Polymorphisms of CYP2C9*2, CYP2C9*3 and VKORC1 genes related to time in therapeutic range in patients with atrial fibrillation using warfarin.
Warfarin continues to be the most widely used anticoagulant in clinical practice around the world for the prevention of thromboembolic events in patients with atrial fibrillation (AF). The evaluation of the quality of anticoagulation control, estimated by time in therapeutic range (TTR), is accepted as a good method to evaluate the quality of anticoagulation. The variability of TTR can be explained by the presence of variants of the CYP2C9 and VKORC1 genes. This study examined the association between polymorphisms of the CYP2C9 and VKORC1 genes and control of oral anticoagulation, through TTR, in patients with AF. A cross-sectional study was conducted within a cohort follow-up. The study comprised of 317 patients with AF, using warfarin, who were followed up for one year. The genotyping of genes CYP2C9 (rs1057910), (rs1799853) and VKORC1 (rs923231) was performed by PCR in real time, using TaqMan probes. Patients who had variant genotypes for the CYP2C9*3 gene (rs1057910) presented higher TTR (TTR 81-100%) when compared to when compared to the <45% and 46-60% TTR groups (p=0.005 and p=0.002, respectively). Regarding VKORC1 (rs923231), patients who had the variant genotype for the VKORC1 (rs923231) gene also presented a higher TTR (TTR 81-100%), when when compared to the <45% and 46-60% TTR groups (p=0.005 and p=0.004, respectively). In a multivariate model, VKORC1 (rs923231) remained associated for comparisons with the TTR groups (<45% vs 81-100% groups, p=0.01; and 46-60% vs 81-100% groups, p=0.01). The genotypes of the CYP2C9*3 (AA) and VKORC1 -1639 (GG) genes were associated with the worst quality of anticoagulation control (TTR) in patients with AF using warfarin in the northeast of Brazil.


Targeting of HER2-expressing tumors using 111In-ABY-025, a second-generation affibody molecule with a fundamentally reengineered scaffold.
Overexpression of the human epidermal growth factor receptor type 2 (HER2) in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a nonimmunoglobulin scaffold have demonstrated a high potential for in vivo molecular imaging of HER2-expressing tumors. The reengineering of the molecular scaffold has led to a second generation of optimized Affibody molecules that have a surface distinctly different from the parental protein domain from staphylococcal protein A. Compared with the parental molecule, the new tracer showed a further increased melting point, stability, and overall hydrophilicity and was more amenable to chemical peptide synthesis. The goal of this study was to assess the potential effects of this extensive reengineering on HER2 targeting, using ABY-025, a DOTA-conjugated variant of the novel tracer. (111)In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. The in vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, rats, and cynomolgus macaques (Macaca fascicularis). (111)In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats, and macaques. A highly specific tumor uptake of 16.7 +/- 2.5 percentage injected activity per gram of tissue was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h and 88 at 4 h and increased up to 3 d after injection. gamma-camera imaging of tumors was already possible at 0.5 h after injection. Furthermore, the repeated intravenous administration of ABY-025 did not induce antibody formation in rats. The biodistribution of (111)In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound reengineering of the nonbinding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumor-bearing mice, leading to high tumor-to-organ-ratios and high-contrast imaging shortly after injection.


Proteomic characterization and three-dimensional electron microscopy study of PSII-LHCII supercomplexes from higher plants.
In higher plants a variable number of peripheral LHCII trimers can strongly (S), moderately (M) or loosely (L) associate with the dimeric PSII core (C2) complex via monomeric Lhcb proteins to form PSII-LHCII supercomplexes with different structural organizations. By solubilizing isolated stacked pea thylakoid membranes either with the α or β isomeric forms of the detergent n-dodecyl-D-maltoside, followed by sucrose density ultracentrifugation, we previously showed that PSII-LHCII supercomplexes of types C2S2M2 and C2S2, respectively, can be isolated [S. Barera et al., Phil. Trans. R Soc. B 67 (2012) 3389-3399]. Here we analysed their protein composition by applying extensive bottom-up and top-down mass spectrometry on the two forms of the isolated supercomplexes. In this way, we revealed the presence of the antenna proteins Lhcb3 and Lhcb6 and of the extrinsic polypeptides PsbP, PsbQ and PsbR exclusively in the C2S2M2 supercomplex. Other proteins of the PSII core complex, common to the C2S2M2 and C2S2 supercomplexes, including the low molecular mass subunits, were also detected and characterized. To complement the proteomic study with structural information, we performed negative stain transmission electron microscopy and single particle analysis on the PSII-LHCII supercomplexes isolated from pea thylakoid membranes solubilized with n-dodecyl-α-D-maltoside. We observed the C2S2M2 supercomplex in its intact form as the largest PSII complex in our preparations. Its dataset was further analysed in silico, together with that of the second largest identified sub-population, corresponding to its C2S2 subcomplex. In this way, we calculated 3D electron density maps for the C2S2M2 and C2S2 supercomplexes, approaching respectively 30 and 28Å resolution, extended by molecular modelling towards the atomic level. This article is part of a special issue entitled: photosynthesis research for sustainability: keys to produce clean energy.


Peer Victimization, Maternal Control, And Adjustment Problems Among Left-Behind Adolescents From Father-Migrant/Mother Caregiver Families.
Left-behind adolescents who are from father-migrant/mother caregiver families have become the main type of left-behind children in China. The migratory of fathers not only makes left-behind adolescents suffer more difficulties but also causes left-behind women to face the challenge of raising the child alone. This study examined the association among peer victimization, maternal psychological control, and adjustment problems among Chinese rural left-behind adolescents. Furthermore, we first explored the moderating role of maternal behavioral control in this relationship. Using cross-sectional design, we recruited 194 left-behind adolescents (49% girls; mean age = 13.51, SD = 1.03) from four junior schools in the Guizhou province of China. Left-behind adolescents completed a battery of self-report questionnaires regarding peer victimization, maternal control, self-injury behaviors, depression, and loneliness. The hierarchical multiple regressions indicated that both peer victimization and maternal psychological control were positively associated with self-injury behaviors, depression, and loneliness. Moreover, maternal behavioral control played a dual role in the impact of peer victimization on self-injury behaviors depending on the levels of maternal psychological control. When left-behind women exerted high psychological control on their children, maternal behavioral control buffered the negative effect of peer victimization on self-injury behaviors. However, when left-behind women exerted low psychological control on their children, maternal behavioral control exacerbated the negative effect of peer victimization on self-injury behaviors. These findings suggest that the effectiveness of behavioral control may depend on different situations, left-behind women should be cautious in exerting behavioral control over their children.


Molecular genetic analyses of polytene chromosome region 72A-D in Drosophila melanogaster reveal a gene desert in 72D.
We have investigated a region of ∼310 kb of genomic DNA within polytene chromosome subdivisions 72A to 72D of Drosophila melanogaster. This region includes 57 predicted protein-coding genes. Seventeen of these genes are in six clusters that appear to have arisen by tandem duplication. Within this region we found 23 complementation groups that are essential for zygotic viability, and we have identified the transcription units for 18 of the 23. We also found a 55 kb region in 72D that is nonessential. Flies deficient for this region are viable and fertile. Within this nonessential region are 48 DNA sequences of 12 to 33 base pairs that are completely conserved among 12 distantly related Drosophila species. These sequences do not have the evolutionary signature of conserved protein-coding DNA sequences, nor do they appear to encode microRNAs, however, the strong selection suggests functions in wild populations that are not apparent in laboratory cultures. This region resembles dispensable gene deserts previously characterized in the mouse genome.


