Reversible thermo-induced spin crossover in a mononuclear cis-dicyanamido-cobalt(ii) complex containing a macrocyclic tetradentate ligand.
We present a unique investigation of a mononuclear cis-dicyanamido-cobalt(ii) complex, [Co(L)(N(CN)2)2] (1) (L = N,N'-di-tert-butyl-2,11-diaza[3,3](2,6)pyridinophane), which displays a reversible thermo-induced HS (S = 3/2) to LS (S = 1/2) Spin Crossover (SCO) with a T1/2 value of around 238 K. The appropriate ligand field strength around the CoN6 coordination environment is obtained using a tetradentate ligand and two dicyanamide [N(CN)2]- coligands at the cis position. Variable temperature XRD and several spectroscopic studies have been performed, which confirm the SCO behavior of 1. Interestingly, complex 1 pronounces redox stimulus responsive reversible spin-state switching from HS Co(ii) to LS Co(iii). These findings represent a rare example of the successful use of pseudohalide to design and synthesize a SCO cobalt(ii) complex.


Postorgasmic illness syndrome: two cases.
We describe the symptoms of a postejaculatory syndrome in two men with spontaneous ejaculations. The syndrome consists of severe fatigue, intense warmth, and a flulike state, with generalized myalgia. These symptoms occur rapidly after ejaculation and only disappear after 4 to 7 days. The symptoms are so severe that sexual activity is avoided. The cluster of symptoms is named postorgasmic illness syndrome (POIS). To date, no explanation has been offered for the etiology and pathogenesis of the symptoms, and the prevalence is unknown. Both cases are presented to draw attention to this syndrome for further research regarding etiology, pathogenesis, and treatment.


Allele-specific regulation of matrix metalloproteinase-3 gene by transcription factor NFkappaB.
Matrix metalloproteinase-3 (MMP3) is implicated in the pathogenesis and progression of atherosclerotic lesions. Previous studies suggested that MMP3 expression is influenced by a polymorphism (known as the 5A/6A polymorphism) in the promoter of the MMP3 gene and that this polymorphism is located within a cis-element that interacts with the transcription factor NFkappaB. In the present study, we sought to investigate whether MMP3 and NFkappaB were co-localized in atherosclerotic lesions and whether NFkappaB had differential effects on the two alleles of the MMP3 5A/6A polymorphism. Immunohistochemical examination showed that MMP3 and both the NFkappaB p50 and p65 subunits were expressed abundantly in macrophages in atherosclerotic lesions and that MMP3 expression was co-localized with p50 and p65. Chromatin immunoprecipitation experiments showed interaction of p50 and p65 with the MMP3 promoter in macrophages, with greater binding to the 5A allele than to the 6A allele. Reporter gene assays in transiently transfected macrophages showed that the 5A allele had greater transcriptional activity than the 6A allele, and that this allele-specific effect was augmented when the cells were treated with the NFkappaB activator lipopolysaccharides or co-transfected with p50 and/or p65 expressing plasmids, but was reduced when the cells were treated with the NFkappaB inhibitor 6-Amino-4-(4-phenoxyphenylethylamino)-quinazoline or transfected with a dominant negative mutant of IkB kinase-beta. These results corroborate an effect of the 5A/6A polymorphism on MMP3 transcription and indicate that NFkappaB has differential effects on the 5A and 6A alleles.


Promoting pollution prevention through community-industry dialogues: the good neighbor model in Minnesota.
This article examines five attempts by communities to promote pollution prevention through direct negotiations with local manufacturing plants. These projects were Good Neighbor Dialogues spearheaded by Citizens for a Better Environment-Minnesota, an environmental advocacy organization. Three community-company partnerships (a container plant, a foundry, and a cabinet manufacturer) were successful and two (a munitions plant and a petroleum refinery) were not. Successful dialogues all shared certain characteristics: the company was open to negotiating with the community; there was an effective "champion" within the company; a skilled, independent facilitator served as moderator; community participants received independent technical assistance; and both the company and community understood the value of cooperative environmental decision making. Results suggest that Good Neighbor Dialogues can, under the right settings and circumstances, be an effective mechanism for building social capital by fostering greater understanding and trust between companies and communities. They offer the prospect of community-company partnerships that promote pollution prevention and other environmental improvements, while at the same time reinforcing and amplifying traditional pollution control strategies.


Detection of Amadori compounds by capillary electrophoresis coupled to tandem mass spectrometry.
Capillary electrophoresis coupled to mass spectrometry (CE-MS) is reported for the first time as an alternative and powerful analytical method for the characterization and monitoring of N-substituted 1-amino-1-deoxyketoses (Amadori compounds). It allows rapid separation and identification of Amadori compounds, while benefiting from the well-known advantages of MS, such as specificity and sensitivity. Amadori compounds of several amino acids, such as glycine, valine, isoleucine, methionine, proline, and phenylalanine, as well as a cysteine-derived compound, were separated and/or discriminated using CE-MS/MS under standard conditions. The technique may also be useful to study the stability and degradation kinetics of other labile charged Maillard intermediates that play an important role in food and medical science.


Flavonoids differentially inhibit guinea pig epidermal cytosolic phospholipase A2.
Cytosolic phospholipase A2 (cPLA2) is believed to involve the regulation of essential cellular processes. Like other cell types, epidermal cPLA2 may participate in various metabolic processes including eicosanoid generation. In this investigation, we demonstrated the presence of cPLA2 in guinea pig epidermis. The epidermal cPLA2 is Ca2+-dependent, active at micromolar concentration of Ca2+ and resistant to disulfide-reducing agents. Furthermore, it is inhibited by methyl arachidonyl fluorophosphonate (MAFP), a selective inhibitor of cPLA2, while 12-epi-scalardial (a sPLA2 inhibitor) did not cause inhibition. A test of several flavonoids revealed that quercetin (flavonol) weakly inhibited cPLA2, while flavanone had negligible inhibitory activity. In contrast, amentoflavone and ginkgetin (biflavones) markedly inhibited cPLA2 activity in the epidermis. These results underscore that different flavonoids do vary in their capability to exert differential effects on arachidonate metabolism in the skin via modulation of epidermal cPLA2 activity.


Fabrication method to maintain mouthguard thickness regardless of the model angle.
The safety and effectiveness of mouthguards depend on the sheet material and thickness. The aim of this study was to investigate the fabrication method for a mouthguard with appropriate thickness using a single sheet regardless of the model angle. Mouthguards were thermoformed using 4.0 mm thick ethylene vinyl acetate sheets and a vacuum forming machine. The working models were three hard plaster models trimmed so that the angle of the anterior teeth to the model base was 90°, 100°, and 110°. The model position was 40 mm from the front of the forming unit. The sheet was softened until it sagged 15 mm, after which the sheet frame was lowered to cover the model. Next, the vacuum was turned on and held for 30 seconds for the control. Under the forming conditions in which the model position (MP) was moved, after the model was covered with the sheet, a scissors handle was positioned at the rear of the model and used to push it forward 20 mm, and then, the vacuum switch was turned on for 30 seconds. Six specimens were formed for each condition. Mouthguard thickness after formation was measured using a specialized caliper. The differences in mouthguard thickness due to forming conditions and model angle were analyzed. The MP was significantly thicker than the control in each model (P < .01). The mouthguard thickness tended to decrease as the model angle increased. The average thickness of the labial surface in the MP was 3 mm or more and was not affected by the model angle. This study suggested that the fabrication method in which moving the model forward by 20 mm just before formation could produce a mouthguard with approximately 3 mm thickness on the labial side with a single sheet regardless of the model angle.


Ecto-5'-nucleotidase CD73 modulates the innate immune response to influenza infection but is not required for development of influenza-induced acute lung injury.
Extracellular nucleotides and nucleosides are important signaling molecules in the lung. Nucleotide and nucleoside concentrations in alveolar lining fluid are controlled by a complex network of surface ectonucleotidases. Previously, we demonstrated that influenza A/WSN/33 (H1N1) virus resulted in increased levels of the nucleotide ATP and the nucleoside adenosine in bronchoalveolar lavage fluid (BALF) of wild-type (WT) C57BL/6 mice. Influenza-induced acute lung injury (ALI) was highly attenuated in A1-adenosine receptor-knockout mice. Because AMP hydrolysis by the ecto-5'-nucleotidase (CD73) plays a central role in and is rate-limiting for generation of adenosine in the normal lung, we hypothesized that ALI would be attenuated in C57BL/6-congenic CD73-knockout (CD73-KO) mice. Infection-induced hypoxemia, bradycardia, viral replication, and bronchoconstriction were moderately increased in CD73-KO mice relative to WT controls. However, postinfection weight loss, pulmonary edema, and parenchymal dysfunction were not altered. Treatment of WT mice with the CD73 inhibitor 5'-(α,β-methylene) diphosphate (APCP) also had no effect on infection-induced pulmonary edema but modestly attenuated hypoxemia. BALF from CD73-KO and APCP-treated WT mice contained more IL-6 and CXCL-10/IFN-γ-induced protein 10, less CXCL-1/keratinocyte chemoattractant, and fewer neutrophils than BALF from untreated WT controls. BALF from APCP-treated WT mice also contained fewer alveolar macrophages and more transforming growth factor-β than BALF from untreated WT mice. These results indicate that CD73 is not necessary for development of ALI following influenza A virus infection and suggest that tissue-nonspecific alkaline phosphatase may be responsible for increased adenosine generation in the infected lung. However, they do suggest that CD73 has a previously unrecognized immunomodulatory role in influenza.


Imaging of coronary artery calcification.
Coronary artery disease is a leading cause of morbidity and mortality among Americans. The traditional methods of evaluating coronary artery disease rely on the evaluation of the patient s symptoms and the presence of advanced disease. Until recently there was no method of early screening for coronary atherosclerosis in an asymptomatic population. However, calcification is a recognized marker for disease and is sometimes a component of the atheromatous plaque. With the advent of electron-beam computed tomography and subsecond helical computed tomography, a method of screening for and quantitating the amount of coronary calcification has been developed. The coronary calcium score is based on both the area and density of the calcification. This methodology can identify patients at risk for coronary artery disease, so that risk factor modification and preventive therapy can be initiated early in the course of the disease.


