencing of hPEBP4 suggests a promising approach for prostate cancer treatment.


Progress toward understanding the neurophysiological basis of predator-induced morphology in Daphnia pulex.
Previous studies have demonstrated that certain pesticides, including carbaryl and endosulfan, can modulate the expression of predator-induced morphology in Daphnia. These pesticides affect the transmission of nervous impulses in vertebrates and invertebrates. The aim of this study was to determine the role of two neurotransmitter systems, excitatory cholinergic transmission and inhibitory gamma-aminobutyric acid (GABA)-mediated transmission, in the regulation of inducible defenses of Daphnia. The effects of chemicals with four different modes of action on the expression of Chaoborus-induced neckteeth in Daphnia pulex were measured. These chemicals included chemicals that could enhance transmission at cholinergic synapses (physostigmine, nicotine), inhibit cholinergic transmission (atropine), stimulate or enhance the effects of GABA (diazepam, muscimol, cis-4-aminocrotonic acid), or antagonise the action of GABA (picrotoxin, bicuculline, SR95531). The development of Chaoborus-induced neckteeth in D. pulex was enhanced by physostigmine and picrotoxin and suppressed by atropine. It was proposed that these chemicals were acting on neurosecretory cells that release the hormones necessary to induce neckteeth development. The results also indicate mechanisms through which anthropogenic pollutants could influence the expression of inducible defenses, leading to inappropriate expression in environments with low predator intensity or to suppression in environments with high risks of predation.


Susceptibility of soil organic carbon to priming after long-term CO2 fumigation is mediated by soil texture.
Elevated CO2 (eCO2) may enhance soil organic carbon (SOC) sequestration via greater input of photosynthetic carbon (C). However, greater rhizodeposits under eCO2 may stimulate microbial decomposition of native SOC. This study aimed to examine the status and stability of SOC in three Australian cropping soils after long-term CO2 enrichment. Samples (0-5 cm) of Chromosol, Vertosol and Calcarosol soils were collected from an 8-year Free-air CO2 Enrichment (SoilFACE) experiment and were used to examine SOC dynamics by physical fractionation and incubation with 13C-glucose. Compared to the ambient CO2 (aCO2) (390-400 μmol mol-1), 8 years of elevated CO2 (eCO2) (550 μmol mol-1) did not increase SOC concentration of all soils, but changed SOC distribution with 12% more C in coarse soil fractions and 5% less C in fine fractions. Elevated CO2 also enhanced the susceptibility of SOC to 13C-glucose-induced priming, but this effect was only significant in the coarse-textured Calcarosol topsoil. The eCO2 history increased labile C (coarse C fraction, +13%) and soil pH (+0.25 units), and decreased available N (-30%) in the Calcarosol, which stimulated microbial biomass C by 28%, leading to an enhanced priming effect. Despite with greater total primed C, the Chromosol that had the highest amount of native C, had lower primed C per unit of SOC when compared to the low-C Calcarosol. In conclusion, the effect of long-term eCO2 enrichment on soil C and N availability in cropping soils depended on soil type with the coarse-textured Calcarosol soil being more susceptible to substrate-induced decomposition of its SOC.


Cryptococcus spp isolated from dust microhabitat in Brazilian libraries.
The Cryptococcus spp is currently composed of encapsulated yeasts of cosmopolitan distribution, including the etiological agents of cryptococcosis. The fungus are found mainly in substrates of animal and plant origin. Human infection occurs through inhalation of spores present in the environment. Eighty-four swab collections were performed on dust found on books in three libraries in the city of Cuiabá, state of Mato Grosso, Brazil. The material was seeded in Sabouraud agar and then observed for characteristics compatible with colonies with a creamy to mucous aspect; the material was then isolated in birdseed (Niger) agar and cultivated at a temperature of 37°C for 5 to 7 days. Identification of isolated colonies was performed by microscopic observation in fresh preparations dyed with India ink, additional tests performed on CGB (L-canavanine glycine bromothymol blue), urea broth, and carbohydrate assimilation tests (auxanogram). Of the 84 samples collected from book dust, 18 (21.4%) were positive for Cryptococcus spp totalizing 41 UFC's. The most frequently isolated species was C. gattii 15 (36.6%); followed by C. terreus, 12 (29.3%); C. luteolus 4 (9.8%); C. neoformans, and C. uniguttulatus 3 (7.3%), and C. albidus and C. humiculus with 2 (4.6%) of the isolates. The high biodiversity of the yeasts of the Cryptococcus genus, isolated from different environmental sources in urban areas of Brazil suggests the possibility of individuals whose immune systems have been compromised or even healthy individuals coming into sources of fungal propagules on a daily bases throughout their lives. This study demonstrates the acquisition possible of cryptococcosis infection from dust in libraries.


Bone marrow infiltrate by a poorly differentiated neuroendocrine carcinoma.
We report a rare case of bone marrow infiltrate by a neuroendocrine carcinoma. The patient was a 66-year-old man who presented with anemia and thrombocytopenia and with a leukoerythroblastic picture on blood films. A bone marrow biopsy revealed extensive tumor infiltrate with morphological and immunohistochemical features of neuroendocrine origin. There were also multiple nodular lesions in the liver, which showed the same pathology as that in the bone marrow. Since none of the lesions could be identified as the primary tumor, the patient was diagnosed to have a poorly differentiated neuroendocrine carcinoma of unknown primary site.


Exercise Prior to Lower Extremity Peripheral Artery Disease Improves Endurance Capacity and Hindlimb Blood Flow by Inhibiting Muscle Inflammation.
Lower extremity peripheral artery disease (PAD) is associated with functional decline. Physical exercise has been proven to be an effective therapeutic strategy for PAD; however the effect of exercise initiated before PAD remains unknown. Here, we investigated the preventive effects of exercise on endurance capacity, hindlimb perfusion, and on polarization profile of circulating monocytes and limb muscle macrophages. ApoE-/- mice were subjected to 5-week running wheel exercise or remained sedentary before induction of hindlimb ischemia. The two groups were thereafter kept sedentary. Exercised mice prior to PAD showed higher exhaustive treadmill running distance and time than sedentary mice. Preventive exercise also increased perfusion, arteriole density, and muscle regeneration in the ischemic hindlimb. Moreover, preventive exercise prevented ischemia-induced increased gene expression of pro-inflammatory M1 macrophages markers and cytokines in the ischemic muscle, while no changes were observed for anti-inflammatory M2 macrophage markers. Flow cytometry analysis showed that the proportion of circulating pro-inflammatory monocyte subtype decreased whereas that of anti-inflammatory monocytes increased with preventive exercise. Overall, we show that exercise initiated before PAD improves endurance performance and hindlimb perfusion in mice probably via inhibition of M1 macrophage polarization and inflammation in the ischemic muscle. Our study provides experimental evidence for a role of regular exercise in primary prevention of PAD.