The Essential Oils and Eucalyptol From Artemisia vulgaris L. Prevent Acetaminophen-Induced Liver Injury by Activating Nrf2-Keap1 and Enhancing APAP Clearance Through Non-Toxic Metabolic Pathway.
Artemisia has long been used in traditional medicine and as a food source for different functions in eastern Asia. Artemisia vulgaris L. (AV) is a species of the genus Artemisia. Essential oils (EOs) were extracted from AV by subcritical butane extraction. EO contents were detected by electronic nose and headspace solid-phase microextraction coupled with gas chromatography (HS-SPME-GC-MS). To investigate the hepatoprotective effects, mice subjected to liver injury were treated intragastrically with EOs or eucalyptol for 3 days. Acetaminophen (APAP) alone caused severe liver injury characterized by significantly increased serum AST and ALT levels, ROS and hepatic malondialdehyde (MDA), as well as liver superoxide dismutase (SOD) and catalase (CAT) depletions. EOs significantly attenuated APAP-induced liver damages. Further study confirmed that eucalyptol is an inhibitor of Keap1, the affinity K D of eucalyptol and Keap1 was 1.42 × 10-5, which increased the Nrf2 translocation from the cytoplasm into the mitochondria. The activated Nrf2 increased the mRNA expression of uridine diphosphate glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), also inhibiting CYP2E1 activities. Thus, the activated Nrf2 suppressed toxic intermediate formation, promoting APAP hepatic non-toxicity, whereby APAP was metabolized into APAP-gluc and APAP-sulf. Collectively, APAP non-toxic metabolism was accelerated by eucalyptol in protecting the liver against APAP-induced injury, indicating eucalyptol or EOs from AV potentials as a natural source of hepatoprotective agent.


Interaction of estrogen with central serotonergic mechanisms in human sensory processing: loudness dependence of the auditory evoked potential and mismatch negativity.
Estrogen may be involved in schizophrenia by inhibiting serotonin-1A (5-HT(1A)) receptor function. We examined the effects of estrogen pre-treatment on modulation of loudness dependence of the auditory evoked potential (LDAEP) and mismatch negativity by the 5-HT(1A) receptor partial agonist, buspirone. Using a double-blind, placebo-controlled, repeated-measures design in healthy female volunteers, we observed that buspirone treatment significantly increased LDAEP slope. Estrogen increased LDAEP slope on its own, and a further LDAEP increase by buspirone was not seen after estrogen pre-treatment. Similar results were observed for mismatch negativity, where buspirone caused a small increase of latency, although not amplitude, after placebo but not estrogen pre-treatment, which enhanced mismatch negativity latency on its own. These results are in line with our previous findings on prepulse inhibition showing an inhibitory effect of estrogen on the action of buspirone. Taken together, these data suggest that estrogen may inhibit 5-HT(1A) receptor-mediated disruptions of auditory processing.


[About the complex system of requirements on the everyday safety of servicemen].
The article is based on studies of medical and technical problems of habitability, livelihoods, military; environment and service troops justified the structure and content of the complex system requirements on the everyday safety of servicemen. It summarizes the scientific and educational methods to the accounting of the human factor in military facilities. Allowable limits and hygienic standards are the foundation of life safety of personnel. Extreme conditions are characterized by emergencies and injury.


Deciphering an Adenovirus F41 Outbreak in Pediatric Hematopoietic Stem Cell Transplant Recipients by Whole-Genome Sequencing.
Human adenovirus (HAdV) represents a major cause of mortality and morbidity in pediatric recipients of allogeneic hematopoietic stem cell transplants (HSCT). HAdV species F type 41 (HAdV-F41) infections in HSCT patients are scarce, whereas HAdV-F41 circulates commonly in healthy individuals. Between March and July 2018, HAdV-F41 infections were identified in four children (A, B, C, and E) who received allogeneic HSCT and one child before HSCT (D) at Robert Debré Hospital, Paris, France. We report here the clinical course of HAdV-F41 infection and the phylogenetic investigation to identify interpatient transmission. HAdV DNA was quantified in stool and plasma samples by real-time PCR. HAdV type was determined by sequencing of the fiber and hexon genes. Phylogenetic investigation was done with whole-genome sequences obtained by next-generation sequencing. HAdV loads in stool samples ranged from 6.60 to 10.10 log10 copies/ml. HAdV-F41 detection in plasma was observed in four patients, but no disseminated disease was reported. Two patients died, but neither death was attributed to HAdV. While sequencing limited to the fiber gene suggested a cluster with four patients, phylogenetic analysis with whole-genome sequencing (WGS) and HVR7 revealed a cluster that included three patients (C, D, and E), suggesting an interpatient transmission in that cluster and two other independent infections. HAdV-F41 levels in stool specimens of pediatric HSCT patients are high and represent a risk of interpatient transmission. WGS helped to identify related cases. Prompt detection of HAdV in stool and control measures are warranted to limit any risk of nosocomial transmission.


Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins: Exploration of the N3 and N9 Positions and Interaction with Multidrug-Resistance Proteins.
Our laboratories have been investigating synthetic analogues of marine alkaloid rigidins that possess promising anticancer activities. These analogues, based on the 7-deazahypoxanthine skeleton, are available in one- or two-step synthetic sequences and exert cytotoxicity by disrupting microtubule dynamics in cancer cells. In the present work we extended the available structure-activity relationship (SAR) data to N3- and N9-substituted derivatives. Although N3 substitution results in loss of activity, the N9-substituted compounds retain nanomolar antiproliferative activities and the anti-tubulin mode of action of the original unsubstituted compounds. Furthermore, our results also demonstrate that multidrug-resistance (MDR) proteins do not confer resistance to both N9-unsubstituted and -substituted compounds. It was found that sublines overexpressing ABCG2, ABCC1, and ABCB1 proteins are as responsive to the rigidin analogues as their parental cell lines. Thus, the study reported herein provides further impetus to investigate the rigidin-inspired 7-deazahypoxanthines as promising anticancer agents.


Risk factors associated with infectious bursal disease vaccination failures in broiler farms in Kenya.
Immunization together with application of biosecurity measures are the principal methods of preventing infectious bursal disease outbreaks in high-risk areas. However, outbreaks in vaccinated chicken flocks have been reported in many parts of the world as a result of factors of vaccine virus, animal, or vaccine handler. In Kenya, such outbreaks have been reported, but the causes have not been studied. This study aimed at determining the risk factors associated with vaccine handling leading to vaccine failure in broiler flocks in Kwale County, Kenya. Structured questionnaires and visual observations were used to collect data from 83 broiler farms, 6 breeding farms, and 17 vaccine outlets. Relative risk (RR) analysis was used to determine the association between identified potential risk factors and vaccination failure. Results show that vaccines were properly handled in all vaccine outlet shops. Breeding farms maintained high levels of biosecurity and employed standard vaccine handling practices. Basic biosecurity practices were poor in broiler farms. Broiler farms failed to meet all the recommended standard procedures for vaccine storage, reconstitution, and administration. Risk factors included poor vaccine storage (RR = 8.7) and use of few drinkers to administer vaccine (RR = 5.8); traces of disinfectants in drinkers used to administer live vaccine (RR = 2.8); use of wrong vaccine-infectious bronchitis instead of infectious bursal disease vaccine (RR = 2.1); and use of improper diluents (RR = 1.6). Broiler farmers need training on basic farm biosecurity measures and standard vaccine handling practices.