A microfluidic chip for highly efficient cell capturing and pairing.
This paper examined the feasibility of a microfluidics chip for cell capturing and pairing with a high efficiency. The chip was fabricated by the polydimethylsiloxane-based soft-lithography technique and contained two suction duct arrays set in parallel on both sides of a main microchannel. Cells were captured and paired by activating two sets of suction ducts one by one with the help of syringe pumps along with switching the cell suspensions inside the main microchannel correspondingly. The effects of suction flow rate and the dimensions of suction channels on the cell capturing and pairing efficiency were characterized. The present chip was capable of creating 1024 pairs of two different cell populations in parallel. The preliminary experimental results showed that the cell capturing efficiency was 100% and the pairing one was 88% with an optimal suction rate of 5 μl/min in the chip in the 2 μm-sized suction duct chip. The cell viability after capture inside the microfluidic device was 90.0 ± 5.3%. With this cell capturing and pairing chip, interaction between cells in a single pair mode can be studied. The ability to create cell pairs has a number of biological applications for cell fusion, cell-cell interaction studies, and cell toxicity screening.


Role of the liver in small-solute transport during peritoneal dialysis.
Peritoneal dialysis (PD) is dependent on the transport of water and solutes from the blood capillaries within the tissues that surround the peritoneal cavity. Because of their large blood supply and surface area, the viscera have been considered the most important tissues for PD transport. In animals, however, removal of the gastrointestinal tract decreases PD small-solute mass transfer by only 10 to 27%. To investigate the theoretical basis for these observations, a distributed model of peritoneal transport was extended to take into account the transport characteristics of four tissue groups that surround the cavity: the liver, the hollow viscera, the abdominal wall, and the diaphragm. The mass transfer-area coefficient (MTAC) of sucrose for each tissue was calculated from the following: MTAC = ([D(pa)]0.5)A, where D is the effective solute interstitial diffusivity, pa is the solute transcapillary permeability-area per unit tissue volume, and A is the apparent peritoneal surface area of the tissue. Our results for the adult human predict that the MTAC for the liver is comparable to that of all of the other viscera and makes up 43% of the total MTAC for the peritoneal cavity. The predicted MTAC is 4 cm3/min (plasma) or 6 cm3/min (blood), in good agreement with published values. It is concluded that the liver is responsible for a major portion of the small-solute MTAC. This also explains the earlier observations in eviscerated animals whose PD transport was likely preserved by intact livers.


Functional crosstalk among oxidative stress and O-GlcNAc signaling pathways.
In metazoans, thousands of intracellular proteins are modified with O-linked β-N-acetylglucosamine (O-GlcNAc) in response to a wide range of stimuli and stresses. In particular, a complex and evolutionarily conserved interplay between O-GlcNAcylation and oxidative stress has emerged in recent years. Here, we review the current literature on the connections between O-GlcNAc and oxidative stress, with a particular emphasis on major signaling pathways, such as KEAP1/NRF2, FOXO, NFκB, p53 and cell metabolism. Taken together, this work sheds important light on the signaling functions of protein glycosylation and the mechanisms of stress responses alike and illuminates how the two are integrated in animal cell physiology.


Genome Sequence Resource of Coniella vitis, a Fungal Pathogen Causing Grape White Rot Disease.
Several fungal pathogens cause grape white rot disease and Coniella vitis is a predominant pathogen in Chinese vineyards. The disease occurs on leaves, vines, and fruit berries, leading to considerable yield losses and even to total destruction of vineyards. Here, we present the first Pacbio and Illumina-sequenced draft genome assembly of C. vitis QNYT13637 and its annotation. This genome sequence provides a unique resource that will be a powerful foundation for future research on exploring virulence-related genes, investigating the pathogenicity mechanism of the pathogen, and, finally, improvement of white rot disease management strategies.


Predicting the Risk of Huntington's Disease with Multiple Longitudinal Biomarkers.
Huntington's disease (HD) has gradually become a public health threat, and there is a growing interest in developing prognostic models to predict the time for HD diagnosis. This study aims to develop a novel prognostic model that leverages multiple longitudinal biomarkers to inform the risk of HD. The multivariate functional principal component analysis was used to summarize the essential information from multiple longitudinal markers and to obtain a set of prognostic scores. The prognostic scores were used as predictors in a Cox model to predict the right-censored time to diagnosis. We used cross-validation to determine the best model in PREDICT-HD (n = 1,039) and ENROLL-HD (n = 1,776); external validation was carried out in ENROLL-HD. We considered six commonly measured longitudinal biomarkers in PREDICT-HD and ENROLL-HD (Total Motor Score, Symbol Digit Modalities Test, Stroop Word Test, Stroop Color Test, Stroop Interference Test, and Total Functional Capacity). The prognostic model utilizing these longitudinal biomarkers significantly improved the predictive performance over the model with baseline biomarker information. A new prognostic index was computed using the proposed model, and can be dynamically updated over time as new biomarker measurements become available. Longitudinal measurements of commonly measured clinical biomarkers substantially improve the risk prediction of Huntington's disease diagnosis. Calculation of the prognostic index informs the patient's risk category and facilitates patient selection in future clinical trials.


Immunological parameters in Darier's disease.
Patients with Darier's disease have frequently been observed to develop severe bacterial and viral infections. Previous studies have indicated some derangement in the immune system, even though no consistent or specific abnormality has yet been demonstrated. We performed the results of immunologic studies in 10 patients with Darier's disease. In each patient humoral immunity and cell-mediated immunity (in vivo and in vitro) were evaluated and leukocyte chemotactic function was assayed. Humoral immunity was normal; as regards clusters of differentiation (CD), a slight increase in CD4 lymphocyte subpopulations was observed in 7 patients and of CD4/CD8 ratio in 1 case. The lymphocyte responses to phytohemagglutinin and concanavalin A were normal, whereas the response to pokeweed mitogen was decreased slightly, but not significantly. Normal random and chemotactic mobility was found in all the patients except one. The data obtained do not show important immunological alterations. Our patients did not have a high propensity to develop severe infections and this may explain the absence of significant immunological derangement. Our data confirm that no immunological derangement is associated with Darier's disease.


Do patients with thromboembolic disease have circulating platelet aggregates?
Reports of circulating platelet aggregates (ie, microemboli) in thromboembolism and other vascular disorders are based on a method (Wu and Hoak , 1974) in which venous blood is collected via scalp vein needle and tubing into either formaldehyde, which fixes aggregates, or EDTA, which disperses them. The ratio of platelet counts in platelet-rich plasma (PRP) from the two blood samples after centrifugation is interpreted as a measure of platelet aggregates in the circulation in vivo. We compared this standard Wu and Hoak technique with a modified one, in which blood was drawn directly into a syringe, and with a third method that avoided centrifugation by counting single platelets in whole blood. Both modified techniques could detect aggregates generated in vitro with adenosine diphosphate (ADP). In 12 normal subjects, the three methods were equivalent, but in 37 patients with thromboembolic disorders, the standard Wu and Hoak method gave a lower ratio than the other methods. Similar results were found in a subset of eight patients with myocardial infarction. Heparin treatment of patients did not influence the results. The data suggest that formation of platelet aggregates occurred during venipuncture. Platelets may be hyperactive in patients with thromboembolic disease and may form aggregates in vitro during collection, but the concept of chronic microembolism in such patients should be reassessed.


Comparison of the transcriptional landscapes between human and mouse tissues.
Although the similarities between humans and mice are typically highlighted, morphologically and genetically, there are many differences. To better understand these two species on a molecular level, we performed a comparison of the expression profiles of 15 tissues by deep RNA sequencing and examined the similarities and differences in the transcriptome for both protein-coding and -noncoding transcripts. Although commonalities are evident in the expression of tissue-specific genes between the two species, the expression for many sets of genes was found to be more similar in different tissues within the same species than between species. These findings were further corroborated by associated epigenetic histone mark analyses. We also find that many noncoding transcripts are expressed at a low level and are not detectable at appreciable levels across individuals. Moreover, the majority lack obvious sequence homologs between species, even when we restrict our attention to those which are most highly reproducible across biological replicates. Overall, our results indicate that there is considerable RNA expression diversity between humans and mice, well beyond what was described previously, likely reflecting the fundamental physiological differences between these two organisms.


Normalization of institutional mealtimes for profoundly retarded persons: effects and noneffects of teaching family-style dining.
Benefits have been reported for certain institutionalized populations when mealtimes are arranged under normal, family-style conditions. In this study, we evaluated a program for teaching family-style mealtime skills to institutionalized persons with skill deficits greater than those targeted in previous research--the profoundly retarded. Results showed that the program, involving forward chaining with a less-to-more intrusive prompting sequence and contingent reinforcement, successfully taught four profoundly retarded persons several family-style skills. Also, systematic measures supported the durability of the skills, social validity of the behavior changes, acceptance of the program by staff trainers, and no detrimental changes in health-related variables associated with food consumption. However, results also indicated that beneficial corollary changes (e.g., increased peer communication) previously reported with higher skilled populations did not occur. These results suggest that with more seriously handicapped populations, multiple changes should not be assumed when normalizing institutional conditions; rather, specific skill training will probably be necessary.


Cadmium-induced glutathionylation of actin occurs through a ROS-independent mechanism: implications for cytoskeletal integrity.
Cadmium disrupts the actin cytoskeleton in rat mesangial cells, and we have previously shown that this involves a complex interplay involving activation of kinase signaling, protein translocation, and disruption of focal adhesions. Here we investigate the role that glutathionylation of actin plays in Cd(2+)-associated cytoskeletal reorganization. Low concentrations of Cd(2+) (0.5-2 μM) caused an increase in actin glutathionylation by 6h, whereas at higher concentrations glutathionylation remained at basal levels. Although oxidation with diamide increased glutathionylation, reactive oxygen species (ROS) were not involved in the Cd(2+)-dependent effect, as only Cd(2+) concentrations above 2 μM were sufficient to increase ROS. However, low [Cd(2+)] increased total glutathione levels without affecting the ratio of reduced/oxidized glutathione, and inhibition of glutathione synthesis suppressed actin glutathionylation. Cadmium increased the activity of the enzyme glutaredoxin, which influences the equilibrium between glutathionylated and deglutathionylated proteins and thus may influence levels of glutathionylated actin. Together these observations show that cadmium-dependent effects on actin glutathionylation are affected by glutathione metabolism and not by direct effects of ROS on thiol chemistry. In vitro polymerization assays with glutathionylated actin show a decreased rate of polymerization. In contrast, immunofluorescence of cytoskeletal structure in intact cells suggests that increases in actin glutathionylation accompanying increased glutathione levels occurring under low Cd(2+) exposure are protective in vivo, with cytoskeletal disruption ensuing only when higher Cd(2+) concentrations increase ROS levels and prevent an increase in actin-glutathione conjugates.


Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study.
The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population-based manner. We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non-infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively. The study cohort comprised 71 379 ATD initiators, with a median follow-up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person-years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person-years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89-fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08-fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22). MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose-dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis.


Practical importance of breast microcalcifications: report on 112 cases.
The authors discuss the results of a diagnostic and therapeutic study of 112 cases of breast microcalcifications with no palpable lesions. The criteria in favor of obtaining a surgical specimen are discussed as a function of population characteristics and a review of the literature. Techniques for the localization of these lesions are defined. Decisions as to the necessity for ulterior treatment of the breast are based on certain criteria, and above all on the risk of evolution of invasive lesions with nodal involvement. The high quality of current mammograms has considerably increased the number of patients referred for biopsy. In the case of microcalcifications masking malignant lesions, the advances made in conservative treatment of breast cancer are not always applicable owing to the risks of failure with such conservative approaches.


[Symptomatic SUNCT with cerebral abscess and subdural empyema].
SUNCT syndrome is a rare form of a primary headache disorder, although secondary causes, particularly posterior fossa abnormalities, are well known. We report a new case in a 67-year-old man suffering SUNCT syndrome secondary to pyogenic cerebral abscess and empyema localized in the convexity portion of the right frontal lobe.


Probability density function of ocean noise based on a variational Bayesian Gaussian mixture model.
Extensive ocean noise records have kurtoses markedly different from the Gaussian distribution and therefore exhibit non-Gaussianity, which influences the performance of many sonar signal processing methods. To model the amplitude distribution, this paper studies a Bayesian Gaussian mixture model (BGMM) and its associated learning algorithm, which exploits the variational inference method. The most compelling feature of the BGMM is that it automatically selects a suitable number of effective components and then can approximate a sophisticated distribution in practical applications. The probability density functions (PDFs) of three types of noise in different frequency bands collected in the South China Sea-ambient noise, ship noise, and typhoon noise-are modeled and the goodness of fit is examined by applying the one-sample Kolmogorov-Smirnov test. The results demonstrate that: (i) Ambient noise in the low-frequency band may be slightly non-Gaussian, ship noise in each considered band is apparently non-Gaussian, and typhoons affect the noise in the low-frequency band to make it apparently non-Gaussian, while the noise in the high-frequency band is less affected and appears to be Gaussian. (ii) BGMM has higher goodness of fit than the Gaussian or Gaussian mixture model. (iii) In the non-Gaussian case, despite some components having small mixing coefficients, they are of great significance for describing the PDF.


Human T Cell Leukemia Virus Type 1 and Eye Diseases.
Human T cell leukemia virus type 1, also known as human T lymphotropic virus type 1 (HTLV-1), is a retrovirus that encodes a reverse transcriptase, which translates viral RNA into a DNA provirus that is integrated into the host genome. The virus was found to be a causative agent of adult T cell leukemia/lymphoma (ATL) in the early 1980s, and was also found to cause the neurological disorder tropical spastic paraparesis (TSP)/HTLV-1-associated myelopathy (HAM) and the inflammatory disorder HTLV-1 uveitis in the mid 1980s and early 1990s, respectively. This article reviews eye diseases caused by or related to HTLV-1: HTLV-1 uveitis, ocular and systemic complications of HTLV-1, keratoconjunctivitis sicca, interstitial keratitis, and ATL.


The cobC gene of Salmonella typhimurium codes for a novel phosphatase involved in the assembly of the nucleotide loop of cobalamin.
We report the identification of a new locus, designated cobC, involved in the assembly of the nucleotide loop of cobalamin in Salmonella typhimurium. The cobC gene has been mapped, cloned, and sequenced. DNA sequence analysis suggested that cobC is divergently transcribed from the adjacent cobD gene and suggests that the regulatory region of these genes overlap. The cobC gene codes for a predicted polypeptide of 26 kDa with striking homology to phosphoglycerate mutase, fructose-2,6-bisphosphatase, and acid phosphatase enzymes. In vitro experiments demonstrated that CobC dephosphorylated the cobalamin biosynthetic intermediate N1-(5-phospho-alpha-D-ribosyl)-5,6-dimethylbenzimidazole to generate N1-alpha-D-ribosyl-5,6-dimethylbenzimidazole. In vivo data showed that the lack of cobC function blocks the synthesis of cobalamin from its precursors cobinamide and 5,6-dimethylbenzimidazole, i.e. it prevents the assembly of the nucleotide loop of cobalamin. Additionally, exogenous N1-alpha-D-ribosyl-5,6-dimethylbenzimidazole rescues the defect of a cobC mutant. We propose that cobC codes for a novel phosphatase whose primary role is in cobalamin biosynthesis. A model for the sequence of biosynthetic steps that assemble the nucleotide loop of cobalamin in S. typhimurium is presented.


The role of health technology assessment bodies in shaping drug development.
The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company's perspective, as market prospects are strongly influenced by third-party payers' coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed.


Rapidly progressing monoparesis caused by Chiari malformation type I without syringomyelia.
Patients with Chiari malformation type I (CM-I) can manifest neurological symptoms, such as headache, neck pain, dysesthesia, swallowing disturbance, and paresis, which are usually stable or slowly progressive even if syringomyelia is coexistent. In some instances, however, acute onset of neurological symptoms has been reported but the pathogenetic mechanism and subsequent clinical course have not been explained. In those cases, it was reported that urgent treatment of foramen magnum decompression (FMD) was very effective. This work reports that an 11-year-old girl with CM-I subacutely developed unique symptoms and that urgent treatment of FMD was very effective. We present here an 11-year-old girl with CM-I who subacutely developed dysphagia, left upper extremity monoparesis and sensory dysesthesia, with the limb assuming a peculiar posture at rest, with the wrist in extension and the elbow joint in flexion. Although her symptoms were assumed to be due to previously diagnosed CM-I without syringomyelia, no differences on magnetic resonance imaging (MRI) could be found except for slight change in the shape of tonsils compared with the previous ones. FMD and C1 removal with duraplasty was performed and resulted in an excellent neurological recovery. This case is a reminder that the presence of a new neurological deficit referable to nuclei within, or tracts that traverse, the cerebromedullary junction is a firm surgical indication for FMD in a patient with CM-I. MRI was nearly identical during the asymptomatic and symptomatic periods in this case, and did not explain the timing of symptom onset.


Application of Metabolomics in Alzheimer's Disease.
Progress toward the development of efficacious therapies for Alzheimer's disease (AD) is halted by a lack of understanding early underlying pathological mechanisms. Systems biology encompasses several techniques including genomics, epigenomics, transcriptomics, proteomics, and metabolomics. Metabolomics is the newest omics platform that offers great potential for the diagnosis and prognosis of neurodegenerative diseases as an individual's metabolome reflects alterations in genetic, transcript, and protein profiles and influences from the environment. Advancements in the field of metabolomics have demonstrated the complexity of dynamic changes associated with AD progression underscoring challenges with the development of efficacious therapeutic interventions. Defining systems-level alterations in AD could provide insights into disease mechanisms, reveal sex-specific changes, advance the development of biomarker panels, and aid in monitoring therapeutic efficacy, which should advance individualized medicine. Since metabolic pathways are largely conserved between species, metabolomics could improve the translation of preclinical research conducted in animal models of AD into humans. A summary of recent developments in the application of metabolomics to advance the AD field is provided below.


Protein Tyrosine Nitration in Plant Nitric Oxide Signaling.
Nitric oxide (NO), which is ubiquitously present in living organisms, regulates many developmental and stress-activated processes in plants. Regulatory effects exerted by NO lies mostly in its chemical reactivity as a free radical. Proteins are main targets of NO action as several amino acids can undergo NO-related post-translational modifications (PTMs) that include mainly S-nitrosylation of cysteine, and nitration of tyrosine and tryptophan. This review is focused on the role of protein tyrosine nitration on NO signaling, making emphasis on the production of NO and peroxynitrite, which is the main physiological nitrating agent; the main metabolic and signaling pathways targeted by protein nitration; and the past, present, and future of methodological and strategic approaches to study this PTM. Available information on identification of nitrated plant proteins, the corresponding nitration sites, and the functional effects on the modified proteins will be summarized. However, due to the low proportion of in vivo nitrated peptides and their inherent instability, the identification of nitration sites by proteomic analyses is a difficult task. Artificial nitration procedures are likely not the best strategy for nitration site identification due to the lack of specificity. An alternative to get artificial site-specific nitration comes from the application of genetic code expansion technologies based on the use of orthogonal aminoacyl-tRNA synthetase/tRNA pairs engineered for specific noncanonical amino acids. This strategy permits the programmable site-specific installation of genetically encoded 3-nitrotyrosine sites in proteins expressed in Escherichia coli, thus allowing the study of the effects of specific site nitration on protein structure and function.


Recent Advances in the Understanding of the Health Benefits and Molecular Mechanisms Associated with Green Tea Polyphenols.
Tea, leaf, or bud from the plant Camellia sinensis, make up some of the beverages popularly consumed in different parts of the world as green tea, oolong tea, or black tea. More particularly, as a nonfermented tea, green tea has gained more renown because of the significant health benefits assigned to its rich content in polyphenols. As a main constituent, green tea polyphenols were documented for their antioxidant, anti-inflammation, anticancer, anticardiovascular, antimicrobial, antihyperglycemic, and antiobesity properties. Recent reports demonstrate that green tea may exert a positive effect on the reduction of medical chronic conditions such as cardiovascular disease, cancer, Alzheimer's disease, Parkinson's disease, and diabetes. The health benefits of green teas, in particular EGCG, are widely investigated, and these effects are known to be primarily associated with the structure and compositions of its polyphenols. This Review focuses on the diverse constituents of green tea polyphenols and their molecular mechanisms from the perspective of their potential therapeutic function. Recent advances of green tea polyphenols on their bioavailability, bioaccessibility, and microbiota were also summarized in this article. Dietary supplementation with green tea represents an attractive alternative toward promoting human health.