An analysis of the properties of monoclonal antibodies directed to epitopes on influenza virus hemagglutinin.
Monoclonal antibodies (MAbs) specific for the hemagglutinin (HA) of the H3 subtype of influenza A virus were grouped according to their inability to bind to particular MAb-selected neutralization escape mutants of the virus having an amino acid substitution in one of the five postulated antigenic sites on the molecule. Additional residues critical to the binding of the MAbs were deduced from their patterns of reactivity with a panel of field strains and receptor mutants of the H3 subtype. The relationship of these residues to the actual epitopes recognized by the MAbs was inferred from their location on the three-dimensional structure of the HA molecule. In this way it was generally possible to identify a number of residues that are critical to the integrity of the epitope recognized by each of the MAbs examined. It was found that: (1) Several of these epitopes appear to be discontinuous and some may depend on residues contributed by more than one monomer. For example, residue 205, in the interface between monomers of the HA, was found to affect the integrity of the epitopes for several MAbs, possibly by stabilizing the conformation of residues around the receptor-binding pocket and/or in site B on the adjacent monomer. The activity of these particular MAbs was greatly decreased if the virus was exposed to pH 5. (2) All the MAbs tested neutralized viral infectivity and inhibited hemagglutination, although the single MAb directed to site C, which is the most distant from the receptor-binding site, was the least efficient. (3) Hemagglutination inhibition, and particularly neutralization tests, were more discriminating than ELISA in discerning subtle differences between the corresponding epitopes recognized by MAbs on different field strains. (4) Efficiency of neutralization of infectivity did not correlate consistently with hemagglutination inhibiting efficiency; MAbs postulated to bind to epitopes close to the receptor-binding pocket were very efficient at inhibiting hemagglutination, whereas neutralization efficiency tended to be more influenced by the affinity of binding of the MAb. (5) A MAb binding to any particular epitope could affect the binding of a second MAb directed to an epitope within the same or even a different antigenic site. The observed effect was most commonly inhibition of binding, which was not always reciprocal; enhancement of binding was also observed with certain combinations of MAbs. The relative affinity of the MAbs, in addition to steric constraints, were shown to be important factors in the ability to compete for interaction with HA.


A Tale of Two Joints: The Role of Matrix Metalloproteases in Cartilage Biology.
Matrix metalloproteinases are a class of enzymes involved in the degradation of extracellular matrix molecules. While these molecules are exceptionally effective mediators of physiological tissue remodeling, as occurs in wound healing and during embryonic development, pathological upregulation has been implicated in many disease processes. As effectors and indicators of pathological states, matrix metalloproteinases are excellent candidates in the diagnosis and assessment of these diseases. The purpose of this review is to discuss matrix metalloproteinases as they pertain to cartilage health, both under physiological circumstances and in the instances of osteoarthritis and rheumatoid arthritis, and to discuss their utility as biomarkers in instances of the latter.


Role of music in the management of chronic obstructive pulmonary disease (COPD): a literature review.
Chronic obstructive pulmonary disease (COPD) is a pulmonary disease characterized by airflow limitation that is not fully reversible. It is projected to be the third leading cause of death worldwide by 2020. The objective of the study was to examine the impact of music on psychological and physiological outcomes among individuals with COPD. The scientific databases PubMed, google scholar and EBSCO were used to search for relevant articles published during a period of 01/01/2005 to 12/31/2012. The search terms "Music and COPD", "Music and Emphysema", "Singing and COPD", "Singing and Emphysema" , "music improves COPD" and "singing therapy on COPD", were used either in single or in combination. The inclusion criteria included studies having an experimental study design, were written in English and were conducted among individuals age 18 years and above. Studies that focused on the healthy population or had a disease other than COPD were excluded. Studies where music therapy was not the primary intervention and were systematic reviews were also excluded from the final analysis. Variables analyzed included year of publication, study location, study setting, target audience, study design, sample size, study duration, intervention and its components and the outcomes including physiological and psychological were assessed. A total of 7 papers that met the inclusion criteria were included in the final analysis. Studies included various music interventions such as singing, listening and playing music. Forty percent of the studies were performed in US. More than half of the studies (70%, n=5) had a randomized control study design and were performed in a hospital setting. The duration of the studies varied from 6 weeks to 21 months. The sample size in these studies varied from 7 to 72. Music showed improvement in the psychological outcomes such as quality of life, dyspnea and anxiety and mixed results in the improvement of physiological outcomes such as FEV, FVC, and breathing control among individuals living with COPD. More research of a longer duration and with a larger sample size is needed to examine the impact of music interventions on clinical, functional, psychological and physiological outcomes among COPD individuals.


Relationship between antibiotic resistance, efflux pumps, and biofilm formation in extended-spectrum β-lactamase producing Klebsiella pneumoniae.
Klebsiella pneumoniae is an important pathogen both in community and hospital environment. In this study, we aimed to determine the antibiotic susceptibilities, expression levels of AcrA, ketM, kdeA, kpnEF, and kexD genes related to efflux pump and biofilm formation in 100 extended-spectrum β-lactamase producing Klebsiella pneumoniae. The relative expression levels of AcrA, ketM, kdeA, kpnEF, and kexD were determined by quantitative real-time PCR and biofilm formation was screened by microtiter plate assay. Based on CLSI breakpoints, zone diameters showed that 72% of isolates were resistant to ceftazidime, 79% to aztreonam, 54% to ciprofloxacin, 32% to ertapenem, 74% to tobramycin, 65% to tetracycline and all isolates were resistant to ampicillin, ceftriaxone, and cefotaxime. The relative expression of AcrA was upregulated in ciprofloxacin susceptible isolates and also upregulation of newly described efflux pump, kexD, was correlated with tobramycin and aztreonam resistance. A significant correlation was observed between resistance-nodulation-division and single-type efflux pumps. On the other hand, ciprofloxacin susceptible isolates formed stronger biofilms than resistant isolates. The up or down regulation of efflux pumps didn't enhance biofilm formation capacity.


A new therapeutic strategy for the eradication of Helicobacter pylori infection.
For the eradication of the Helicobacter pylori infection, authors have tested 50 HP-positive subjects (28 females and 22 males; mean age 47 years): 21 duodenal ulcers and 29 gastritis. All patients received the following treatment: omeprazole 40 mg for 30 days, azithromycin 500 mg in a single daily dose for 3 days for 2 cycles and metronidazole 250 mgx4 for 14 days. One month after the end of therapy, patients have been controlled: the HP eradication rates have been 76% (35/46), duodenal ulcer was cured in 90% (18/20). No important side-effects were reported by patients during the treatment. In conclusion the new therapeutic scheme with azithromycin represents a semplificated alternative treatment in the eradication of Helicobacter pylori.


Active surveillance of acute paediatric hospitalisations demonstrates the impact of vaccination programmes and informs vaccine policy in Canada and Australia.
Sentinel surveillance of acute hospitalisations in response to infectious disease emergencies such as the 2009 influenza A(H1N1)pdm09 pandemic is well described, but recognition of its potential to supplement routine public health surveillance and provide scalability for emergency responses has been limited. We summarise the achievements of two national paediatric hospital surveillance networks relevant to vaccine programmes and emerging infectious diseases in Canada (Canadian Immunization Monitoring Program Active; IMPACT from 1991) and Australia (Paediatric Active Enhanced Disease Surveillance; PAEDS from 2007) and discuss opportunities and challenges in applying their model to other contexts. Both networks were established to enhance capacity to measure vaccine preventable disease burden, vaccine programme impact, and safety, with their scope occasionally being increased with emerging infectious diseases' surveillance. Their active surveillance has increased data accuracy and utility for syndromic conditions (e.g. encephalitis), pathogen-specific diseases (e.g. pertussis, rotavirus, influenza), and adverse events following immunisation (e.g. febrile seizure), enabled correlation of biological specimens with clinical context and supported responses to emerging infections (e.g. pandemic influenza, parechovirus, COVID-19). The demonstrated long-term value of continuous, rather than incident-related, operation of these networks in strengthening routine surveillance, bridging research gaps, and providing scalable public health response, supports their applicability to other countries.