Advising on the care of the uncircumcised penis: A survey of pediatric urologists in the United States.
Parents of uncircumcised boys often report confusion regarding the proper care and hygiene practices for the uncircumcised penis. The lack of guidance from healthcare providers may be due to a lack of consensus on the proper care of the prepuce. The aim of this study was to determine whether or not there exists consensus among pediatric urologists on the care of the uncircumcised penis and on the advice they provide to parents. An electronic survey was delivered to 514 members of the Society for Pediatric Urology (SPU). The survey contained demographical and clinical questions which were analyzed using descriptive statistics. Of 261 SPU members who opened the e-mail invitation, a total of 204 responses were received for a response rate of 78% (overall response rate 40%). Nine responses were excluded for members practicing outside of the United States or whose locations were not disclosed for a final number of responses of 195. Overall, pediatric urologists reported a high level of confidence in providing advice to parents with a median confidence score of 10 (scale 1-10, IQR 9-10). Only 66% reported providing advice to parents on when to begin retracting the foreskin, with 48% basing their advice on the patient's age and 19% on the patient's toilet training status (Figure). Respondents who based their advice on age, advised beginning retraction at 2-5 years (61%), 6-11 years (17%), less than 2 years (12%), and greater than 12 years (10%). For frequency of retraction before toilet training, 50% recommended no retraction, 25% with cleaning or baths, 10% with each diaper change, and 13% provided no advice. After toilet training, 48% of respondents recommended retracting the foreskin with cleaning or baths, 41% with each void, and 19% recommended no retraction. The majority of respondents agreed that problems with voiding (77%), infection (74%), and hygiene (64%) were indications for treatment of phimosis. In asymptomatic cases, 47% believed that phimosis required treatment if persisting beyond a specific age, the most common being greater than 12 years of age (40%). Although pediatric urologists reported being highly confident in advising parents on the care of the uncircumcised penis, there is not a clear consensus among these subspecialists on when to begin and how often to retract the foreskin, or when phimosis requires treatment. These findings offer insight into current practice patterns to better inform primary care providers and parents.


Medicaid-dependent hospitals and their patients: how have they fared?
To examine how private hospitals dependent on Medicaid for a large proportion of their revenues have fared in the face of substantial Medicaid (and more modest Medicare) reimbursement cutbacks and growing managed care. We specifically test three hypotheses regarding Medicaid-dependent hospitals: (1) that they are more likely to "cost-shift" cutbacks to private patients; (2) that they are more likely to cut services for Medicaid (and other) patients; and (3) that they are more likely to close. DATA/STUDY SETTING: Private short-term hospitals in California a state that has experienced a rapid growth in managed care since the early 1980s. Data are drawn from the California Office of Statewide Health Planning and Development (OSHPD) Hospital Disclosure Files for fiscal years 1983 and 1992. We compare changes in net prices and the provision of services, proxied by list price-adjusted charges, at hospitals for Medicaid, Medicare, and privately insured patients between fiscal years 1983 and 1992 controlling for hospital and market characteristics, case mix, and the proportion of revenues from Medicaid patients. We also examine the probability that a hospital closed during the study period as a function of hospital and market characteristics and payer mix. Although the growth of managed care is hypothesized to reduce opportunities for "cost shifting," it may also confound our analysis of price changes if Medicaid-dependent hospitals are unattractive to managed care patients and respond by offering lower prices to plans. We find no evidence that Medicaid-dependent hospitals raised prices to private patients in response to Medicaid (or Medicare) cutbacks; if anything, they lowered them. However, we find that service levels fell for Medicaid (and Medicare) patients relative to those for privately insured patients and that reductions were greater at Medicaid-dependent hospitals. In addition, our findings suggest that service levels also fell for private patients at Medicaid-dependent hospitals, although reductions were smaller for these patients, suggesting that quality, may be a public good at hospitals. Finally, Medicaid-dependent hospitals were more likely to close. It been suggested that private hospitals may respond to public reimbursement cutbacks by simply "shifting" costs to privately insured patients, limiting overall cost savings but insulating public patients and hospitals from the effects of cutbacks. We find no evidence of cost shifting. Rather, our results suggest that patients and hospitals bore the brunt of cutbacks; service levels fell at Medicaid-dependent hospitals and such hospitals were more likely to go out of business. This suggests that the consequences of proposed Medicare and Medicaid cutbacks could be severe for public patients and the hospitals that care for them.


Red, rank, and romance in women viewing men.
In many nonhuman species of vertebrates, females are attracted to red on male conspecifics. Red is also a signal of male status in many nonhuman vertebrate species, and females show a mating preference for high-status males. These red-attraction and red-status links have been found even when red is displayed on males artificially. In the present research, we document parallels between human and nonhuman females' response to male red. Specifically, in a series of 7 experiments we demonstrate that women perceive men to be more attractive and sexually desirable when seen on a red background and in red clothing, and we additionally show that status perceptions are responsible for this red effect. The influence of red appears to be specific to women's romantic attraction to men: Red did not influence men's perceptions of other men, nor did it influence women's perceptions of men's overall likability, agreeableness, or extraversion. Participants showed no awareness that the research focused on the influence of color. These findings indicate that color not only has aesthetic value but can carry meaning and impact psychological functioning in subtle, important, and provocative ways.


Hesperidin protects against stress induced gastric ulcer through regulation of peroxisome proliferator activator receptor gamma in diabetic rats.
Stress induced gastric ulcer is a serious health problem in diabetic patients. Some studies reported that hesperidin (HDN), a citrus bioflavonoid, can bind to and stimulate peroxisome proliferator-activator receptor-gamma (PPAR-γ) which may mediate its antidiabetic, anti-inflammatory and anti-oxidant effects. This work aims to study the possible protective effect of HDN against stress induced gastric ulcer in diabetic rats as well as the possible involvement of PPARγ in this effect. Type 2 diabetes was induced using streptozotocin and nicotinamide. Diabetic rats received either HDN (100 mg/kg/day, orally) & omeprazole (20 mg/kg/day, orally) or HDN (100 mg/kg/day, orally) + GW9662, PPARγ antagonist, (1 mg/kg/day, i.p.) for 8 weeks then acute gastric injury was induced by cold restraint stress technique. Glycemic controls and gastroprotective effects were evaluated by measuring serum levels of glucose and insulin, gastric free and total acidity and gastric ulcer indices. Histopathological examination of gastric mucosa was also performed. To determine the underlying mechanism of action, gastric mucosal expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hemeoxygenase-1 (HO-1), cluster of differentiation 45 (CD45), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NFκB) and inducible nitric oxide synthase (iNOS), gastric contents of reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and nitric oxide (NO); as well as superoxide dismutase (SOD) and catalase activities were measured. HDN significantly improved glycemic level; it also reduced gastric acidity and gastric ulcer index and histopathological changes comparable to that produced by omeprazole. Moreover, HDN reduced lipid peroxidation and inflammatory markers levels and enhanced antioxidant capacity. The use of GW9662 significantly abrogated the gastric protective effect of HDN as well as reduced the antioxidant and anti-inflammatory effects. Our work showed, for the first time that, HDN has promising protective effect against stress induced gastric ulcer in diabetic rats through activation of PPARγ.


Parallel liquid-phase synthesis of N-substituted 6-aminosulfonyl-2-oxo-1,2-dihydroquinoline-4-carboxamide and 6-aminosulfonylquinoline-4-carboxamide derivatives.
Two efficient strategies for solution-phase parallel synthesis of libraries of quinoline derivatives are described. The first synthetic pathway features the Pfitzinger reaction of isatin with diethyl malonate and sulfochlorination of the resulting 2-oxo-1,2-dihydroquinoline-4-carboxylate followed by generation of sulfonamide library. The second strategy employs the unusual behavior of 5-sulfamoylisatins in Pfitzinger reactions, which results in formation of 6-sulfamoyl-4-carboxyquinolines instead of the anticipated 2-oxo-1,2-dihydroquinoline structures. The obtained carboxylates appeared to be convenient synthetic intermediates for the generation of the corresponding carboxamide libraries. Using these reagents, the parallel solution-phase synthesis of more than 500 substituted quinoline and 2-oxo-1,2-dihydroquinoline derivatives has been accomplished on the 50-100-mg scale. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures to give high-purity final products. The scope and limitations of the developed approaches are discussed.


Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.
Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.