Synthesis and Evaluation of a Linkable Functional Group-Equipped Analogue of the Epothilones.
An approach to the validation of a linker strategy for the epothilone family of microtubule-stabilizing agents is reported. An analogue of epothilone B in which the C(6) methyl group has been replaced with a 4-azidobutyl group has been prepared by total chemical synthesis, and amides derived from the azido group have been shown to retain the activity of the parent compound. These results set the stage for an evaluation of the potential of the epothilones to serve as the drug component of antibody-drug conjugates and other selective tumor cell-targeting conjugates.


Local arginase inhibition does not modulate cutaneous vasodilation or sweating in young and older men during exercise.
Age-related impairments in cutaneous vascular conductance (CVC) and sweat rate (SR) during exercise may result from increased arginase activity, which can attenuate endogenous nitric oxide (NO) production. We therefore evaluated whether arginase inhibition modulates these heat-loss responses in young (n = 9, 23 ± 3 yr) and older (n = 9, 66 ± 6 yr) men during two 30-min bouts of moderate-intensity cycling (Ex1 and Ex2) in the heat (35°C). CVC and SR were measured at forearm skin sites perfused with 1) lactated Ringer's (control), 2) NG-nitro-L-arginine methyl ester (L-NAME; NO synthase-inhibited), or 3) Nω-hydroxy-nor-arginine and S-(2-boronoethyl)-l-cysteine (Nor-NOHA + BEC; arginase-inhibited). In both groups, CVC was reduced at L-NAME relative to control and Nor-NOHA + BEC (both P < 0.01). Likewise, SR was attenuated with L-NAME compared with control and Nor-NOHA + BEC during each exercise bout in the young men (all P ≤ 0.05); however, no influence of treatment on SR in the older men was observed (P = 0.14). Based on these findings, we then evaluated responses in 7 older men (64 ± 7 yr) during passively induced elevations in esophageal temperature (∆Tes) equal to those in Ex1 (0.6°C) and Ex2 (0.8°C). L-NAME reduced CVC by 18 ± 20% CVCmax at a ∆Tes of 0.8°C (P = 0.03) compared with control, whereas Nor-NOHA + BEC augmented CVC by 20 ± 18% CVCmax, on average, throughout heating (both P ≤ 0.03). SR was not influenced by either treatment (P = 0.80) Thus, arginase inhibition does not modulate CVC or SR during exercise in the heat but, consistent with previous findings, does augment CVC in older men during passive heating. NEW & NOTEWORTHY In the current study, we demonstrate that local arginase inhibition does not influence forearm cutaneous vasodilatory and sweating responses in young or older men during exercise-heat stress. Consistent with previous findings, however, we observed augmented cutaneous blood flow with arginase inhibition during whole-body passive heat stress. Thus, arginase differentially affects cutaneous vasodilation depending on the mode of heat stress but does not influence sweating during exercise or passive heating.


[Skin adverse drug reactions].
Adverse drug reactions are common and important complications of therapy. The clinical picture of drug-induced reactions is characterised by considerable polymorphism: from mild local lesions to fatal systemic processes. The classification of drug hypersensitivity encompasses systemic or specific organ forms. Skin has a special position in the diagnostics of adverse drug-induced reactions. Cutaneous lesions are almost universal and highly pathognomonic symptoms of drug-induced hypersensitivity. Urticaria, erythema-like skin reactions, drug-induced exanthemas, purpuric and hemorrhagic reactions are the most common cutaneous drug-induced manifestations.


Digital subtraction angiography abnormalities in sudden unilateral profound hearing loss.
The reduced caliber of the anterior inferior cerebellar artery (AICA) on the affected side in patients with sudden unilateral profound hearing loss (SUPHL) may reflect a perfusion deficit which, combined to a lesser degree with anatomic abnormalities in the vertebrobasilar system, would be implicated in the pathogenesis of SUPHL. To identify existing hemodynamic disturbances and anatomic abnormalities in patients with SUPHL using digital subtraction angiography. Ten patients aged 18-66 years and a control group of 25 subjects were included in the study. Both vertebral arteries (VAs) were selectively catheterized in all the patients. In 7/10 patients (70%) the AICA on the side affected by SUPHL was smaller in caliber than the contralateral one after injection of contrast medium into the VA on the affected side. The situation was significantly different in the control group, whose angiography results demonstrated similarly sized AICAs in 84% of cases. Tortuosity of the VA on the affected side was encountered in two patients and important VA asymmetry in one.


Fast and Accurate Construction of Confidence Intervals for Heritability.
Estimation of heritability is fundamental in genetic studies. Recently, heritability estimation using linear mixed models (LMMs) has gained popularity because these estimates can be obtained from unrelated individuals collected in genome-wide association studies. Typically, heritability estimation under LMMs uses the restricted maximum likelihood (REML) approach. Existing methods for the construction of confidence intervals and estimators of SEs for REML rely on asymptotic properties. However, these assumptions are often violated because of the bounded parameter space, statistical dependencies, and limited sample size, leading to biased estimates and inflated or deflated confidence intervals. Here, we show that the estimation of confidence intervals by state-of-the-art methods is inaccurate, especially when the true heritability is relatively low or relatively high. We further show that these inaccuracies occur in datasets including thousands of individuals. Such biases are present, for example, in estimates of heritability of gene expression in the Genotype-Tissue Expression project and of lipid profiles in the Ludwigshafen Risk and Cardiovascular Health study. We also show that often the probability that the genetic component is estimated as 0 is high even when the true heritability is bounded away from 0, emphasizing the need for accurate confidence intervals. We propose a computationally efficient method, ALBI (accurate LMM-based heritability bootstrap confidence intervals), for estimating the distribution of the heritability estimator and for constructing accurate confidence intervals. Our method can be used as an add-on to existing methods for estimating heritability and variance components, such as GCTA, FaST-LMM, GEMMA, or EMMAX.


ECOLOGICAL AND EVOLUTIONARY APPLICATIONS FOR ENVIRONMENTAL SEX REVERSAL OF FISH.
Environmental sex reversal (ESR), which results in a mismatch between genotypic and phenotypic sex, is well documented in numerous fish species and may be induced by chemical exposure. Historically, research involving piscine ESR has been carried out with a view to improving profitability in aquaculture or to elucidate the processes governing sex determination and sexual differentiation. However, recent studies in evolution and ecology suggest research on ESR now has much wider applications and ramifications. We begin with an overview of ESR in fish and a brief review of the traditional applications thereof. We then discuss ESR and its potential demographic consequences in wild populations. Theory even suggests sex-reversed fish may be purposefully released to manipulate population dynamics. We suggest new research directions that may prove fruitful in understanding how ESR at the individual level translates to population-level processes. In the latter portion of the review we focus on evolutionary applications of ESR. Sex-reversal studies from the aquaculture literature provide insight in to the evolvability of determinants of sexual phenotype. Additionally, induced sex reversal can provide information about the evolution of sex chromosomes and sex-linked traits. Recently, naturally occurring ESR has been implicated as a mechanism contributing to the evolution of sex chromosomes.


Adding fuel to the fire: Coronary artery dissection complicating blunt chest trauma.
A 21year-old male presented to the emergency department with 6 h of atypical chest pain after suffering blunt chest trauma. His electrocardiogram revealed 1-1.5mm ST segment elevation in leads V1-V3 with reciprocal depressions in II, III, and aVF. Mid-anterior wall akinesis was observed on echocardiography associated with an estimated left ventricular ejection fraction of 40%. A left main coronary artery dissection was diagnosed and treated surgically with a bypass graft. Although rare, coronary dissections can be a catastrophic complication of chest trauma.


Terahertz quantum cascade laser frequency combs with optical feedback.
Optical feedback exists in most laser configurations and strongly affects laser performances depending on the feedback strength, length, and phase. In this paper, we investigate the frequency comb behaviour of a semiconductor quantum cascade laser emitting around 4.2 THz with external optical feedback. A periodic evolution of the laser inter-mode beatnote from single-line to multiple-line structures is experimentally observed with a minor change of optical feedback length (phase) on the wavelength scale. The comb stability of the laser with feedback is also measured and compared with the same laser without feedback. Furthermore, our simulations reveal that the dynamical oscillations invoked by optical feedback are responsible for the measured multiple-line beatnotes. It is found that the characteristic feedback period is determined by the half wavelength of the laser, while the comb operation is maintained at most feedback length positions. Therefore, terahertz quantum cascade laser combs are robust against the minor position vibration of the feedback mirror in practice, owing to the much smaller feedback phase change than that of common near-infrared laser diodes.


Genetic variants of beta-lactoglobulin gene and its association with milk composition traits in riverine buffalo.
A study was carried out to determine genetic variants of beta-lactoglobulin gene and to explore associations between these and milk composition traits in riverine buffalo. Single strand conformation polymorphism was employed to detect the genetic variants of the gene. Two fragments of this gene i.e. 119 bp of exon I and 400 bp spanning exon IV and intron IV were included in the study. For 119 bp fragment, three alleles namely, A, B and C were observed in all the buffalo breeds whereas four alleles (A, B, C and D) were detected for 400 bp fragment. The frequency distribution of alleles was different in different breeds of buffaloes for both the fragments. For exon I fragment, the milk composition traits such as total SNF, protein, solid, fat and whey protein yield were found to be significantly (P<0.05) associated with genotypes in Murrah and Bhadawari buffalo whereas in Mehsana breed genotypes were significantly (P<0.05) co-related with total SNF, solid and fat yield. Genotypes of 400 bp fragment, only total fat yield in Mehsana buffalo was found to be significantly (P<0.05) associated with genotypes.