[Prognostic value of metastatic lymph node ratio for gastric cancer patients with less than 15 lymph nodes dissection].
To evaluate the prognostic value of metastatic lymph node ratio (MLR) for gastric cancer patients with less than 15 lymph nodes dissected. Clinical data of 610 gastric cancer patients undergoing operation in Tianjin Cancer Hospictal from January 2003 to July 2007 were analyzed retrospectively. Patients were divided into two groups: <15 lymph nodes dissected group (n=320) and ≥ 15 lymph nodes dissected group (n=290). MLR was classified based on the following intervals: rN1 ≤ 10%, rN2 10%-30%, rN3 30%-60% and rN4 >60%. Survival was determined by Kaplan-Meier method and difference was assessed by Log-rank test. Multivariate analysis was performed using Cox proportional hazard regression model. Survival rates were compared between two groups in pN and rN stages respectively. In <15 nodes group, all the survival differences among various rN stages were not significant (all P>0.05), while in same rN stage, all the survival differences among various pN stages were not significant (all P>0.05). Significant differences of 5-year cumulative survival rates were found between the two groups in pN2 and pN3a stage patients (both P<0.05) while no significant differences were found among different rN stages (all P>0.05). Multivariate analysis demonstrated rN stage was an independent prognostic factor for gastric cancer patients with <15 lymph nodes dissected (P=0.012, RR=1.617, 95%CI:1.111-2.354). The rN staging system based on MLR can predict the prognosis of gastric cancer patients with less than 15 lymph nodes dissected.


Classification and visualization based on derived image features: application to genetic syndromes.
Data transformations prior to analysis may be beneficial in classification tasks. In this article we investigate a set of such transformations on 2D graph-data derived from facial images and their effect on classification accuracy in a high-dimensional setting. These transformations are low-variance in the sense that each involves only a fixed small number of input features. We show that classification accuracy can be improved when penalized regression techniques are employed, as compared to a principal component analysis (PCA) pre-processing step. In our data example classification accuracy improves from 47% to 62% when switching from PCA to penalized regression. A second goal is to visualize the resulting classifiers. We develop importance plots highlighting the influence of coordinates in the original 2D space. Features used for classification are mapped to coordinates in the original images and combined into an importance measure for each pixel. These plots assist in assessing plausibility of classifiers, interpretation of classifiers, and determination of the relative importance of different features.


Molecular effects of dimethylanatoxin on the peripheral nicotinic acetylcholine receptor.
N,N-dimethylanatoxin (DMAnTX), the quaternary derivative of the potent nicotinic agonist (+)-anatoxin-a (AnTX), has been evaluated for potency and efficacy at nicotinic acetylcholine receptors of frog motor endplates and Torpedo electric organs. DMAnTX was only weakly effective in eliciting contracture of the frog rectus abdominis and was orders of magnitude less potent than AnTX. Biochemical assay showed that DMAnTX was a weak inhibitor of [125I]alpha-bungarotoxin binding to the receptors in frog muscle and Torpedo electroplaque membranes: the IC50 values were 60 and 14 microM, respectively. A low frequency of single channel currents recorded from isolated interosseal fibers at concentrations from 20 to 100 microM of DMAnTX and the stimulation of [3H]perhydrohistrionicotoxin [( 3H]H12-HTX) binding (half-maximal at 0.3 microM) confirmed the weak activation of the receptor. DMAnTX also exhibited antagonist effects. In muscle twitch assays, 100 microM of DMAnTX effectively decreased the tension induced by nerve stimulation, although DMAnTX did not affect muscle membrane action potentials. The binding of [3H] perhydrohistrionicotoxin was also inhibited at high micromolar concentrations of DMAnTX. Combination of DMAnTX with acetylcholine in single channel current experiments demonstrated that DMAnTX possesses ion channel blocking properties, which become apparent at low micromolar concentrations, and DMAnTX enhances the desensitization induced by acetylcholine above 10 microM AnTX. The difference in agonist potency between AnTX and DMAnTX may be attributed to a change in conformation of the molecular skeleton induced by the N-methyl groups.


Measurement of density profile and fluctuations using a multi-channel terahertz solid-state interferometer system on Keda Torus eXperiment (KTX).
A five-chord interferometer based on terahertz solid state sources has been successfully installed on the Keda Torus eXperiment (KTX), a reversed field pinch machine. The optical design has been carefully optimized for the uniform distribution of beam light to fully use the limited power source (∼2 mW). By setting the telescopic mirror unit, the beam waist is located in the center of the vacuum vessel and its diameter is in the range of the Rayleigh length. The beam width across the plasma area is improved to ∼20 mm to minimize crosstalk and beam energy loss. After careful beam alignment, the phase noise for each channel can reach 0.004π. The radial profiles of electron density on the KTX are inverted, and density fluctuation associated with instabilities is shown based on the forward-scattering signals.


[Bacteriological and parasitological investigations in public indoor swimming baths (author's transl)].
The importance of the public swimming bath for the dissemination of Trichomonas vaginalis is disputed. 30 samples, each of 250 ml bath water from four indoor swimming baths, were examined for trichomonads. All the samples were negative. 218 smears taken from the wet places on the heated benches and other seating accommodation in these swimming baths were cultured for trichomonads and bacteria. Trichomonas vaginalis could not be demonstrated. Fecal organisms were found in 56 places, antibiotic-sensitive staphylococci were cultured from 20 samples and Ps. aeruginosa from 8. The negative tests for trichomonads suggests that the indoor swimming bath has no epidemiological importance in the dissemination of this parasite.


The epidemiology of bilateral slipped capital femoral epiphysis. A study of children in Michigan.
The records of 224 children who had a slipped capital femoral epiphysis and who had no underlying metabolic or endocrine disorder were studied retrospectively to investigate the epidemiology of bilateral slipped capital femoral epiphysis. Eighty-two (37 per cent) of the 224 children (fifty-one boys and thirty-one girls) had a bilateral slip. Sixty-four of these children were black and eighteen were white. The age at the time of the diagnosis of the first slip was 13 +/- 1.7 years (mean and standard deviation), the duration of the symptoms was 5 +/- 5.0 months, and the angle of the slip was 26 +/- 16 degrees. Obese children were younger at the time of the diagnosis of the first slip (12 +/- 1.6 compared with 13 +/- 1.6 years for the children who were not obese, p = 0.001). The diagnosis of a slipped capital femoral epiphysis was made simultaneously in both hips in forty-one children and sequentially in forty-one children. Compared with the children in whom both hips were diagnosed simultaneously, the children in whom the hips were diagnosed sequentially had had a shorter duration of the symptoms before the diagnosis of the first slip (3 +/- 2.4 compared with 7 +/- 5.9 months, p = 0.0003), were younger at the time of the diagnosis of the first slip (12 +/- 1.9 compared with 13 +/- 1.2 years, p = 0.001), and tended to be more obese (p = 0.025). In 88 per cent of the patients who had sequential slips, the second slip was diagnosed within eighteen months after the diagnosis of the first slip.(ABSTRACT TRUNCATED AT 250 WORDS)