Metal-free catalytic hydrogenation of polar substrates by frustrated Lewis pairs.
In 2006, our group reported the first metal-free systems that reversibly activate hydrogen. This finding was extended to the discovery of "frustrated Lewis pair" (FLP) catalysts for hydrogenation. It is this catalysis that is the focal point of this article. The development and applications of such FLP hydrogenation catalysts are reviewed, and some previously unpublished data are reported. The scope of the substrates is expanded. Optimal conditions and functional group tolerance are considered and applied to targets of potential commercial significance. Recent developments in asymmetric FLP hydrogenations are also reviewed. The future of FLP hydrogenation catalysts is considered.


Cephalopod species identification using integrated analysis of machine learning and deep learning approaches.
Despite the high commercial fisheries value and ecological importance as prey item for higher marine predators, very limited taxonomic work has been done on cephalopods in Malaysia. Due to the soft-bodied nature of cephalopods, the identification of cephalopod species based on the beak hard parts can be more reliable and useful than conventional body morphology. Since the traditional method for species classification was time-consuming, this study aimed to develop an automated identification model that can identify cephalopod species based on beak images. A total of 174 samples of seven cephalopod species were collected from the west coast of Peninsular Malaysia. Both upper and lower beaks were extracted from the samples and the left lateral views of upper and lower beak images were acquired. Three types of traditional morphometric features were extracted namely grey histogram of oriented gradient (HOG), colour HOG, and morphological shape descriptor (MSD). In addition, deep features were extracted by using three pre-trained convolutional neural networks (CNN) models which are VGG19, InceptionV3, and Resnet50. Eight machine learning approaches were used in the classification step and compared for model performance. The results showed that the Artificial Neural Network (ANN) model achieved the best testing accuracy of 91.14%, using the deep features extracted from the VGG19 model from lower beak images. The results indicated that the deep features were more accurate than the traditional features in highlighting morphometric differences from the beak images of cephalopod species. In addition, the use of lower beaks of cephalopod species provided better results compared to the upper beaks, suggesting that the lower beaks possess more significant morphological differences between the studied cephalopod species. Future works should include more cephalopod species and sample size to enhance the identification accuracy and comprehensiveness of the developed model.


Low serum uric acid levels in patients with acute central nervous system viral infections.
Most acute central nervous system (CNS) viral infections lead to either encephalitis or meningitis. Many neurotropic viruses may cause CNS dysfunctions through various mechanisms including oxidative stress. Serum uric acid (SUA) levels, which are associated with oxidative stress and antioxidant status, are reduced in patients with various neurological disorders, including multiple sclerosis. We investigated the possible correlation between SUA levels and clinical disease status in patients with acute CNS viral infections. We measured SUA concentrations in 336 individuals, including 179 healthy individuals and 157 patients with acute CNS viral infections. We found that the patients had lower SUA levels than the healthy individuals did irrespective of sex. Effective therapy significantly increased SUA levels. The patients' SUA levels were correlated inversely with outcomes as measured with the Glasgow Outcome Scale. SUA levels may be a biomarker for predicting treatment outcomes and prognoses for patients with acute CNS viral infections with inflammatory components.


Calcium ionophore upregulation of AUUUA-specific binding protein activity is contemporaneous with granulocyte macrophage colony-stimulating factor messenger RNA stabilization in AML14.3D10 cells.
Eosinophils produce granulocyte macrophage colony-stimulating factor (GM-CSF), which enhances their survival and function. In T cells and fibroblasts, GM-CSF production is controlled predominantly by variable messenger RNA (mRNA) stability involving 3' untranslated region (3' UTR) adenosine-uridine-rich elements (AREs) and sequence-specific mRNA binding proteins. However, the mode of regulation of this critical cytokine remains unknown in eosinophils. Therefore, we measured GM-CSF mRNA decay in an eosinophil-like cell line (AML14.3D10) and, with a radiolabeled GM-CSF RNA probe, asked whether ARE-specific, mRNA binding proteins were present in cytoplasmic lysates of these cells. Human GM-CSF mRNA transfected into unstimulated AML14.3D10 cells decayed with a half-life of 6 min, which increased to 14 min after 1 h, and to 22 min after 2 h, of ionophore-mediated activation. GM-CSF RNA mobility shift assays using cytoplasmic extracts from resting or ionophore-stimulated AML14.3D10 cells revealed multiple RNA-protein complexes of 55, 60, 85, 100, and 125 kD. A 47-kD complex was also detected with an 80-base RNA probe containing four consecutive AUUUA motifs. On the basis of competition studies, all of the observed binding protein activities interacted with the 3' UTR AREs. In addition, binding activity increased 2.5-fold in cytoplasmic lysates from cells stimulated with calcium ionophore for 2 h, contemporaneous with GM-CSF mRNA stabilization. These data provide direct evidence that ionophore stabilizes GM-CSF mRNA in AML14.3D10 cells and simultaneously increases the activity of a series of AUUUA-specific mRNA binding proteins. We conclude that the interaction of AU-specific binding proteins may stabilize GM-CSF mRNA in activated eosinophil-like cell lines.


Pertussis surveillance results from a French general practitioner network, France, 2017 to 2020.
IntroductionIn France, three complementary surveillance networks involving hospitals and paediatrician practices currently allow pertussis surveillance among infants (<1 year old) and children (1-12 years old). Data on incidences among adolescents (13-17 years old) and adults (≥ 18 years) are scarce. In 2017, a sentinel surveillance system called Sentinelles network, was implemented among general practitioners (GPs).AimThe purpose of Sentinelles network is to assess pertussis incidence, monitor the cases' age distribution and evaluate the impact of the country's vaccination policy. We present the results from the first 4 years of this surveillance.MethodsGPs of the French Sentinelles network reported weekly numbers of epidemiologically or laboratory-confirmed cases and their characteristics.ResultsA total of 132 cases were reported over 2017-2020. Estimated national incidence rates per 100,000 inhabitants were 17 (95% confidence interval (CI): 12-22) in 2017, 10 (95% CI: 6-14) in 2018, 15 (95% CI: 10-20) in 2019 and three (95% CI: 1-5) in 2020. The incidence rate was significantly lower in 2020 than in 2017-2019. Women were significantly more affected than men (83/132; 63% of women, p = 0.004); 66% (87/132) of cases were aged 15 years or over (median age: 31.5 years; range: 2 months-87 years). Among 37 vaccinated cases with data, 33 had received the recommended number of doses for their age.ConclusionsThese results concur with incidences reported in other European countries, and with studies showing that the incidences of several respiratory diseases decreased in 2020 during the COVID-19 pandemic. The results also suggest a shift of morbidity towards older age groups, and a rapid waning of immunity after vaccination, justifying to continue this surveillance.


Sedation/agitation monitoring using a wearable device for ventilated children.
Developing continuous and labor-saving sedation/agitation monitoring methods in ventilated children is important to avoid undesirable events such as unplanned extubation. The existing scales are often challenging to use. We therefore aimed to evaluate the feasibility of sedation/agitation monitoring using a wearable device with a built-in accelerometer for ventilated children. This prospective observational pilot study included children aged 15 years or less, admitted to the pediatric intensive care unit on mechanical ventilation after cardiac catheterization between December 2021 and April 2022. The wearable device with a built-in accelerometer was attached to either of the upper limbs, and accelerations due to upper limb movements were measured for 2 h after admission or until extubation, whichever was earliest. Accelerations were measured at 0.02 s intervals, with the mean acceleration calculated for each 1 min interval. The State Behavioral Scale (SBS) was completed at 1 min intervals, with the SBS score (-1, 0, 1, or 2) compared with the mean acceleration. The study included 20 children with a median age of 12 months. The mean accelerations and SBS scores were positively correlated (Kendall's τ, 0.22; p < 0.001), with an increase in the median (interquartile range) acceleration from an SBS score of -1 through 2, as follows: SBS -1, 0.200 (0.151-0.232) m/s2 ; SBS 0, 0.202 (0.190-0.235) m/s2 ; SBS, 1, 0.312 (0.236-0.427) m/s2 ; SBS 2, 0.455 (0.332-0.517) m/s2 . No adverse events were observed. This study showed that continuous, labor-saving sedation/agitation monitoring of ventilated children was feasible using a wearable device with a built-in accelerometer.