Critical superfluid velocity in a trapped dipolar gas.
We investigate the superfluid properties of a dipolar Bose-Einstein condensate (BEC) in a fully three-dimensional trap. Specifically, we estimate a superfluid critical velocity for this system by applying the Landau criterion to its discrete quasiparticle spectrum. We test this critical velocity by direct numerical simulation of condensate depletion as a blue-detuned laser moves through the condensate. In both cases, the presence of the roton in the spectrum serves to lower the critical velocity beyond a critical particle number. Since the shape of the dispersion, and hence the roton minimum, is tunable as a function of particle number, we thereby propose an experiment that can simultaneously measure the Landau critical velocity of a dipolar BEC and demonstrate the presence of the roton in this system.


Development of REM sleep drive and clinical implications.
Rapid eye movement (REM) sleep in the human declines from approximately 50% of total sleep time ( approximately 8 h) in the newborn to approximately 15% of total sleep time (approximately 1 h) in the adult, and this decrease takes place mainly between birth and the end of puberty. We hypothesize that without this developmental decrease in REM sleep drive, lifelong increases in REM sleep drive may ensue. In the rat, the developmental decrease in REM sleep occurs 10-30 days after birth, declining from >70% of total sleep time in the newborn to the adult level of approximately 15% of sleep time during this period. Rats at 12-21 days of age were anesthetized with ketamine and decapitated, and brain stem slices were cut for intracellular recordings. We found that excitatory responses of pedunculopontine nucleus (PPN) neurons to N-methyl-D-aspartic acid decrease, while responses to kainic acid increase, over this critical period. During this developmental period, inhibitory responses to serotonergic type 1 agonists increase but responses to serotonergic type 2 agonists do not change. The results suggest that as PPN neurons develop, they are increasingly activated by kainic acid and increasingly inhibited by serotonergic type 1 receptors. These processes may be related to the developmental decrease in REM sleep. Developmental disturbances in each of these systems could induce differential increases in REM sleep drive, accounting for the postpubertal onset of a number of different disorders manifesting increases in REM sleep drive. Examination of modulation by PPN projections to ascending and descending targets revealed the presence of common signals modulating ascending arousal-related functions and descending postural/locomotor-related functions.


Effect of self-assembling peptide P11 -4 on enamel erosion: AFM and SEM studies.
The aim of the present in vitro study was to evaluate the protective effect of self-assembling peptide P11 -4 (Curodont™ Protect/Credentis) on enamel erosion produced by a soft-drink, by using Atomic Force Microscopy (AFM) and Scanning Electron Microscopy (SEM). Thirty human incisors were equally and randomly assigned to 6 groups. Group 1: intact enamel, group 2: soft drink, group 3: Curodont(™) Protect applied, group 4: Curodont(™) Protect applied + soft drink, group 5: soft drink + Curodont(™) Protect applied, group 6: soft drink + Curodont(™) Protect applied + soft drink. Specimens were observed through atomic force microscopy (AFM). The root mean-square roughness (Rrms) was obtained from the AFM images and the differences in the averaged values among the groups were analyzed by Shapiro-Wilk test in order to assess the normality of the distribution. Parametric ANOVA and post hoc Tuckey test were performed to assess the differences between the different groups. After demineralization process, enamel demonstrated a high degree of surface porosity. This morphological aspect was reflected in the increase of Rrms values. No significant differences (p > 0.05) were reported between intact enamel and enamel only treated with P11 -4 and between eroded enamel and enamel treated with P11 -4 and then demineralized. However significant differences (p < 0.05) were recorded when comparing softened enamel with softened enamel further remineralized with biomimetic self-assembling peptides and enamel treated with the protective paste between two acid attacks. The use of P11 -4 remineralizing may offer a degree of protection from enamel erosion. SCANNING 38:344-351, 2016. © 2015 Wiley Periodicals, Inc.


miR-365 induces hepatocellular carcinoma cell apoptosis through targeting Bcl-2.
Hepatocellular carcinoma (HCC) is currently ranked as the third leading cause of cancer-related mortality worldwide. microRNAs (miRs) serve important roles in the development and progression of HCC. miR-365 has been demonstrated to function as a tumor suppressor in several types of cancer, including HCC; however, the mechanisms by which miR-365 regulates HCC apoptosis remains to be elucidated. In the present study, reverse transcription-quantitative polymerase chain reaction was performed to determine miR-365 expression levels in HCC and normal liver (LO2) cells. miR-365 overexpression was induced in SMC7721 cells using a plasmid-based system, and Cell Counting Kit-8 and TUNEL assays were performed to detect cell activity and apoptosis following miR-365 transfection. A luciferase assay was performed to determine the direct target of miR-365 in apoptosis regulation. Furthermore, a subcutaneously transplanted tumor model was established to evaluate the effects of miR-365 on tumor growth in vivo. The tumor tissue was used for further proliferation and apoptosis detection. The results of the present study indicated that miR-365 expression was significantly lower in HCC cells compared with LO2 cells (P<0.01). Transfection of SMC7721 cells with miR-365 plasmid significantly inhibited cell activity by inducing apoptosis (P<0.01). Luciferase assay indicated that miR-365 targets B-cell lymphoma 2 (Bcl-2) directly and therefore induces the downstream expression of pro-apoptotic proteins. The SMC7721 primary tumor growth was significantly reduced by miR-365 transfection (P<0.01). Further investigation demonstrated that the miR-365 group contained significantly fewer cells that were positive for proliferating cell nuclear antigen (P<0.01) and significantly more apoptotic cells (P<0.01). In conclusion, the results of the present study demonstrated that miR-365 may serve a role in inducing HCC apoptosis via directly targeting Bcl-2. This may provide a novel diagnosis and therapy target for the treatment of patients with HCC.


Enhanced Doubly Activated Dual Emission Fluorescent Probes for Selective Imaging of Glutathione or Cysteine in Living Systems.
The development of novel fluorescent probes for monitoring the concentration of various biomolecules in living systems has great potential for eventual early diagnosis and disease intervention. Selective detection of competitive species in biological systems is a great challenge for the design and development of fluorescent probes. To improve on the design of fluorescent coumarin-based biothiol sensing technologies, we have developed herein an enhanced dual emission doubly activated system (DACP-1 and the closely related DACP-2) for the selective detection of glutathione (GSH) through the use of one optical channel and the detection of cysteine (Cys) by another channel. A phenylselenium group present at the 4-position completely quenches the fluorescence of the probe via photoinduced electron transfer to give a nonfluorescent species. Probes are selective for glutathione (GSH) in the red region and for cysteine/homocysteine (Cys/Hcy) in the green region. When they were treated with GSH, DACP-1 and DACP-2 showed strong fluorescence enhancement in comparison to that for closely related species such as amino acids, including Cys/Hcy. Fluorescence quantum yields (ΦF) increased for the red channel (<0.001 to 0.52 (DACP-1) and 0.48 (DACP-2)) and green channel (Cys) (<0.001 to 0.030 (DACP-1) and 0.026 (DACP-2)), respectively. Competing fluorescent enhancements upon addition of closely related species were negligible. Fast responses, improved water solubility, and good cell membrane permeability were all properly established with the use of DACP-1 and DACP-2. Live human lung cancer cells and fibroblasts imaged by confocal microscopy, as well as live mice tumor model imaging, confirmed selective detection.


Precursor skyrmion states near the ordering temperatures of chiral magnets.
In noncentrosymmetric magnets, chiral Dzyaloshinskii-Moriya interactions (DMI) provide a distinctive mechanism for the stabilization of localized skyrmion states in two and three dimensions with a fixed sense of rotation. Near the ordering transition, the skyrmion strings develop attractive skyrmion-skyrmion interactions and ultimately become confined in extended clusters or textures [A. O. Leonov and U. K. Rößler, Nanomaterials, 2023, 13, 891], which is a consequence of the coupling between the magnitude and the angular part of the order parameter. Multi-skyrmionic states built from isolated skyrmions (IS) can form multiple modulated magnetic phases that may underlie the exotic magnetic phenomena of "partial order" or the field-driven "A-phase" observed in MnSi and other cubic helimagnets. Based on the standard phenomenological Dzyaloshinskii model, we obtain numerically exact solutions for skyrmion lattices (SkL), formulate their basic properties, and elucidate physical mechanisms of their formation and stability. Our detailed numerical studies show that the bound skyrmion states arise as hexagonal lattices of ±π-skyrmions (with the magnetization in the center along or opposite to the magnetic field) or square staggered lattices of π/2-skyrmions, which contain defect lines with zero modulus value and thus may form thermodynamically stable states only near the ordering temperature. In the simplest case of a two-dimensional (2D) skyrmionic texture, the structure is homogeneous in the third dimension (3D). The skyrmions preserve an ideal axisymmetric "double twist" core in condensed phases, while continuation into a space-filling texture is frustrated. The evolution of skyrmion lattices in an increasing magnetic field leads to a succession of phase transitions of first or second kind between diverse textures and finally ends due to the formation of isolated skyrmion-filaments with fixed radius and shape embedded in a homogeneously magnetized matrix. In the framework of the phenomenological model including only isotropic interactions (exchange, Zeeman, and DM energy contributions), the considered skyrmion lattices are only metastable states as the competing conical one-dimensional spiral forms the equilibrium state. But due to the weak couplings between skyrmions, secondary effects like anisotropies can stabilize skyrmionic textures as compared to simple helices. Also the topological nature of skyrmion condensates makes the magnetization processes in chiral magnets history-dependent and hysteretic.


Handwashing Practices in Neonatal Intensive Care Unit, Paediatric Intensive Care Unit and Neonatal Nurseries in Patan Hospital.
Hand hygiene has been identified as the single most important factor in minimising hospital acquired infections. However, compliance of handwashing guidelines has remained low. The aim of this study was to study the handwashing practices in the Paediatric and Neonatal intensive care units and Neonatal nurseries in Patan Hospital, and secondly to re-evaluate the improvement on compliance of handwashing guidelines after intervention. Pre-intervention study was conducted by covertly observing the handwashing practices by the healthcare workers. The healthcare workers were then shown the video demonstrating correct methods of handwashing as recommended by World health organization. The cycle was completed by discretely re-observing the handwashing practices following intervention. Sixty five samples were collected initially. Only 6 (9.2%) had completed all steps of handwashing correctly. Post- intervention, 51 samples were collected, out of which 35 (68.6%) had correctly completed all the steps. Following audio-visual demonstration, 100% correctly completed 8/10 steps of handwashing with soap and water. 8 (16%) failed to dry hands using a single use towel and 14 (28%) failed to turn off the tap using elbow. Post- intervention, 100% correctly completed 4/7 steps of handwashing using chlorhexidine. Four (15%) still failed to rub backs of fingers to opposite palm, eight (30%) failed to palm to palm with fingers interlaced, and rub thumb to opposite palm. Compliance in hand hygiene is low despite the known fact that it reduces nosocomial infections. However, a simple intervention like video demonstration can improve the compliance among healthcare workers.