American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients--2002 update.
In these clinical practice guidelines, specific recommendations are made for determining the most effective methods of diagnosing and treating hypogonadism in adult male patients. The target populations for these guidelines include the following: (1) men with primary testicular failure requiring testosterone replacement (hypergonadotropic hypogonadism); (2) male patients with gonadotropin deficiency or dysfunction who may have received testosterone replacement therapy or treatment for infertility (hypogonadotropic hypogonadism); and (3) aging men with symptoms relating to testosterone deficiency who could benefit from testosterone replacement therapy. Initial hormonal evaluation generally consists of a testosterone determination, in conjunction with a free testosterone or sex hormone-binding globulin level, inpatients with clear symptoms and signs but normal-range total testosterone, follicle-stimulating hormone, luteinizing hormone, and prolactin levels. Other possible tests include semen analysis, pituitary imaging studies, genetic studies, bone densitometry, testicular ultrasonography,testicular biopsy, and specialized hormonal dynamic testing. Therapeutic options generally consist of testosterone replacement by injections, patches, or topically applied gel in hypergonadotropic patients and in hypogonadotropic patients not interested in fertility. In hypogonadotropic patients interested in fertility, gonadal stimulation option scan be considered, including human chorionic gonadotropin stimulation therapy with or without human menopausal gonadotropin (or follicle-stimulating hormone) or gonadotropin-releasing hormone pump therapy. These therapies may be combined with assisted reproductive technologies such as in vitro fertilization with intracytoplasmic sperm injection, which may allow pregnancy to occur with very low numbers of sperm.


Deep SVDD and Transfer Learning for COVID-19 Diagnosis Using CT Images.
The novel coronavirus disease (COVID-19), which appeared in Wuhan, China, is spreading rapidly worldwide. Health systems in many countries have collapsed as a result of this pandemic, and hundreds of thousands of people have died due to acute respiratory distress syndrome caused by this virus. As a result, diagnosing COVID-19 in the early stages of infection is critical in the fight against the disease because it saves the patient's life and prevents the disease from spreading. In this study, we proposed a novel approach based on transfer learning and deep support vector data description (DSVDD) to distinguish among COVID-19, non-COVID-19 pneumonia, and intact CT images. Our approach consists of three models, each of which can classify one specific category as normal and the other as anomalous. To our knowledge, this is the first study to use the one-class DSVDD and transfer learning to diagnose lung disease. For the proposed approach, we used two scenarios: one with pretrained VGG16 and one with ResNet50. The proposed models were trained using data gathered with the assistance of an expert radiologist from three internet-accessible sources in end-to-end fusion using three split data ratios. Based on training with 70%, 50%, and 30% of the data, the proposed VGG16 models achieved (0.8281, 0.9170, and 0.9294) for the F1 score, while the proposed ResNet50 models achieved (0.9109, 0.9188, and 0.9333).


Anodic TiO2 nanotubular arrays with pre-synthesized hydroxyapatite--an effective approach to enhance the biocompatibility of titanium.
Electrochemically anodized TiO2 nanotubular arrays can provide large surface areas for biological species attachment. In order to further enhance the biocompatibility of Ti medical implants, we deposited a pre-synthesized hydroxyapatite inside and on the nanotubular arrays, and examined the biocompatibility of the anodized TiO2 nanotubular arrays with pre-synthesized hydroxyapatite by in vitro assessment in simulated body fluid, and in vitro cell culture. The results showed that the hydroxyapatite coating was able to be induced on TiO2 nanotubular arrays with pre-synthesized hydroxyapatite within 5 days while only a thin film composed of calcium phosphorous chemicals formed on as-formed TiO2 nanotubular arrays. The cell culture evaluation further proved the enhancement of cell attachment and proliferation on TiO2 nanotubular arrays with pre-synthesized hydroxyapatite as opposed to those without pre-synthesized hydroxyapatite. The present study proves that formation of TiO2 nanotubular arrays with pre-synthesized hydroxyapatite a promising method to enhance the biocompatibility of Ti implants.


Ability to follow drug treatment with calcium and vitamin D in postmenopausal women with reduced bone mass.
The aim of this study was to evaluate the ability of women with reduced bone mass to follow calcium/vitamin D treatment in relation to prescribed regimen, dose, indication, mode of intake, and the associated factors. A cross-sectional study of postmenopausal women taking medication after bone mineral density diagnosis of osteopenia or osteoporosis was conducted using the MedTake questionnaire. A total of 186 patients attending a menopause clinic were studied. Sociodemographic characteristics, history of comorbid conditions, concomitant use of medication, length of medication use, and ability to follow treatment in relation to prescribed regimen, dose, indication, and mode of ingestion were assessed. The mean (SD) age of the women analyzed was 61.6 (8.21) years. The mean time since menopause was 16.8 years. Most women reported having difficulty reading, and 79% were white. The ability to follow treatment, evaluated using MedTake, was lower than 60% in most women. Taking the wrong dose was the most frequent error. The only factor associated with inadequate treatment was the use of concomitant medication (odds ratio, 2.32; 95% CI, 1.06-5.08). The ability to follow adjuvant calcium and vitamin D treatment for decreased bone mass is low and associated with concomitant use of medication.


Effects of various pretreatments on the hepatotoxicity of inhaled styrene in the B6C3F1 mouse.
1. The roles of cytochrome P450 monooxygenases (P450) and glutathione (GSH) in styrene hepatotoxicity were investigated in mice by pretreating with either phenobarbital (PB; P450 inducer), SKF 525A (P450 inhibitor), N-acetylcysteine (NAC; GSH precursor), or saline (vehicle control) prior to a 6-h exposure to either 500 ppm styrene on air. 2. Styrene caused hepatocellular degeneration or necrosis in all groups; these changes were more extensive and severe in mice pretreated with PB. Styrene significantly increased relative liver weights and serum ALT and SDH levels only in mice pretreated with PB. NAC did not prevent GSH depletion or hepatotoxicity. 3. In the fat of SKF 525A-pretreated mice a slight but statistically significant increase in styrene levels was observed, suggesting that metabolism was decreased; the SO/styrene ratio in the fat of PB-pretreated mice showed a slight, but statistically significant, increase indicating a slight increase in styrene metabolism. Neither SKF 525A nor PB caused changes in microsomal enzyme activity in vitro. 4. These results suggest that styrene may be activated by a pathway not totally dependent upon P450 enzyme activity, or more likely that PB and SKF 525A are not specific for the P450 enzymes involved in activation and detoxification of styrene.