CB1 Receptor Signaling Modulates Amygdalar Plasticity during Context-Cocaine Memory Reconsolidation to Promote Subsequent Cocaine Seeking.
Contextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, i.p.) during memory reconsolidation altered (1) subsequent drug context-induced cocaine-seeking behavior as well as (2) cellular adaptations and (3) excitatory synaptic physiology in the basolateral amygdala (BLA) in male Sprague Dawley rats. Systemic CB1R antagonism, during, but not after, cocaine-memory reconsolidation reduced drug context-induced cocaine-seeking behavior 3 d, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene (IEG) expression and changes in BLA AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous EPSC (sEPSC) frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA that may facilitate cocaine-memory strength by enhancing reconsolidation or synaptic reentry reinforcement, or by inhibiting extinction-memory consolidation. These findings identify the CB1R as a potential therapeutic target for relapse prevention.SIGNIFICANCE STATEMENT Drug relapse can be triggered by the retrieval of context-drug memories on re-exposure to a drug-associated environment. Context-drug associative memories become destabilized on retrieval and must be reconsolidated into long-term memory stores to persist. Hence, targeted interference with memory reconsolidation can weaken maladaptive context-drug memories and reduce the propensity for drug relapse. Our findings indicate that cannabinoid type 1 receptor (CB1R) signaling is critical for context-cocaine memory reconsolidation and subsequent drug context-induced reinstatement of cocaine-seeking behavior. Furthermore, cocaine-memory reconsolidation is associated with CB1R-dependent immediate-early gene (IEG) expression and changes in excitatory synaptic proteins and physiology in the basolateral amygdala (BLA). Together, our findings provide initial support for CB1R as a potential therapeutic target for relapse prevention.


Prevalence of coronary risk factors among Indian physicians.
Prevalence of coronary risk factors has not been well studied in Indian physicians, therefore, to determine prevalence of selected lifestyle and biochemical coronary risk factors we performed this study. Physicians attending a national conference were invited to participate. Of the 1000 questionnaires circulated 256 physicians (221 males, 35 females) responded and were examined for presence of smoking, obesity, truncal obesity, hypertension and ECG abnormalities. Two hundred and thirty four physicians (91.4%, 203 males, 31 females) underwent a fasting blood examination for determination of glucose and lipid profile. Subjects were divided into three age groups: Group I aged < 40 years; Group II 40-49 years; and Group III > or = 50 years. Mean age of the study population was 41.7 +/- 9.3 years (range 26-70). There was no significant difference in the distribution of height, weight, body-mass index (BMI), waist and hip circumference and waist-hip ratio (WHR) in different age-groups. Systolic blood pressure (BP) and fasting glucose and triglyceride levels increased with age in both males and females, while diastolic BP, total - LDL and HDL cholesterol levels did not change. Smoking or tobacco use was seen in five males (2.3%). Prevalence of obesity (BMI > or = 25.0 kg/m2) was in 104 (48.6%) males and 18 (51.4%) females. Truncal obesity diagnosed by WHR > 0.9 in males and > 0.8 in females was in 160 (72.4%) males and 23 (65.7%) females and a large waist circumference, > or = 100 cm in males and > or = 90 cm in females, was in 58 (26.2%) males and 7 (20.0%) females. Hypertension (> or = 140/90) was in 74 (33.5%) males and 7 (20%) females. A high prevalence of diabetes diagnosed using fasting blood glucose > or = 126 mg/dl or previous history was noted in males 19 (9.4%), females 4 (12.9%). Prevalence of high total cholesterol levels > or = 200 mg/dl was in 91 (44.8%) males and 10 (32.3%) females. High LDL cholesterol level (> or = 100 mg/dl) was in 144 (70.9%) males and 22 (70.9%) females and LDL levels > or = 130 mg/dl in 70 (34.5%) males and 9 (29.0%) female physicians. High triglyceride levels (> or = 200 mg/dl) were in 38 (18.7%) males and 4 (12.9%) females. Electrocardiographic abnormalities were present in seven subjects: Q-waves in two males and one female and ST-T changes in three males and one female. BMI correlated significantly (p < 0.05) with systolic BP, fasting glucose, and triglycerides and WHR with systolic BP, diastolic BP, fasting glucose, cholesterol and triglyceride levels. There is a high prevalence of obesity, truncal obesity, hypertension and hypercholesterolaemia in Indian physicians while smoking, low HDL cholesterol and hypertriglyceridemia is low. The overall coronary risk is lower among Indian physicians as compared to previous Indian population studies.


How shared is shared decision-making? A care-ethical view on the role of partner and family.
The aim of shared decision-making (SDM) is to provide information to patients in order to enable them to decide autonomously and freely about treatment together with the doctor, without interference, force or coercion by others. Relatives may be considered as hindering or impeding a patient's own decision. Qualitative-empirical research into lived experience of SDM of patients with cancer, however, problematises the patient's autonomy when facing terminal illness and the need to make decisions regarding treatment. Confronted with this difficulty, this contribution tries to think through patients' dependency of others, and make their autonomy more relational, drawing on care-ethical critics of a one-sided view of autonomy and on Ricoeur's view of the fundamentally intersubjective, relational self. We aim to conceptualise relatives not as a third party next to the doctor and the patient, but as co-constituents of the patient's identity and as such present in the decision-making process from the outset. What is more, partners and the family may be of inestimable help in retrieving the patient's identity in line with the past, present and possible future.


Gas chromatography-mass spectrometry based metabolomic approach for optimization and toxicity evaluation of earthworm sub-lethal responses to carbofuran.
Despite recent advances in understanding mechanism of toxicity, the development of biomarkers (biochemicals that vary significantly with exposure to chemicals) for pesticides and environmental contaminants exposure is still a challenging task. Carbofuran is one of the most commonly used pesticides in agriculture and said to be most toxic carbamate pesticide. It is necessary to identify the biochemicals that can vary significantly after carbofuran exposure on earthworms which will help to assess the soil ecotoxicity. Initially, we have optimized the extraction conditions which are suitable for high-throughput gas chromatography mass spectrometry (GC-MS) based metabolomics for the tissue of earthworm, Metaphire posthuma. Upon evaluation of five different extraction solvent systems, 80% methanol was found to have good extraction efficiency based on the yields of metabolites, multivariate analysis, total number of peaks and reproducibility of metabolites. Later the toxicity evaluation was performed to characterize the tissue specific metabolomic perturbation of earthworm, Metaphire posthuma after exposure to carbofuran at three different concentration levels (0.15, 0.3 and 0.6 mg/kg of soil). Seventeen metabolites, contributing to the best classification performance of highest dose dependent carbofuran exposed earthworms from healthy controls were identified. This study suggests that GC-MS based metabolomic approach was precise and sensitive to measure the earthworm responses to carbofuran exposure in soil, and can be used as a promising tool for environmental eco-toxicological studies.