Hydantoin: The mechanism of its in vitro anti-enterovirus activity revisited.
It has been generally accepted that hydantoin [5-(3,4-dichlorophenyl)methylhydantoin] exerts its anti-enterovirus activity by solely inhibiting viral assembly. However, we here show that hydantoin inhibits enteroviral RNA synthesis as well as subgenomic replication in a dose-dependent manner. We demonstrate that inhibition of RNA synthesis is the predominant mechanism of action at relatively high concentrations of hydantoin. However, at lower concentrations inhibition of viral morphogenesis is the main mechanism of action. Thus, hydantoin inhibits enteroviral replication by two distinct mechanisms.


Scoping Review of Family and Community Engagement Strategies Used in School-Based Interventions to Promote Healthy Behaviors.
School efforts to promote health among students are more successful when families and community members are involved. We conducted a scoping review to summarize and categorize family and community engagement strategies used in US school and out-of-school time (OST) interventions to address physical activity (PA) and nutrition in kindergarten through 12th grade students. The National Network of Partnership Schools' Six Keys to Success framework was useful in organizing the types of family and community engagement strategies used in included interventions. Many interventions used multiple family and community engagement strategies, with the most common being communicating with families and community members; providing support or education to families; and collaborations among school/OST program and community to support students and their families. This review identified six common family and community engagement strategies used in school and OST interventions for PA and nutrition. Including family and community engagement strategies in school and OST interventions could play an important role in maximizing support, resources, and expertise to promote healthy behaviors among all students.


Closed total dislocation of talus without any accompanying fractures.
Total talar dislocation, ie, disruption of the talus from the calcaneus, navicula, and tibia, is a rare and severe injury. We present a case of closed peritalar dislocation without any accompanying fractures and, thus, discuss the conflicts encountered in this rare injury. A 25-year-old male patient presented with severe pain, swelling, and deformity in his right ankle within 30 minutes of a fall from a height. There were no wounds around the ankle. Radiographs revealed that the talus was disrupted from the calcaneus, navicula, and tibia moving in the anterolateral direction. No accompanying fractures were seen in the talus or in surrounding bones. After an unsuccessful closed reduction attempt, a further decision was open reduction. It was seen that the interposed joint capsula was preventing reduction. After reduction, stability of the ankle was checked and found to be satisfactory, so no fixation material was used. It has been 2 years since the first injury, and the patient is functioning well, with no pain. The ankle has the same range of motion as the unaffected side. No sign of an avascular necrosis or sclerosis is seen on the final radiographs. Closed total dislocation of the talus without any accompanying fractures is a rare entity. The injury is open to various important complications, such as avascular necrosis, infection in patients with open wounds, and arthritic changes. To achieve a good outcome, early reduction of the dislocation has key importance.


[A clinical analysis on liver transplantation for hepatocellular carcinomas].
Currently, the role of liver transplantation in the treatment of hepatocellular carcinoma (HCC) with cirrhosis is controversial. What remain to be determined are the best treatment protocol and who are likely to have a good outcome after liver transplantation. Twenty-five patients with hepatocellular carcinoma underwent liver transplantation between 1993 and 2001 at the Department of Surgery, Catholic University of Korea. The follow-up period was from one month to 51 months. The pathologic findings, the recurrence, and survival of the 25 cases were analyzed. Two patients had a tumor larger than 5 cm in diameter and three patient had above 3 nodules in number. Five patients had bilobar tumors. Vascular invasion was present in 11 patients (45.8%). Among the 25 patients, postsurgical TNM staging was stage III in 3 patients, stage IVA in 5 patients, and stage IVB in 1 patient. Number of high risk patients were 16 (64%). During follow-up, 23 of the 25 patients (92%) were alive and the number of disease-free survivals was 21 among the 23 patients (91.3%). According to our small experience, HCC can be a good indication of liver transplantation, especially in low risk patients and even in the recurrent cases. A long-term survival can be achieved by aggressive treatment. However, the best protocol remains to be determined, especially for the case with large tumors.


Drug-induced gingival hyperplasia - experimental model.
Several causes of gingival hyperplasia are known, the most widely accepted being the drug-induced gingival augmentation, a side effect associated mainly with three classes of drugs: anticonvulsants (Phenytoin), immunosuppressants (Cyclosporine A), and various calcium channel blockers (Nifedipine, Verapamil, Diltiazem). We studied the effect of Cyclosporine A (CsA) and Nifedipine on gingival fibroblasts extracted from the rat gum. Gingival fibroblasts were isolated from 6-week-old male rats weighing 150-170 g, from gingival explants, and grown in a specific culture medium consisting of Dulbecco's Modified Eagle's Medium (DMEM) supplemented with antibiotic and 10% fetal bovine serum (FBS). The medium was also supplemented with CsA (1 μg÷mL) and Nifedipine (3 mM). We also used a control group that received no treatment. The cells were photographed at 7, 14 and 30 days, with a Nikon Eclipse TE300 phase contrast microscope. For cell viability evidence, we used immunofluorescence (flow cytometry) with a FACS (fluorescence-activated cell sorting) Calibur device and its software. We noticed that the proliferation of these cells increased with the period of drug administration, and the subsequent morphological changes that occurred were related to the presence of drug accumulations in the cell cytoplasm. Modern molecular techniques are needed to shed some light upon the pathogenesis of drug induced gingival overgrowth and, thereby, provide novel information for preventative and effective future therapeutic strategies.


Peroxisomal beta-oxidation. Purification of four novel 3-hydroxyacyl-CoA dehydrogenases from rat liver peroxisomes.
Peroxisomes are capable of beta-oxidizing a variety of substrates including the CoA esters of straight chain fatty acids, 2-methyl-branched fatty acids and the bile acid intermediates di- and trihydroxycoprostanic acids. The first reaction of peroxisomal beta-oxidation is catalyzed by an acyl-CoA oxidase. Rat liver peroxisomes contain three acyl-CoA oxidases: 1) palmitoyl-CoA oxidase, oxidizing straight chain acyl-CoAs; 2) pristanoyl-CoA oxidase, oxidizing 2-methyl-branched acyl-CoAs; and 3) trihydroxycoprostanoyl-CoA oxidase, oxidizing the CoA esters of the bile acid intermediates (Van Veldhoven, P.P., Vanhove, G., Asselberghs, S., Eyssen, H. J., and Mannaerts, G. P. (1992) J. Biol. Chem. 267, 20065-20074). We have now investigated whether the third step of peroxisomal beta-oxidation, catalyzed by a 3-hydroxyacyl-CoA dehydrogenase, is also catalyzed by multiple enzymes, using the 3-hydroxyacyl-CoA derivatives of palmitic acid, 2-methylpalmitic acid, and trihydroxycoprostanic acid as the substrates to monitor the dehydrogenase activities. In order to avoid contamination with mitochondrial 3-hydroxyacyl-CoA dehydrogenases, highly purified peroxisomes from untreated rats were employed as the enzyme source. Subfractionation of the peroxisomes revealed that the major portion of the dehydrogenase activities with all three substrates was present in the peripheral membrane protein fraction. Separation of this fraction on various chromatographic columns resulted in the purification of the well known multifunctional protein, a 78-kDa monomeric protein that displays 3-hydroxyacyl-CoA dehydrogenase plus hydratase activity, as well as of four additional novel dehydrogenases with different substrate specificities. Three of the enzymes are monomeric proteins of 35 kDa, 56 kDa, and 79 kDa, respectively. The latter enzyme also displays hydratase activity. The fourth enzyme is a dimer of 89 kDa, the subunits of which form a doublet at 40 kDa. The exact physiological role of each of the 3-hydroxyacyl-CoA dehydrogenases requires further investigation.


Remote Ischemic Preconditioning and Clinical Outcomes in On-Pump Coronary Artery Bypass Grafting: A Meta-Analysis of 14 Randomized Controlled Trials.
The purpose of this article is to perform the first pooled analysis on remote ischemic preconditioning (RIPC) used for the improvement of clinical outcomes of patients only undergoing on-pump coronary artery bypass grafting (CABG) in randomized controlled trials (RCTs). A systematic search was performed using PubMed, the Cochrane Library, and the Web of Science to identify studies that described the effect of RIPC on postoperative mortality in patients only undergoing on-pump CABG. The outcomes included postoperative mortality, postoperative morbidity (including incidence of myocardial infarction, atrial fibrillation, stroke, acute kidney injury, and renal replacement therapy), mechanical ventilation (MV), intensive care unit length of stay (ICU LOS), and hospital length of stay (HLOS). A total of 14 RCTs (2830 participants) were included. Our meta-analysis found that RIPC failed to reduce the postoperative mortality in patients only undergoing on-pump CABG compared with control individuals (odds ratio, 0.81; 95% confidence interval, [0.40, 1.64]; P = 0.55; I2 = 25%). Moreover, there were no differences in postoperative morbidity, ICU LOS, and HLOS between the two groups. However, MV in the RIPC group was shorter than that in control individuals (standard mean difference, -0.41; 95% confidence interval, [-0.80, -0.01]; P = 0.04; I2 = 73%). The present meta-analysis found that RIPC failed to improve most of clinical outcomes in patients only undergoing on-pump CABG; however, MV was reduced. Adequately powered trials are warranted to provide more evidence in the future.