Complete success of intradermal vaccination against hepatitis B in advanced chronic renal failure and hemodialysis patients.
Incomplete protection and response variability have been reported in chronic renal failure (CRF) and hemodialysis (HD) patients vaccinated against hepatitis B with the recombinant vaccine (rHBV). We vaccinated 12 consecutive patients (7 CRF and 5 HD), 7 males and 5 females, 61 years old (range 22-82); HD patients were on treatment from 1 to 12 months. CRF patients had a residual renal function (creatinine clearance) of 11 +/- 3 mL/min. Six patients had been already vaccinated unsuccessfully, as defined by the absence of detectable specific antibody S (Abs) 1 month after the completion of vaccination by the classical intramuscular method, with a median of 7 (range 3-18) doses of 20 micrograms. rHBV was given intradermally (i.d.) at the dose of 5 micrograms every fortnight up to 8 doses or until titers of Abs rose above 1000 mIU/mL. Levels above 10 mIU/mL were considered as protective. Abs titers were monitored during the whole vaccination period every 15 days and at the 1st, 3rd, and 6th month after its completion. Median number of i.d. doses given was 7 (range 4-8). Antibody titers rose gradually; surface antibodies (AbS) were detected as early as the end of the first month (2nd dose). Age and sex had no influence on the immune response, its duration, or antibody titers. i.d. administration of rHBV in repeated small injections was found to be absolutely effective, in both CRF and HD patients. AbS titers after multiple i.d. vaccination rose gradually in CRF and HD patients, and were protective for at least 6 months after the last injected dose. Protective levels were achieved even in patients not responding to multiple-double quantity intramuscular (i.m.) doses. Patients with stronger initial response to the vaccine (after the 4th dose) gave significantly higher AbS titers (at least in 50% of the follow-up measurements), although they received fewer injections and smaller total dose of vaccine.


Early manifestations of replicative aging in the yeast Saccharomyces cerevisiae.
The yeast Saccharomyces cerevisiae is successfully used as a model organism to find genes responsible for lifespan control of higher organisms. As functional decline of higher eukaryotes can start as early as one quarter of the average lifespan, we asked whether S. cerevisiae can be used to model this manifestation of aging. While the average replicative lifespan of S. cerevisiae mother cells ranges between 15 and 30 division cycles, we found that resistances to certain stresses start to decrease much earlier. Looking into the mechanism, we found that knockouts of genes responsible for mitochondria-to-nucleus (retrograde) signaling, RTG1 or RTG3, significantly decrease the resistance of cells that generated more than four daughters, but not of the younger ones. We also found that even young mother cells frequently contain mitochondria with heterogeneous transmembrane potential and that the percentage of such cells correlates with replicative age. Together, these facts suggest that retrograde signaling starts to malfunction in relatively young cells, leading to accumulation of heterogeneous mitochondria within one cell. The latter may further contribute to a decline in stress resistances.


A rigorous detection of interstellar CH3NCO: An important missing species in astrochemical networks.
The recent analysis of the composition of the frozen surface of comet 67P/Churyumov-Gerasimenko has revealed a significant number of complex organic molecules. Methyl isocyanate (CH3NCO) is one of the more abundant species detected on the comet surface. In this work we report extensive characterization of its rotational spectrum resulting in a list of 1269 confidently assigned laboratory lines and its detection in space towards the Orion clouds where 399 lines of the molecule have been unambiguously identified. We find that the limited mm-wave laboratory data reported prior to our work require some revision. The abundance of CH3NCO in Orion is only a factor of ten below those of HNCO and CH3CN. Unlike the molecular abundances in the coma of comets, which correlate with those of warm molecular clouds, molecular abundances in the gas phase in Orion are only weakly correlated with those measured on the comet surface. We also compare our abundances with those derived recently for this molecule towards Sgr B2 (Halfen et al. 2015). A more accurate abundance of CH3NCO is provided for this cloud based on our extensive laboratory work.


Low-level laser therapy in collagenase-induced Achilles tendinitis in rats: analyses of biochemical and biomechanical aspects.
NSAIDs are widely prescribed and used over the years to treat tendon injuries despite its well-known long-term side effects. In the last years several animal and human trials have shown that low-level laser therapy (LLLT) presents modulatory effects on inflammatory markers, however the mechanisms involved are not fully understood. The aim of this study was to evaluate the short-term effects of LLLT or sodium diclofenac treatments on biochemical markers and biomechanical properties of inflamed Achilles tendons. Wistar rats Achilles tendons (n = 6/group) were injected with saline (control) or collagenase at peritendinous area of Achilles tendons. After 1 h animals were treated with two different doses of LLLT (810 nm, 1 and 3 J) at the sites of the injections, or with intramuscular sodium diclofenac. Regarding biochemical analyses, LLLT significantly decreased (p < 0.05) COX-2, TNF-α, MMP-3, MMP-9, and MMP-13 gene expression, as well as prostaglandin E(2) (PGE(2) ) production when compared to collagenase group. Interestingly, diclofenac treatment only decreased PGE(2) levels. Biomechanical properties were preserved in the laser-treated groups when compared to collagenase and diclofenac groups. We conclude that LLLT was able to reduce tendon inflammation and to preserve tendon resistance and elasticity.


Student Hunger on Campus: Food Insecurity Among College Students and Implications for Academic Institutions.
To estimate the prevalence of food insecurity among students at a large mid-Atlantic publicly funded university; examine the association between food insecurity, demographic characteristics, potential financial risk factors, and self-reported physical and mental health and academic performance; and identify possible risk factors for food insecurity. Cross-sectional survey. Large, public mid-Atlantic university. Two hundred thirty-seven undergraduate students. US Department of Agriculture (USDA) 18-item Household Food Security Survey Module (HFSSM) and questions on demographics, student status, economic factors, housing stability, living arrangements, academic performance, and self-rated physical health and depression symptoms. Multivariate logistic regression analysis. Among students surveyed, 15% were food insecure; an additional 16% were at risk of food insecurity. Students who were African American, other race/ethnicity, receiving multiple forms of financial aid, or experiencing housing problems were more likely to be food insecure or at the risk of food insecurity (Adjusted Odds Ratio [AOR] = 4.00, 95% confidence interval [CI] = 1.83-8.71, P value < .0001; AOR = 5.26, 95% CI = 1.85-14.98, P value = .002; AOR = 3.43, 95% CI = 1.85-6.37, P value <.001; AOR = 8.00, 95% CI = 3.57-17.93, P value < .0001, respectively). Food secure students were less likely to report depression symptoms than at-risk or food insecure students. Food insecurity among college students is an important public health concern that might have implications for academic performance, retention, and graduation rates. Universities that measure food insecurity among their students will be better positioned to advocate for policy changes at state and federal levels regarding college affordability and student financial assistance.


[Breed-dependent anomalies in ornamental birds].
Following a definition of the terms pet bird and domestication, and a description of important mechanisms which may have played a role during domestication, a short review is given on the various changes that occurred and have been used selectively by humans: changes in body size, skin and feathers, skull, metabolisms, and the central nervous system including behavior and disturbances of behavior. Implications for animal welfare are considered.


Sexual dysfunction in postmenopausal women: the role of medical management.
A general decline in postmenopausal sexual activity, compounded by various physiologic changes related to the menopause, can be the source of much anxiety for older women. Many may wish to remain sexually active, yet fail to see that their problem is, in part, a medical one which a concerned physician can treat. Strategies for physician intervention, clinical management, and general support are reviewed for one of older patients' more undertreated maladies.