BCL6 promoter interacts with far upstream sequences with greatly enhanced activating histone modifications in germinal center B cells.
BCL6 encodes a transcriptional repressor that is essential for the germinal center (GC) reaction and important in lymphomagenesis. Although its promoter has been well studied, little is known concerning its possible regulation by more distal elements. To gain such information, we mapped critical histone modifications associated with active transcription within BCL6 as well as far upstream sequences at nucleosomal resolution in B-cell lines and in normal naive and GC B cells. Promoter-associated and intronic CpG islands (CGIs) in BCL6 showed a reciprocal pattern of histone modifications. Gene expression correlated with a paradoxical loss from the intronic CGI of histone H3 lysine-4 trimethylation, normally associated with transcription, suggesting that the intronic CGI may interfere with transcription. In an approximately 110-kb region extending 150-260 kb upstream of BCL6, highly active histone modifications were present only in normal GC B cells and a GC B-cell line; this region overlaps with an alternative breakpoint region for chromosomal translocations and contains a GC-specific noncoding RNA gene. By chromosome conformation capture, we determined that the BCL6 promoter interacts with this distant upstream region. It is likely that transcriptional enhancers in this region activate BCL6 and overcome strong autorepression in GC B cells.


Measurement of multiple biomarkers in advanced stage heart failure patients treated with pulmonary artery catheter guided therapy.
This study was carried out to investigate the prognostic utility of biomarkers in advanced stage heart failure (HF) patients requiring ICU admission for pulmonary artery catheter (PAC) guided therapy. Thirty patients admitted to an ICU for PAC guided HF therapy were enrolled; concentrations of soluble ST2 (sST2), highly sensitive troponin I, an experimental ultrasensitive troponin I, amino-terminal pro-B type natriuretic peptide, cystatin C, and myeloperoxidase were measured over the first 48 hours. Outcomes included response of filling pressures and hemodynamics to tailored therapy and 90-day event-free survival (death, left ventricular assist device implantation, transplant). Of the biomarkers evaluated, only sST2 concentrations were higher in those who failed to achieve goals for central venous pressure ((CVP), 225.3 versus 104.6 ng/mL; P = 0.003) and pulmonary capillary wedge pressure ((PCWP), 181.7 versus 88.2 ng/mL; P = 0.05). Only sST2 concentrations were associated with adverse events (186.7 versus 92.2 ng/mL; P = 0.01). In age-adjusted Cox proportional hazards analysis, an elevated sST2 during the first 48 hours following ICU admission independently predicted 90-day outcomes (Hazard Ratio = 5.53; P = 0.03) superior to the Simplified Acute Physiology Score for this application; in Kaplan-Meier analysis the risk associated with elevated sST2 concentrations was present early and sustained through the duration of follow-up (log rank P = 0.01). In patients undergoing HF therapy guided by invasive monitoring, sST2 concentrations were associated with impending failure to reduce filling pressures and predicted impending events. Elevated sST2 values early in the ICU course theoretically could assist therapeutic decision-making in advanced stage HF patients. ClinicalTrials.gov Identifier: NCT00595738.


Symbol interdependency in symbolic and embodied cognition.
Whether computational algorithms such as latent semantic analysis (LSA) can both extract meaning from language and advance theories of human cognition has become a topic of debate in cognitive science, whereby accounts of symbolic cognition and embodied cognition are often contrasted. Albeit for different reasons, in both accounts the importance of statistical regularities in linguistic surface structure tends to be underestimated. The current article gives an overview of the symbolic and embodied cognition accounts and shows how meaning induction attributed to a specific statistical process or to activation of embodied representations should be attributed to language itself. Specifically, the performance of LSA can be attributed to the linguistic surface structure, more than special characteristics of the algorithm, and embodiment findings attributed to perceptual simulations can be explained by distributional linguistic information.


Artificial selection on larval growth curves in Tribolium: correlated responses and constraints.
Body size is often constrained from evolving. Although artificial selection on body size in insects frequently results in a sizable response, these responses usually bear fitness costs. Further, these experiments tend to select only on size at one landmark age, rather than selecting for patterns of growth over the whole larval life stage. To address whether constraints may be caused by larval growth patterns rather than final size, we implemented a function-valued (FV) trait method of selection, in which entire larval growth curves from Tribolium were artificially selected. The selection gradient function used was previously predicted to give the maximal response and was implemented using a novel selection index in the FV framework. Results indicated a significant response after one generation of selection, but no response in subsequent generations. Correlated responses included increased mortality, increased critical weight, and decreased development time (DT). The lack of response in size and development time after the first generation was likely caused by increased mortality suffered in selected lines; we demonstrated that the selection criterion caused both increased body size and increased mortality. We conclude that artificial selection on continuous traits using FV methods is very efficient and that the constraint of body size evolution is likely caused by a suite of trade-offs with other traits.


Net energy content of canola meal fed to growing pigs and effect of experimental methodology on energy values.
An experiment was conducted to determine the digestible energy (DE), metabolizable energy (ME), and net energy (NE) contents of canola meal (CM) and to investigate the effects of basal diet [corn diet vs. corn-soybean meal (SBM) diet] and methodology (difference method vs. regression method) on energy values of CM. Thirty-six growing barrows (20.8 ± 1.0 kg initial body weight [BW]) were individually housed in metabolism crates and randomly allotted to one of six dietary treatments to give six replicates per treatment. The six experimental diets included a corn diet, a corn-SBM diet, a corn diet with 15 or 30% of CM, and a corn-SBM diet with 15 or 30% of CM. The DE, ME, and NE of CM were determined using the corn diet or the corn-SBM diet as a basal diet. In each basal diet, two additional diets containing 15 or 30% of CM were formulated to compare the determined energy values by the difference method and estimated energy values from the regression method. Feeding level was set at 550 kcal ME/kg BW0.6 per day. Pigs were fed experimental diets for 16 d including 10 d for adaptation and 6 d for total collection of feces and urine. Pigs were then moved into indirect calorimetry chambers to determine 24 h heat production (HP) and 12 h fasting HP. The DE, ME, and NE of CM determined by the difference method were within the 95% confidence intervals estimated for the DE, ME, and NE of CM by the regression method regardless of the basal diets used, which indicates that the difference and regression methods give equivalent DE, ME, and NE of CM. However, when the goodness of fit for the linear model was compared, the r2 of the regression analysis from the corn-SBM diet (0.78) was relatively greater than that from corn diet (0.40). The estimated NE of CM by the prediction equations generated by either the corn diet or corn-SBM diets were 2,096 kcal/kg and 1,960 kcal/kg (as-fed basis), respectively, whereas those values determined by the difference method were 2,233 kcal/kg and 2,106 kcal/kg (as-fed basis), respectively. In conclusion, the NE of CM determined in the current study was, on average, 2,099 kcal/kg (as-fed basis). The difference and regression methods do not give different NE value of CM fed to growing pigs. Although the NE values of CM determined using either the corn diet or the corn-SBM diet were not different, the greater r2 of the regression analysis from the corn-SBM diet than that from the corn diet suggests that the corn-SBM diet is a more appropriate basal diet for NE determination of ingredients.


Menstrual changes after COVID-19 vaccine administration: a systematic review.
During the mass vaccination campaign for COVID-19, cases of menstrual cycle changes in women emerged, so it was thought that the COVID-19 vaccine could affect the menstrual cycle. Over time, these observations have become more frequent, which strengthens the idea. This systematic review aims to show changes in the menstrual cycle after COVID-19 vaccination. This study was carried out following the guidelines of the Cochrane Collaboration and the Meta-analysis of Observational Studies in Epidemiology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes. A suitable bibliography on PubMed/Medline and Scopus was searched by combining text, words, and titles of medical topics. After completing the search, a total of 42 articles were included in this systematic review. The COVID-19 vaccines may have an impact on the quality of life of women. The changes in the menstrual cycle tend to resolve within 2-3 months of vaccination and the symptoms are mild to moderate and tend to self-limit over time.