Priapism as the initial manifestation of a penile and lower limb cutaneous metastasis of prostate adenocarcinoma with low serum PSA level.
Penile and/or cutaneous metastases from prostate adenocarcinoma rarely occur. Here, we detail the case of a 78-year-old man suffering from priapism caused by metastatic prostate cancer with both penile and lower limb cutaneous spread. His serum prostate-specific antigen level was 0.09 μg/L when priapism developed. Corpora cavernosa biopsy was refused by the patient and radical penectomy was performed. Postoperative pathologic and immunohistochemical studies revealed undifferentiated prostate adenocarcinoma cells growing in corpora cavernosa. Two months later, the patient presented with multiple, erythematous nodules over the right lower leg. The prostate-specific antigen level was found to be 0.264 μg/L. Biopsy of a skin nodule revealed neoplastic cells consistent with metastatic prostate adenocarcinoma. This is the first known case of metastatic prostate cancer found in both penis and skin with a low serum prostate-specific antigen level. Priapism presented as the initial clinical manifestation of metastatic prostate cancer.


Prediction of ADME-Tox properties and toxicological endpoints of triazole fungicides used for cereals protection.
Within this study we have considered 9 triazole fungicides that are approved to be used in European Union for protecting cereals: cyproconazole, epoxiconazole, flutriafol, metconazole, paclobutrazole, tebuconazole, tetraconazole, triadimenol and triticonazole. We have summarized the few available data that support their effects on humans and used various computational tools to obtain a widely view concerning their possible harmful effects on humans. The results of our predictive study reflect that all triazole fungicides considered in this study reveal good oral bioavailability, are envisaged as being able to penetrate the blood brain barrier and to interact with P-glycoprotein and with hepatic cytochromes. The predictions concerning the toxicological endpoints for the investigated triazole fungicides reveal that they. reflect potential of skin sensitization, of blockage of the hERG K+ channels and of endocrine disruption, that they have not mutagenic potential and their carcinogenic potential is not clear. Epoxiconazole and triadimenol are predicted to have the highest potentials of producing numerous harmful effects on humans and their use should be avoided or limited.


Purification and characterization of extremely thermophilic and thermostable 5'-methylthioadenosine phosphorylase from the archaeon Sulfolobus solfataricus. Purine nucleoside phosphorylase activity and evidence for intersubunit disulfide bonds.
5'-Methylthioadenosine phosphorylase from Sulfolobus solfataricus, a thermoacidophilic archaeon optimally growing at 87 degrees C, has been purified to homogeneity. Reducing agents are not required for catalytic activity. The enzyme has a molecular mass of 160 kDa and is composed of six apparently identical subunits of 27 kDa. The NH2-terminal sequence shows high homology (50%) with the NH2-terminal sequence of Escherichia coli purine nucleoside phosphorylase. Physicochemical and kinetic features are reported. 5'-Methylthioadenosine phosphorylase is highly thermophilic, with an optimum temperature of 120 degrees C. The enzyme is characterized by extreme thermal stability, remaining completely active after 2 h at 100 degrees C and showing half-inactivation times of 15 and 5 min when incubated at 130 and 140 degrees C, respectively. An apparent melting temperature of 132 degrees C has been calculated. After 24 h of incubation at room temperature no loss of activity is detected in the presence of 9 M urea, 4 M guanidine hydrochloride, 0.075% SDS, 50% methanol, 50% ethanol, 50% dimethylformamide, 1 M NaCl, and 1% Triton X-100. Data are also reported on the enzyme's resistance to proteolysis and on the effect of salts, detergents, solvents, and reducing agents on enzyme thermostability. Labeling experiments with iodo[2-14C]acetic acid resulted in the incorporation of approximately 12 mol of labeled iodoacetate/mol of protein, indicating the presence of six disulfide bonds that, on the basis of SDS-polyacrylamide gel electrophoresis, are probably positioned intersubunits, resulting in the organization of the enzyme into two trimers. 5'-Methylthioadenosine (MTA) phosphorylase is endowed with a broad substrate specificity, being able to phosphorolytically cleave inosine, guanosine, and adenosine with a better efficiency than MTA, allowing us to hypothesize that in S. solfataricus the same enzyme is responsible for the catabolism of MTA and of these purine nucleosides.


G6PC1 and G6PC2 influence G6P flux but not HSD11B1 activity.
In the endoplasmic reticulum (ER) lumen, glucose-6-phosphatase catalytic subunit 1 and 2 (G6PC1; G6PC2) hydrolyze glucose-6-phosphate (G6P) to glucose and inorganic phosphate whereas hexose-6-phosphate dehydrogenase (H6PD) hydrolyzes G6P to 6-phosphogluconate (6PG) in a reaction that generates NADPH. 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) utilizes this NADPH to convert inactive cortisone to cortisol. HSD11B1 inhibitors improve insulin sensitivity whereas G6PC inhibitors are predicted to lower fasting blood glucose (FBG). This study investigated whether G6PC1 and G6PC2 influence G6P flux through H6PD and vice versa. Using a novel transcriptional assay that utilizes separate fusion genes to quantitate glucocorticoid and glucose signaling, we show that overexpression of H6PD and HSD11B1 in the islet-derived 832/13 cell line activated glucocorticoid-stimulated fusion gene expression. Overexpression of HSD11B1 blunted glucose-stimulated fusion gene expression independently of altered G6P flux. While overexpression of G6PC1 and G6PC2 blunted glucose-stimulated fusion gene expression, it had minimal effect on glucocorticoid-stimulated fusion gene expression. In the liver-derived HepG2 cell line, overexpression of H6PD and HSD11B1 activated glucocorticoid-stimulated fusion gene expression but overexpression of G6PC1 and G6PC2 had no effect. In rodents, HSD11B1 converts 11-dehydrocorticosterone (11-DHC) to corticosterone. Studies in wild-type and G6pc2 knockout mice treated with 11-DHC for 5 weeks reveal metabolic changes unaffected by the absence of G6PC2. These data suggest that HSD11B1 activity is not significantly affected by the presence or absence of G6PC1 or G6PC2. As such, G6PC1 and G6PC2 inhibitors are predicted to have beneficial effects by reducing FBG without causing a deleterious increase in glucocorticoid signaling.


Relationship Between Medical Therapy, Long-Term Care Insurance, and Comorbidity in Elderly Patients With Heart Failure With Systolic Dysfunction.
Although guideline-directed medical therapy (GDMT), including β-blockers, angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), improves survival and quality of life, most patients with heart failure with reduced (HFrEF) and mildly reduced (HFmrEF) ejection fraction are treated with inadequate medications. We investigated the prescription patterns of GDMT in elderly patients with HFrEF and HFmrEF and their characteristics, including the certification of long-term care insurance (LTCI), which represents frailty and disability.Methods and Results: This retrospective cross-sectional study analyzed 1,296 elderly patients with symptomatic HFrEF and HFmrEF with diuretic use (median age 78 years; 63.8% male; median left ventricular ejection fraction 40%). Prescription rates of GDMT were inadequate (ACEi, ARBs, β-blockers, and MRAs: 27.0%, 30.1%, 54.1%, and 41.9%, respectively). LTCI certification was independently associated with reduced prescription of all medications (ACEi/ARB: odds ratio [OR] 0.591, 95% confidence interval [CI] 0.449-0.778, P=0.001; β-blockers: OR 0.698, 95% CI 0.529-0.920, P<0.001; MRAs: OR 0.743, 95% CI 0.560-0.985, P=0.052). Patients with LTCI certification also had a high prevalence of polypharmacy and prescription of diuretics. Vulnerable patients with LTCI may be an explanation for the challenges in implementing GDMT, and communicating is required for favorable heart failure care in this population.


Pulmonary artery dissection and rupture in Eisenmenger's syndrome.
A patient with ventricular septal defect and pulmonary arterial hypertension (Eisenmenger's syndrome) associated with aortic coarctation with follow-up for 19 years, and with rupture of an aneurysmatic pulmonary artery is described. An incident of extreme fright with a possible transient systemic hypertension may have precipitated the dissection of the pulmonary arterial intima and the rupture.


Estimation of nonpreventable dental emergencies in U.S. Marine Corps personnel.
Previous studies of military personnel have reported that 26% to 75% of dental emergencies cannot be prevented. The aims of this study were (1) to estimate the percentage of dental emergencies for which causative conditions were not indicated for urgent treatment on the previous annual dental examination (nonpreventable dental emergency) and (2) to estimate the rate of dental emergencies that can be expected if all urgent treatment is completed. This retrospective cohort study of Marine Corps recruits revealed that 58.4% to 70.3% of conditions resulting in dental emergencies were nonpreventable. Therefore, the estimated range of dental emergencies that can be expected if all urgent treatment indicated on the previous dental examination is completed is 77 to 92 dental emergencies per 1,000 personnel per year. The rate of nonpreventable dental emergencies should be considered when staffing for level I care.


Three cases of posterior reversible encephalopathy syndrome with chronic kidney disease triggered by infection.
Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological condition with diverse neurological manifestations. Many clinical factors are known causes of PRES, but only a few cases of PRES have been reported in patients with chronic kidney disease (CKD) and infectious disease. We describe three cases of PRES in patients with CKD triggered by various infectious diseases. Characteristic hyperintense signals on magnetic resonance imaging (MRI) indicating reversible vasogenic brain oedema in various parts of the brain were observed. To explain the pathophysiology of PRES, the hypertension/hyperperfusion and hypoperfusion/vasoconstriction theories have been proposed. Patients with CKD have many complications including uraemia, hypertension, and immunosuppression. Therefore, physicians should recognize that patients with CKD are at high risk of PRES triggered by infectious diseases and promptly diagnose PRES because immediate treatment of the triggers often leads to complete resolution.


Successful combination immunotherapy of anti-gamma aminobutyric acid (GABA)A receptor antibody-positive encephalitis with extensive multifocal brain lesions.
A 78-year old woman who presented with akinetic mutism was admitted to our hospital. Brain MRI showed multifocal increased T2/FLAIR signal with extensive cortical-subcortical involvement. We suspected autoimmune encephalitis and the patient received methylprednisolone pulse. Her conscious level gradually recovered, but later relapsed again and presented with refractory status epilepticus. We treated her with intravenous immunoglobulin, plasma exchange and pulsed cyclophosphamide, with satisfactory response. A brain biopsy showed perivascular lymphocytic infiltrates and reactive gliosis. Anti-gamma aminobutyric acid (GABA)A receptor antibodies test came back to be positive after her recovery, and the diagnosis of anti-GABAA receptor antibody-positive encephalitis was made. This is a very rare case where brain biopsies were performed in a patient with anti-GABAA receptor antibody-positive encephalitis.