An Enigmatic Stramenopile Sheds Light on Early Evolution in Ochrophyta Plastid Organellogenesis.
Ochrophyta is an algal group belonging to the Stramenopiles and comprises diverse lineages of algae which contribute significantly to the oceanic ecosystems as primary producers. However, early evolution of the plastid organelle in Ochrophyta is not fully understood. In this study, we provide a well-supported tree of the Stramenopiles inferred by the large-scale phylogenomic analysis that unveils the eukaryvorous (nonphotosynthetic) protist Actinophrys sol (Actinophryidae) is closely related to Ochrophyta. We used genomic and transcriptomic data generated from A. sol to detect molecular traits of its plastid and we found no evidence of plastid genome and plastid-mediated biosynthesis, consistent with previous ultrastructural studies that did not identify any plastids in Actinophryidae. Moreover, our phylogenetic analyses of particular biosynthetic pathways provide no evidence of a current and past plastid in A. sol. However, we found more than a dozen organellar aminoacyl-tRNA synthases (aaRSs) that are of algal origin. Close relationships between aaRS from A. sol and their ochrophyte homologs document gene transfer of algal genes that happened before the divergence of Actinophryidae and Ochrophyta lineages. We further showed experimentally that organellar aaRSs of A. sol are targeted exclusively to mitochondria, although organellar aaRSs in Ochrophyta are dually targeted to mitochondria and plastids. Together, our findings suggested that the last common ancestor of Actinophryidae and Ochrophyta had not yet completed the establishment of host-plastid partnership as seen in the current Ochrophyta species, but acquired at least certain nuclear-encoded genes for the plastid functions.


[Current medical therapies for Crohn's disease in Japan].
Current available therapies for Crohn's disease in Japan are reviewed in this report. Elemental diet is most effective for both inducing and maintaining remission in Japan. There appears to be no difference between elemental diet, oligopeptide diet and intact nutrients in effectiveness for active Crohn's disease. Although corticosteroid is also useful for treating active Crohn's disease, low dose of it is not effective for maintaining remission. Steroid has important role in combined therapy with elemental diet. New steroid, budesonide appears to be fascinate because of less adverse effects. Recently, instead of salazosulfapyridine, 5-aminosalicylic acid (5-ASA) proved to be more effective not only for active disease but also for maintenance of remission including small intestinal type of Crohn's disease with reduced adverse effects. Azathioprine, 6-mercaptopurine (6-MP), methotrexate and metronidazole are second choice treatment in patients whose disease relapse frequently. Although methotrexate appears to be effective for active Crohn's disease, the role of it has to be defined. Evidences support the use of 5-ASA and methotrexate for prophylaxis after surgery. It is important to chose and combine the therapies, thinking of the situation of each patient.


Stratégies Cognitives et Processus D'autorégulation Chez Des Familles en Situation de Resolution de Problemes Logiques.
The family is a fundamental learning environment for many basic skills such as the ability to solve everyday domestic problems. A lack of competence in this type of problem solving would expose the individual to more frustration and possibly create the conditions for greater aggression. Forty-two low SES families, each including an aggressive boy, were invited to the laboratory for a problem-solving session on two occasions, at an interval of two years. Subjects were asked to find four preset combinations of colours by systematic permutations of four colours using a computer. Three types of cognitive performance were examined: resolution strategies, autoregulation strategies and the success rate in finding the solution. Results showed that most of the families were consistent in their use of anon-systematic strategy. Although some improvement in planning is observed during the second testing, no other improvement in autoregulation strategies was observed. In general, families had a better rate of success in finding the solution in the second session. The low cognitive level of these families and its stability are discussed.


Adolescent suicide as a global public health issue.
Youth suicide is a major global mental health problem. This review looks at the epidemiology, risk and protective factors associated with youth suicide, and global strategies to address this important issue. To better understand factors contributing to youth suicide, global gender differences in suicide were examined. Global rates of suicide amongst young men are higher than young women. However, there are anomalously higher rates of female youth suicide in India and China, and possible causes of this are examined further. It is likely that underestimation of youth suicide is a major factor affecting the accuracy of suicide epidemiology. Risk factors for youth suicide are varied. Psychiatric factors include various psychiatric illnesses, substance use (particularly amongst refugee and homeless youth). Psychosocial risk factors include family conflict, physical and sexual childhood abuse, isolation, socioeconomic disadvantage, discrimination and acculturation. Vulnerable populations are at increased risk, including refugee/immigrant/indigenous youth, those in foster care and homeless youth. Protective factors can include family cohesion and strong interpersonal relationships, as well as increased access to care. Global strategies to prevent youth suicide include reducing lethal means to suicide and reducing harmful media reporting. Various psychosocial interventions may be helpful, including individual support, and family, school and community based interventions. Strategies can also increase evaluation of psychiatric disorders and access to care, as well as promote psycho-education and reduce stigma against mental illness.


An evaluation of Knutson's formula for estimating age-specific DMF teeth.
The present study evaluated a formula suggested by Knutson for obtaining an age-specific estimate of mean DMFT in a population on the basis of the age-specific percentage of individuals with 1 or more DMFT. A total of 149 previously collected age-specific data sets from low-flouride areas in the U.S.A. were used, and the two parameters K and B were estimated using the method of weighted least squares. The analysis showed that the formula could be used with good accuracy for certain restrictions of age (5--11 years) and percentage of individuals with 1 or more DMFT (less than or equal to 70%).


Coupling of mitochondrial translation with the formation of respiratory complexes in yeast mitochondria.
In contrast to most other eukaryotic organisms, yeast can survive without respiration. This ability has been exploited to investigate nuclear genes required for expression of mitochondrial DNA. Availability of complete Saccharomyces cerevisiae genomic sequence has provided additional help in detailed molecular analysis. Seven of the eight major products encoded by mitochondrial DNA are hydrophobic subunits of respiratory complexes in the inner membrane. Localization of the translation process in the same cellular compartment ensures synthesis of mitochondrially encoded proteins near sites of their assembly into multimeric respiratory complexes. Association of mitochondrial ribosomes with the membrane is mediated by mRNA-specific translational activators, that are involved in the recognition of initiation codon. The newly synthesized mitochondrial proteins are transferred to membrane by a specific export system. This review discusses the role of membrane-localized factors responsible for quality control and turnover of mitochondrially synthesized subunits as well as for assembly of respiratory complexes.


Transforming growth factor β and its role in heart disease.
Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational changes, through the active participation of transforming growth factor β (TGFβ) and its signaling pathways. TGFβ appears to be a 'Master of all trades', with respect to cardiac fibrosis, as it can promote cardiomyocyte apoptosis and cardiac hypertrophy. TGFβ signaling involves its binding to TGFβ receptor type II (TGFβRII), which recruits TGFβ receptor type I (TGFβRI), which are also known as activin receptor-like kinase (ALK) in five different isoforms. In canonical signaling pathways, ALK5 activates Smads 2 and 3, and ALK1 activates Smads 1 and 5. These pairs of Smads form a corresponding complex and then bind to Smad 4, to translocate into the nucleus, where transcriptional reprogramming is carried out to promote myofibroblast formation and ECM production, eventually leading to cardiac fibrosis. TGFβ levels are elevated in MI, thereby aggravating the myocardial injury further. Several microRNAs are involved in the regulation of TGFβ signaling at different steps, affecting different components. Therapeutic targeting of TGFβ signaling at ALK1-5 receptor activity level has met with limited success and extensive research is needed to develop therapies based on the components of TGFβ signaling pathway, for instance cardiac dysfunction and heart failure.