Mini Peltier Cell Array System for the Generation of Controlled Local Epicardial Heterogeneities.
The present study aims to design and fabricate a system capable of generating heterogeneities on the epicardial surface of an isolated rabbit heart perfused in a Langendorff system. The system consists of thermoelectric modules that can be independently controlled by the developed hardware, thereby allowing for the generation of temperature gradients on the epicardial surface, resulting in conduction slowing akin to heterogeneities of pathological origin. A comprehensive analysis of the system's viability was performed through modeling and thermal simulation, and its practicality was validated through preliminary tests conducted at the experimental cardiac electrophysiology laboratory of the University of Valencia. The design process involved the use of Fusion 360 for 3D designs, MATLAB/Simulink for algorithms and block diagrams, LTSpice and Altium Designer for schematic captures and PCB design, and the integration of specialized equipment for animal experimentation. The objective of the study was to efficiently capture epicardial recordings under varying conditions.Clinical relevance- The proposed system aims to induce local epicardial heterogeneities to generate labeled correct signals that can serve as a golden standard for improving algorithms that identify and characterize fibrotic substrates. This improvement will enhance the efficacy of ablation processes and potentially reduce the ablated surface area.


Parieto-occipital encephalomalacia in children; clinical and electrophysiological features of twenty-seven cases.
Brain injuries occurring at a particular time may cause damages in well-defined regions of brain. Perinatal hypoxic ischemic encephalopathy and hypoglycemia are some of the most common types of brain injuries. Neonatal hypoglycemia can cause abnormal myelination in parietal and occipital lobes resulting in parieto-occipital encephalomalacia. There is a small number of studies about clinical and electroencephalographic (EEG) features of children with parieto-occipital encephalomalacia. They might have important neurologic sequelae such as cortical visual loss, seizures, and psychomotor retardation. We aimed to evaluate the causes of parieto-occipital encephalomalacia and evaluate the clinical and electrophysiological features of children with parieto-occipital encephalomalacia. We evaluated clinical features and EEGs of 27 children with parieto-occipital encephalomalacia. Descriptive statistics were used. Hospitalization during the neonatal period was the most common cause (88.9%) of parieto-occipital brain injury. Eleven patients (40.7%) had a history of neonatal hypoglycemia. Twenty-three patients (85.2%) had epilepsy and nine of the epileptic patients (39%) had refractory seizures. Most of the patients had bilateral (50%) epileptic discharges originating from temporal, parietal, and occipital lobes (56.2%). However, some patients had frontal sharp waves and some had continuous spike and wave discharges during sleep. Visual abnormalities were evident in 15 (55.6%) patients. Twenty-two (81.5%) had psychomotor retardation. Fine motor skills, social contact and language development were impaired more than gross motor skills. In our study, most of the patients with parieto-occipital encephalomalacia had an eventful perinatal history. Epilepsy, psychomotor retardation, and visual problems were common neurologic complications.


Myocardial deformation parameters predict outcome in patients with repaired tetralogy of Fallot.
Parameters of myocardial deformation have been suggested to be superior to conventional measures of ventricular function and to predict outcome in repaired tetralogy of Fallot (ToF). We aimed to test the hypothesis that parameters of myocardial deformation on cardiac MRI (CMR) relate to symptoms and provide prognostic information in patients with repaired ToF. We included 372 patients with ToF (median age 16 years; 55% male), recruited within a nationwide, prospective study. Longitudinal (LS), circumferential (CS) and radial global strain (RS) were analysed by CMR-based feature tracking (FT). A combined endpoint of death, successful resuscitation or documented ventricular tachycardia was employed. Parameters of global strain were associated with New York Heart Association (NYHA) class and symptomatic deterioration. During a median follow-up of 7.4 years, 20 events occurred. Left ventricular (LV) CS and right ventricular (RV) LS emerged as predictors of outcome, independent of QRS duration, LV/RV ejection fraction and volumes, NYHA class and peak oxygen uptake. In combination, these parameters also identified a subgroup of patients at significantly increased risk of adverse of outcomes (HR 3.3, p=0.002). Furthermore, LV LS, RS, CS and RV LS were related to the risk of death and nearly missed death (p<0.05 for all). FT-CMR provides myocardial deformation parameters, easily derived from standard CMR studies. They relate to symptoms and clinical deterioration in patients with ToF. More importantly, they predict adverse outcome independent of established risk markers, and should be considered as a useful adjunct to established outcome predictors, especially in younger patients with ToF. http://www.clinicaltrials.gov: NCT00266188; Results.


M-Chem: a Modular Software Package for Molecular Simulation that Spans Scientific Domains.
We present a new software package called M-Chem that is designed from scratch in C++ and parallelized on shared-memory multi-core architectures to facilitate efficient molecular simulations. Currently, M-Chem is a fast molecular dynamics (MD) engine that supports the evaluation of energies and forces from two-body to many-body all-atom potentials, reactive force fields, coarse-grained models, combined quantum mechanics molecular mechanics (QM/MM) models, and external force drivers from machine learning, augmented by algorithms that are focused on gains in computational simulation times. M-Chem also includes a range of standard simulation capabilities including thermostats, barostats, multi-timestepping, and periodic cells, as well as newer methods such as fast extended Lagrangians and high quality electrostatic potential generation. At present M-Chem is a developer friendly environment in which we encourage new software contributors from diverse fields to build their algorithms, models, and methods in our modular framework. The long-term objective of M-Chem is to create an interdisciplinary platform for computational methods with applications ranging from biomolecular simulations, reactive chemistry, to materials research.


Targeting of two Arabidopsis H(+)-ATPase isoforms to the plasma membrane.
More than 11 different P-type H(+)-ATPases have been identified in Arabidopsis by DNA cloning. The subcellular localization for individual members of this proton pump family has not been previously determined. We show by membrane fractionation and immunocytology that a subfamily of immunologically related P-type H(+)-ATPases, including isoforms AHA2 and AHA3, are primarily localized to the plasma membrane. To verify that AHA2 and AHA3 are both targeted to the plasma membrane, we added epitope tags to their C-terminal ends and expressed them in transgenic plants. Both tagged isoforms localized to the plasma membrane, as indicated by aqueous two-phase partitioning and sucrose density gradients. In contrast, a truncated AHA2 (residues 1-193) did not, indicating that the first two transmembrane domains alone are not sufficient for plasma membrane localization. Two epitope tags were evaluated: c-myc, a short, 11-amino acid sequence, and beta-glucuronidase (GUS), a 68-kD protein. The c-myc tag is recommended for its sensitivity and specific immunodetection. GUS worked well as an epitope tag when transgenes were expressed at relatively high levels (e.g. with AHA2-GUS944); however, evidence suggests that GUS activity may be inhibited when a GUS domain is tethered to an H(+)-ATPase complex. Nevertheless, the apparent ability to localize a GUS protein to the plasma membrane indicates that a P-type H(+)-ATPase can be used as a delivery vehicle to target large, soluble proteins to the plasma membrane.


Inverse spin-galvanic effect in the interface between a topological insulator and a ferromagnet.
When a ferromagnet is deposited on the surface of a topological insulator the topologically protected surface state develops a gap and becomes a two-dimensional quantum Hall liquid. We demonstrate that the Hall current in such a liquid, induced by an external electric field, can have a dramatic effect on the magnetization dynamics of the ferromagnet by changing the effective anisotropy field. This change is dissipationless and may be substantial even in weakly spin-orbit coupled ferromagnets. We study the possibility of dissipationless current-induced magnetization reversal in monolayer-thin, insulating ferromagnets with a soft perpendicular anisotropy and discuss possible applications of this effect.