Tick-tock: is your cardiometabolic risk on the clock?
Governing a large amount of cellular processes in mammalian cells is a 24-h regulatory mechanism known as the circadian clock. Through the release of neurohormonal factors, the master central clock is able to regulate the otherwise independent peripheral clocks situated in all vital organs. It has recently been shown that forced misalignment of the circadian cycles, often as a consequence of lifestyle factors, is an independent cardiometabolic risk factor and may thus potentially predispose certain groups, such as nightshift workers, to cardiovascular disease. In this review, we will analyse some of the recent advances regarding circadian clock dysfunction and the development of cardiovascular diseases. Finally, we will touch on the developing link between circadian dysfunction and myocardial infarctions.


The use of sorbitol-MacConkey agar in conjunction with a specific antiserum for the detection of Vero cytotoxin-producing strains of Escherichia coli O 157.
Using DNA probes specific for the genes encoding Vero cytotoxins 1 and 2 in hybridization experiments on faecal samples, Vero cytotoxin-producing Escherichia coli (VTEC) of serogroup O 157 were detected in 21 of 63 cases of haemorrhagic colitis, 9 of 31 cases of non-bloody diarrhoea and 14 of 68 cases of haemolytic uraemic syndrome. Compared with these results sorbitol-MacConkey agar in conjunction with a specific O 157 antiserum gave a sensitivity of 62% in haemorrhagic colitis, 56% in non-bloody diarrhoea and 57% in haemolytic uraemic syndrome. The specificity of this method was 100% in all three groups. This demonstrates that sorbitol-MacConkey agar is a useful screening method for the detection of VTEC of serogroup O 157 when used in conjunction with a specific homologous antiserum. However, this method does not detect VTEC belonging to other serogroups and such strains were found, particularly in cases of haemolytic uraemic syndrome.


Establishment and validation of an individualized nomogram for survival prediction of primary mediastinal germ cell tumors based on the SEER database.
Primary mediastinal germ cell tumors (PMGCT) represent a rare but sometimes highly aggressive type of mediastinal tumors. The current prognostic models for PMGCT are insufficient. This study was undertaken to establish and validate an individualized nomogram for predicting the overall survival (OS) of patients with PMGCT. We conducted a retrospective analysis of patients with PMGCT diagnosed between 2000 and 2018 in the Surveillance, Epidemiology, and End Results (SEER) database in the United States. Clinical variables included surgery subtype, gender, treatment regimens, age, histology, tumor size, stage, chemotherapy, radiation, race, and survival-related information. The main outcome measure was survival duration. The Kaplan-Meier method along with the log-rank test were utilized to estimate the OS. Independent prognostic factors were identified by performing the univariate and multivariate Cox proportional hazards regression analyses, from which an individualized nomogram was constructed to predict 3-, 5-, and 10-year OS of patients with PMGCT. The concordance index (C-index) and calibration curve were used to verify the discrimination and accuracy of the nomogram. A total of 845 patients with PMGCT were recruited from the SEER database and further randomly assigned to a training set (n=635) and a validation set (n=210) at a ratio of 7:3. The 3-, 5-, and 10-year OS for overall PMGCT was 70.0%, 67.1%, and 63.9%, respectively. Cox regression analysis indicated that age, tumor size, stage, chemotherapy, radiation, histology, and surgery type were as independent factors for OS in patients with PMGCT (P<0.05). An individualized nomogram for OS was constructed utilizing these variables, with the C-index of 0.714 [95% confidence interval (CI): 0.695 to 0.743] and 0.756 (95% CI: 0.735 to 0.787) in the training and validation groups. Moreover, good levels of agreement were observed according to the calibration curve between the predicted and actual 3-, 5-, and 10-year survival rates both in the training and validated cohorts, showing that the model could accurately predict patient prognosis. This study documented the first attempt at establishing and validating a novel nomogram for predicting the 3-, 5-, and 10-year OS probabilities of PMGCT. The prognostic nomogram was demonstrated to have good performance for predicting individualized OS of patients with PMGCT.


[Pulse pressure and mean pressure relationship of intracranial pressure and lumbar cerebrospinal fluid pressure].
Intracranial pressure fluctuates due to heart beat, respiration, neuro-regulation, etc. Traditional intracranial pressure study focuses on the static pressure and related factors, putting emphasis on mean intracranial pressure, while paying little attention to the pulse components. This study was composed of two parts: animal experiment and theoretical analysis. The animal experiment was performed on 14 mongrel dogs, studying the variation of intracranial pressure wave form under different intracranial pressure level. The dogs were installed epidurally with latex sacculus to establish models of increased intracranial pressure. The degree of intracranial pressure and volume could be altered by changing the volume of fluid in the sacculus. During the process, pressure transducers were arranged to monitor and record the variations of the pressure of intracranial ventricle and lumbar subarachnoid cavity. The result demonstrated that, with the continual increase of intracranial pressure, intracranial pulse pressure increased correspondingly, showing a linear relationship with the change of intracranial pressure. After the sacculus was emptied and reinfused, the slope of the linear relationship was determined to be greater than the former slope. The same result was obtained in the lumbar cerebrospinal fluid pressure. Therefore, the lumbar cerebrospinal fluid pressure is consistent with the intracranial pressure. Intracranial pulse pressure is in linear relationship with mean pressure, and the slope of their linear relationship predicts the perform of intracranial autoregulation.


Pharmacokinetics of subcutaneously administered etanercept in subjects with psoriasis.
To present the results of the pharmacokinetic analysis of the concentration-time profiles of etanercept, a soluble receptor tumour necrosis factor (TNF) antagonist, in more than 1300 subjects with psoriasis. Pharmacokinetic samples were collected in one phase-2 and two phase-3 placebo-controlled, randomized clinical trials. Study 1 evaluated a 25-mg twice weekly (BIW) etanercept dosing regimen administered by subcutaneous (s.c.) injection for 24 weeks. Study 2 evaluated 25-mg BIW and 50-mg BIW s.c. doses for 12 weeks. Study 3 evaluated 25 mg once weekly (QW), 25 mg BIW and 50 mg BIW s.c. doses for 24 weeks. The mean +/- SD steady-state predose serum concentrations of etanercept for the 25-mg BIW arm at 12 weeks in study 1 were 1590 +/- 885 ng ml(-1). In study 2, mean +/- SD etanercept steady-state concentrations at 12 weeks were 1900 +/- 1110 ng ml(-1) in the 25-mg BIW group and 3830 +/- 1870 ng ml(-1) in the 50-mg BIW group. The mean +/- SD steady-state predose serum concentrations of etanercept at 12 weeks in study 3 were 768 +/- 475 ng ml(-1) for the 25-mg QW regimen, 1990 +/- 1030 ng ml(-1) for the 25-mg BIW regimen and 4020 +/- 2100 ng ml(-1) for the 50-mg BIW regimen. Pharmacokinetic results were highly consistent across clinical trials. The concentration-time profiles displayed dose proportionality. Etanercept concentrations in subjects with psoriasis are similar to the concentrations in subjects with rheumatoid arthritis.


External ear canal exostosis and aquatic sports.
Many reports suppose that the development of aural exostosis depends on the action of an irritative stimulus like frequent and repeated cold water contact. This survey studies the incidence of this lesion in a group of 433 athletes practicing aquatic sports on a highly competitive level. Among these, water activities like sailing and deep-sea diving, which up to now were never considered, were also studied. 32 exostoses were found to affect 12 subjects monolaterally and 20 subjects bilaterally. Not one of a control group of 476 athletes was found to be affected by aural exostosis. For each athlete in this study the following parameters are considered: age and sex, type of sport, total amount of hours spent in water contact, aural pathology history and otoscopic findings. The authors suggest the existence of facilitating factors other than total water contact time, as shown by the absence of a precise correlation between this parameter and the presence of the aural hyperostotic lesion.


Chemical Electron Microscopy (CEM) for Heterogeneous Catalysis at Nano: Recent Progress and Challenges.
Chemical electron microscopy (CEM), a toolbox that comprises imaging and spectroscopy techniques, provides dynamic morphological, structural, chemical, and electronic information about an object in chemical environment under conditions of observable performance. CEM has experienced a revolutionary improvement in the past years and is becoming an effective characterization method for revealing the mechanism of chemical reactions, such as catalysis. Here, we mainly address the concept of CEM for heterogeneous catalysis in the gas phase and what CEM could uniquely contribute to catalysis, and illustrate what we can know better with CEM and the challenges and future development of CEM.


Gonadotropin-releasing hormone antagonist in the management of prostate cancer.
Luteinizing hormone-releasing hormone (LHRH) agonist therapy to induce medical castration has become the most common form of hormonal therapy for advanced and metastatic prostate cancer. When treatment is started, LHRH agonists initially stimulate the release of LH, causing a surge in serum testosterone that can precipitate a "flare" phenomenon or worsening of disease, particularly in patients with bone metastatic disease. Gonadotropin-releasing hormone (GnRH) receptor antagonism represents a newer approach to medical castration. Abarelix is a pure GnRH receptor antagonist that is devoid of any LHRH agonist activity. Results from 1 phase II and 3 phase III clinical trials demonstrate that abarelix produces medical castration more quickly and without causing testosterone surge, as compared with LHRH agonists with or without a nonsteroidal antagonist. The safety profile in terms of adverse events is comparable between the 2 types of treatment, but the lack of testosterone surge with abarelix might confer a safety advantage by abolishing the risk of a disease flare.


[Results of behavioral investigations of broilers kept on various litter materials].
Behavioural investigations by the help of time-sampling-method with broilers kept on different litter materials (wood chip deep litter with or without mixing, straw resp.) in 5 rounds (per round investigated: 5 days x 8 hours x 12 values/hr x 10 broilers = 24000 behavioural data) showed no evident differences between keeping systems which could lead to preferring or rejecting a system. A lower frequency of scratching and ground pecking and a higher percentage of comfort behaviour was found in broilers kept on straw because of increasing amount of faeces and compression of litter material. From the view point of ethology and animal hygiene wood chip deep litter system without mixing and a 10 cm layer of new wood pieces after every round could be recommended if economical aspects allow.