Motivational interviewing in promoting oral health: A literature review.
Behavioral sciences are a group of disciplines that involve the study of human actions. Various behavioral models have been used in the past 50 years in behavior modification. One behavioral model currently being studied for its application in oral healthcare is motivational interviewing (MI). Motivational interviewing is a patient-centered psycho-behavioral method used in various fields of medicine and psychology to help patients change their health-affecting behaviors. Effective health promotion is important, since in developed countries, the majority of deaths and diseases are caused by chronic conditions. Controlling and treating chronic diseases require sustained commitment. This literature review aimed to describe the current methods of health promotion for oral health, based on various disease models, with a thorough discussion of the psycho-behavioral method known as MI, and its applications in dentistry and oral health. There is evidence that MI is applied in various health and dental areas, such as oral health promotion, early childhood caries (ECC), periodontal disease, smoking cessation, and improving the quality of life during and after cancer treatment. The clinical and research limitations of this method were also addressed. Comparing the general ideas and ethos of MI to the definition of health promotion by the World Health Organization (WHO), it can be stated that they represent a common approach to promoting health.


DNA-immunisation with dengue virus E protein domains I/II, but not domain III, enhances Zika, West Nile and Yellow Fever virus infection.
Dengue virus (DENV), the causative agent of dengue disease, is among the most important mosquito-borne pathogens worldwide. DENV is composed of four closely related serotypes and belongs to the Flaviviridae family alongside other important arthropod-borne viral pathogens such as Zika virus (ZIKV), West Nile virus (WNV) and Yellow Fever virus (YFV). After infection, the antibody response is mostly directed to the viral E glycoprotein which is composed of three structural domains named DI, DII and DIII that share variable degrees of homology among different viruses. Recent evidence supports a close serological interaction between ZIKV and DENV. The possibility of worse clinical outcomes as a consequence of antibody-dependent enhancement of infection (ADE) due to cross-reactive antibodies with poor neutralisation activity is a matter of concern. We tested polyclonal sera from groups of female Balb/C mice vaccinated with DNA constructs expressing DI/DII, DIII or the whole sE from different DENV serotypes and compared their activity in terms of cross-reactivity, neutralisation of virus infection and ADE. Our results indicate that the polyclonal antibody responses against the whole sE protein are highly cross-reactive with strong ADE and poor neutralisation activities due to DI/DII immunodominance. Conversely, anti-DIII polyclonal antibodies are type-specific, with no ADE towards ZIKV, WNV and YFV, and strong neutralisation activity restricted only to DENV.


A highly stable chain-based EuIII metal-organic framework as a turn-on and blue-shift luminescent sensor for dipicolinic acid.
The development of a rapid and selective method for the identification of dipicolinic acid (DPA), a specific biomarker in Bacillus anthracis spores, is of great importance for the avoidance of anthrax infection. Herein, a chain-based EuIII metal-organic framework with the formula {[Eu3(BTDB)3(μ3-OH)3(H2O)]·solvents}n (JXUST-38, H2BTDB = (benzo[c][1,2,5]thiadiazole-4,7-diyl)dibenzoic acid) was obtained using 2-fluorobenzoic acid as the pH regulator. JXUST-38 exhibits good chemical and thermal stability and can specifically recognize DPA in N,N-dimethylformamide solution through luminescence enhancement and blue-shift effects with a detection limit of 0.05 μM. Furthermore, the significant luminescence enhancement and blue shift under UV lamps are obviously observable by the naked eye. The luminescence sensing mechanism is attributed to absorbance-induced enhancement between JXUST-38 and DPA. Test paper and mixed-matrix membrane based on JXUST-38 are designed for DPA detection. In addition, the feasibility of using JXUST-38 in biosensing is discussed in detail.


Regulation of the nitric oxide oxidase activity of myeloperoxidase by pharmacological agents.
The leukocyte-derived heme enzyme myeloperoxidase (MPO) is released extracellularly during inflammation and impairs nitric oxide (NO) bioavailability by directly oxidizing NO or producing NO-consuming substrate radicals. Here, structurally diverse pharmacological agents with activities as MPO substrates/inhibitors or antioxidants were screened for their effects on MPO NO oxidase activity in human plasma and physiological model systems containing endogenous MPO substrates/antioxidants (tyrosine, urate, ascorbate). Hydrazide-based irreversible/reversible MPO inhibitors (4-ABAH, isoniazid) or the sickle cell anaemia drug, hydroxyurea, all promoted MPO NO oxidase activity. This involved the capacity of NO to antagonize MPO inhibition by hydrazide-derived radicals and/or the ability of drug-derived radicals to stimulate MPO turnover thereby increasing NO consumption by MPO redox intermediates or NO-consuming radicals. In contrast, the mechanism-based irreversible MPO inhibitor 2-thioxanthine, potently inhibited MPO turnover and NO consumption. Although the phenolics acetaminophen and resveratrol initially increased MPO turnover and NO consumption, they limited the overall extent of NO loss by rapidly depleting H2O2 and promoting the formation of ascorbyl radicals, which inefficiently consume NO. The vitamin E analogue trolox inhibited MPO NO oxidase activity in ascorbate-depleted fluids by scavenging NO-consuming tyrosyl and urate radicals. Tempol and related nitroxides decreased NO consumption in ascorbate-replete fluids by scavenging MPO-derived ascorbyl radicals. Indoles or apocynin yielded marginal effects. Kinetic analyses rationalized differences in drug activities and identified criteria for the improved inhibition of MPO NO oxidase activity. This study reveals that widely used agents have important implications for MPO NO oxidase activity under physiological conditions, highlighting new pharmacological strategies for preserving NO bioavailability during inflammation.


Comparison of toxicities of acrylamide and 2,5-hexanedione in hens and rats on 3-week dosing regimens.
Survival rates, changes in body weight, gait/ataxia scores, and neuropathological lesions were compared between adult Long-Evans rats and adult White Leghorn hens given equivalent dosages of the peripheral neurotoxicants acrylamide and 2,5-hexanedione (12, 25, and 50 mg/kg acrylamide 3 times per week; or 75, 105, 150, 225, or 350 mg 2,5-hexanedione/kg/d, with hens receiving the lowest 3 dosages of 2,5-hexanedione and rats receiving the highest 3 dosages of this test compound). All rats survived the 3-wk acrylamide study period, although those given 50 mg/kg did not gain weight and showed alterations in gait. Hens given 50 mg/kg acrylamide were moribund by 2 wk and were sacrificed before the end of the 3-wk study period. By this time they had lost 29 +/- 3% of their body weight, but none showed significant renal or hepatic lesions on necropsy. Hens given all doses of acrylamide showed dose-related ataxia, weakness, and depression. Gait changes were seen in rats given the high dose of acrylamide for the 3-wk test period. Neuropathological studies revealed that both rats and hens given acrylamide had distal myelinated fibers with dose-related neurofilament-rich axonal swelling and Wallerian-like degeneration, better developed in the rodents. In addition, high-dose acrylamide rats had recent necrosis of cerebellar Purkinje cells. Deaths occurred in all groups of hens given 2,5-hexanedione (75, 105, or 150 mg/kg) before sacrifice at 3 wk, but all rats given 2,5-hexanedione (150, 225, 350 mg/kg) survived a 4-wk study period, even though gait changes were evident in the 225 and 350 mg/kg dosage groups by 3 wk. Neither hens nor rats dosed with 2,5-hexanedione for 3 wk had significant neuropathic lesions, although the hens showed dose-related ataxia, weakness, and depression. Early neurofilamentous intraaxonal masses in distal levels of selected myelinated tracts were seen in rats given the high dose of 2,5-hexanedione for an additional week. These studies suggest that hens are sensitive to acrylamide and 2,5-hexanedione toxicities, and that the rat is more likely than the hen to develop neuropathological lesions.


Mortality risk prediction of the electrocardiogram as an informative indicator of cardiovascular diseases.
The electrocardiogram (ECG) may be the most popular test in the management of cardiovascular disease (CVD). Although wide applications of artificial intelligence (AI)-enabled ECG have been developed, an integrating indicator for CVD risk stratification was not investigated. Since mortality may be the most important global outcome, this study aimed to develop a survival deep learning model (DLM) to establish a critical ECG value and explore the associations with various CVD events. We trained a DLM with 451,950 12-lead resting ECGs obtained from 210,552 patients, for whom 23,592 events occurred. The internal validation set included 27,808 patients with one ECG for each patient. The external validations were performed in a community hospital with 33,047 patients and two transnational data sets with 233,647 and 1631 ECGs. We distinguished the cause of mortality and additionally investigated CVD-related outcomes, including new-onset acute myocardial infarction (AMI), stroke (STK), and heart failure (HF). The DLM achieved C-indices of 0.858/0.836 in internal/external validation sets by using ECG over a 10-year period. The high-mortality-risk group identified by the proposed DLM presented a hazard ratio (HR) of 14.16 (95% confidence interval (CI): 11.33-17.70) compared to the low-risk group in the internal validation and presented a higher risk of cardiovascular (CV) mortality (HR: 18.50, 95% CI: 9.82-34.84), non-CV mortality (HR: 13.68, 95% CI: 10.76-17.38), AMI (HR: 4.01, 95% CI: 2.24-7.17), STK (HR: 2.15, 95% CI: 1.70-2.72), and HF (HR: 6.66, 95% CI: 4.54-9.77), which was consistent in an independent community hospital. The transnational validation also revealed HRs of 4.91 (95% CI: 2.63-9.16) and 2.29 (95% CI: 2.15-2.44) for all-cause mortality in the SaMi-Trop and Clinical Outcomes in Digital Electrocardiography 15% (CODE15) cohorts. The mortality risk by AI-enabled ECG may be applied in passive electronic-health-record-based CVD risk screening, which may identify more asymptomatic and unaware high-risk patients.


Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis.
Epidemiological and experimental evidence suggests that dietary flavonoids, including apigenin, have anticancer roles. Apigenin has been reported to elevate p53, a critical molecule in the induction of apoptosis. The present study aimed to investigate whether apigenin, a dietary flavonoid, improves the cytotoxic effect of cisplatin in a cancer cell culture system, and to elucidate the mechanism of this effect. Multiple tumor cell types were treated with apigenin, cisplatin or both drugs. Cell viability was evaluated, and the cytotoxic effect was determined biochemically and microscopically. Treatment with apigenin increased cisplatin-induced DNA damage and the apoptosis of tumor cells in a p53-dependent manner. Apigenin, when used with cisplatin, inhibited cell proliferation and promoted mitogen-activated protein kinase activation and subsequent p53 phosphorylation, leading to p53 accumulation and upregulation of proapoptotic proteins. Cisplatin is one of the most commonly used chemotherapeutic drugs for malignant tumors, but resistance to this drug occurs. The current results therefore demonstrate that dietary flavonoids may diminish the resistance of cancers to cisplatin.


A double-blind randomised controlled investigation into the efficacy of Mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): study protocol for a randomised controlled trial.
Delayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation. EMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5-25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. The EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique 'cytotopic' property that permits its retention in the organ microvasculature. ISRCTN registry, ISRCTN49958194 . Registered on 3 August 2012.


Five questiouns dentists should ask about their money. Question 4: how do the communities (family, practice, profession, culture, neighborhood, etc.) in which I live affect my financial decisions?
Communities, and the personal value you place on them, affect all your spending, both business and personal. Once you begin questioning and analyzing how they affect your financial decisions, you will begin making more complete choices - the better-informed, the greater chance of success. Society has attached many financial expectations to dentists - both good and bad. By participating in this part of the Five Questions process, you will be able to separate the business of dentistry from the practice of dentistry and your persona beliefs from the beliefs of your communities'.


A letter on a hand: Rotating together or separately?
The motor system plays a role in some object mental rotation tasks, and researchers have reported that people may use a strategy of motor simulation to mentally rotate objects. In this study, we used images of a hand with a letter printed on the palm to directly determine whether a hand image can be automatically rotated during the deliberate mental rotation of an object and whether the hand and object are rotated in the same trajectory. A total of 41 participants were shown the stimuli and asked to decide whether the letters, which were upright or tilted at specific degrees, were normal or mirrored. The hand images in the background showed either a left or a right hand in the palm view, with fingers pointing upwards, medial, downwards, or lateral. Reaction times and error rates were measured to determine the speed and accuracy of mental rotation. A complex interaction between the hand posture and letter orientation revealed that the hand image was mentally rotated automatically, together with the deliberate mental rotation of the letter. The biomechanical constraints of the hand also influenced reaction times, suggesting the involvement of the motor system in the concomitant mental rotation of the hand image. Consistent with the motor simulation theory, the participants seemed to imagine the hand carrying the object in its movement. These behavioural data support the motor simulation theory and elucidate specific processes of mental rotation that have not been addressed by neuroimaging studies.


Sustained release of vascular endothelial growth factor A and basic fibroblast growth factor from nanofiber membranes reduces oxygen/glucose deprivation-induced injury to neurovascular units.
Upregulation of vascular endothelial growth factor A/basic fibroblast growth factor (VEGFA/bFGF) expression in the penumbra of cerebral ischemia can increase vascular volume, reduce lesion volume, and enhance neural cell proliferation and differentiation, thereby exerting neuroprotective effects. However, the beneficial effects of endogenous VEGFA/bFGF are limited as their expression is only transiently increased. In this study, we generated multilayered nanofiber membranes loaded with VEGFA/bFGF using layer-by-layer self-assembly and electrospinning techniques. We found that a membrane containing 10 layers had an ideal ultrastructure and could efficiently and stably release growth factors for more than 1 month. This 10-layered nanofiber membrane promoted brain microvascular endothelial cell tube formation and proliferation, inhibited neuronal apoptosis, upregulated the expression of tight junction proteins, and improved the viability of various cellular components of neurovascular units under conditions of oxygen/glucose deprivation. Furthermore, this nanofiber membrane decreased the expression of Janus kinase-2/signal transducer and activator of transcription-3 (JAK2/STAT3), Bax/Bcl-2, and cleaved caspase-3. Therefore, this nanofiber membrane exhibits a neuroprotective effect on oxygen/glucose-deprived neurovascular units by inhibiting the JAK2/STAT3 pathway.