A sequence motif within chromatin entry sites directs MSL establishment on the Drosophila X chromosome.
The Drosophila MSL complex associates with active genes specifically on the male X chromosome to acetylate histone H4 at lysine 16 and increase expression approximately 2-fold. To date, no DNA sequence has been discovered to explain the specificity of MSL binding. We hypothesized that sequence-specific targeting occurs at "chromatin entry sites," but the majority of sites are sequence independent. Here we characterize 150 potential entry sites by ChIP-chip and ChIP-seq and discover a GA-rich MSL recognition element (MRE). The motif is only slightly enriched on the X chromosome ( approximately 2-fold), but this is doubled when considering its preferential location within or 3' to active genes (>4-fold enrichment). When inserted on an autosome, a newly identified site can direct local MSL spreading to flanking active genes. These results provide strong evidence for both sequence-dependent and -independent steps in MSL targeting of dosage compensation to the male X chromosome.


Taste evaluation of a novel midazolam tablet for pediatric patients: In vitro drug dissolution, in vivo animal taste aversion and clinical taste perception profiles.
Harmonized methodologies are urgently required for the taste evaluation of novel pediatric medicines. This study utilized in vitro, in vivo and clinical data to evaluate the palatability of a novel midazolam chocolate tablet. In vitro dissolution experiments showed the crushed tablet to release within 5 min 1.68 mg of midazolam into simulated saliva. This translated to a drug level of 0.84 mg/ml in the oral cavity, which would be higher than the midazolam bitterness detection threshold concentration of 0.03 mg/ml determined in a rat 'brief access taste aversion' (BATA) model. The visual analogue scale scores of patients aged 4-16 years prescribed with midazolam pre-surgery showed a clear preference for the midazolam chocolate tablets (3.35 ± 1.04, n = 20) compared to the control midazolam solution (1.47 ± 0.62, n = 17). The clinical data was in agreement with the in vivo rodent data in showing the novel chocolate tablet matrix to be effective at taste-masking the bitter midazolam.


Tension chylothorax complicating acute malignant airway obstruction.
Acute upper airway obstruction represents one of the most challenging emergencies in pediatric practice. In particular, a tension chylothorax complicating a malignant airway obstruction is a rare and life-threatening complication. We report a rapidly progressing tension chylothorax associated with a cervical mass in a 10-month-old male infant. To our knowledge, the extension of a cervical mass to the supraclavear region resulting in a compressive chylothorax represents an exceptional event in pediatrics. Early recognition and prompt treatment resulted to be essential to relieve the compression and to avoid end-stage hemodynamic and respiratory function derangement.


Small molecule activation by multimetallic uranium complexes supported by siloxide ligands.
The synthesis and reactivity of uranium compounds supported by the tris-tert-butoxysiloxide ligand is surveyed. The multiple binding modes of the tert-butoxysiloxide ligand have proven very well suited to stabilize highly reactive homo- and heteropolymetallic complexes of uranium that have shown an unusual high reactivity towards small molecules such as CO2, CS2, chalcogens and azides. Moreover, these ligands have allowed the isolation of dinuclear nitride and oxide bridged complexes of uranium in various oxidation states. The ability of the tris-tert-butoxysiloxide ligands to trap alkali ions in these nitride or oxide complexes leads to unprecedented ligand based and metal based reduction and functionalization of N2, CO, CO2 and H2.


[Bilroth-I subtotal resection and its efficacy in the treatment of distal gastric cancer].
The experience with 260 Bilrot-I resections for cancer of a distal part of the stomach is analyzed. Postoperative lethality was 2.69%, rate of dumping-syndrome -- 12.3%. Among 215 followed-up patients treated surgically 5- and 10-year survival was 65.1 and 24.7%, respectively. Original surgical methods for improvement of immediate and long-term functional results have been developed and applied in clinical practice.


Specialist palliative care improves the quality of life in advanced neurodegenerative disorders: NE-PAL, a pilot randomised controlled study.
This study analysed the impact on palliative care outcomes of a new specialist palliative care service for patients severely affected by amyotrophic lateral sclerosis (ALS/MND), multiple sclerosis, Parkinson's disease and related disorders (multiple system atrophy progressive supranuclear palsy, MSA-PSP). The design followed the Medical Research Council Framework for the evaluation of complex interventions. A phase II randomised controlled trial (RCT) was undertaken comparing an immediate referral to the service (FT, fast track) to a 16-week wait (standard track (ST), standard best practice) using a parallel arm design. The main outcome measures were Quality of Life (measured with Schedule for the Evaluation of Individual Quality of Life Direct Weight, SEIQoL-DW) and burden of the carers (Caregivers Burden Inventory, CBI), with secondary outcomes of symptoms, psychosocial and spiritual issues. 50 patients severely affected by neurodegenerative conditions and their informal family carers were randomised: 25 FT, 25 ST. At baseline (T0), there were no differences between groups. 4 patients died during the follow-up (2 FT, 2 ST) and 2 FT patients dropped out before the end of the study. After 16 weeks (T1), FT participants scored significant improvement in the SEIQoL-DW index, pain dyspnoea sleep disturbance and bowel symptoms. This exploratory RCT provides evidence that no harm was experienced by SPCS for patients severely affected by neurodegenerative disorders. There was an improvement in quality of life and physical symptoms for neurological patients in palliative care. Caregiver burden was not affected by the service.


Multiple O-glycoforms on the spore coat protein SP96 in Dictyostelium discoideum. Fuc(alpha1-3)GlcNAc-alpha-1-P-Ser is the major modification.
A decreased level of fucosylation on certain spore coat proteins of Dictyostelium discoideum alters the permeability of the spore coat. Here the post-translational modifications of a major spore coat protein, SP96, are studied in a wild type strain (X22) and a fucosylation-defective mutant (HU2470). A novel phosphoglycan structure on SP96 of the wild type strain, consisting of Fuc(alpha1-3)GlcNAc-alpha-1-P-Ser(,) was identified by electrospray ionization mass spectrometry and NMR. It was shown using monosaccharide and gas chromatography mass spectrometry analysis that SP96 in the mutant HU2470 contained approximately 20% of wild type levels of fucose, as a result of a missing terminal fucose on the novel glycan structure. The results support previous predictions, based on inhibition studies on different fucose-deficient strains, about the nature of monoclonal antibody epitopes identified by monoclonal antibodies MUD62 and MUD166, which are known to identify O-linked glycans (Champion, A., Griffiths, K., Gooley, A. A., Gonzalez, B. Y., Gritzali, M., West, C. M., and Williams, K. L. (1995) Microbiology 141, 785-797). Quantitative studies on wild type SP96 indicated that there were approximately 60 sites with phosphodiester-linked N-acetylglucosamine-fucose disaccharide units and a further approximately 20 sites with fucose directly linked to the protein. Over 70% of the serine sites are modified, with less than 1% of these sites as phosphoserine. Threonine and tyrosine residues were not found to be modified.


Benzo[b]tiophen-3-ol derivatives as effective inhibitors of human monoamine oxidase: design, synthesis, and biological activity.
A series of benzo[b]thiophen-3-ols were synthesised and investigated as potential human monoamine oxidase (hMAO) inhibitors in vitro as well as ex vivo in rat cortex synaptosomes by means of evaluation of 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio and lactate dehydrogenase (LDH) activity. Most of these compounds possessed high selectivity for the MAO-B isoform and a discrete antioxidant and chelating potential. Molecular docking studies of all the compounds underscored potential binding site interactions suitable for MAO inhibition activity, and suggested structural requirements to further improve the activity of this scaffold by chemical modification of the aryl substituents. Starting from this heterocyclic nucleus, novel lead compounds for the treatment of neurodegenerative disease could be developed.


[Dependence on androgen metabolism in the hypophysis and hypothalamus on age in rats].
The in vitro metabolism of 3H-testosterone, 3H-dihydrotestosterone, 3H-5 alpha-androstan-3 alpha, 17 beta-diol and 3H-5 alpha-androstan-3 beta, 17 beta-diol was studied in hypophyses and hypothalamuses of the rats at the age from 5 to 60 days. The androgen metabolites were separated by means of chromatography in thin layers of silicogel. The rate of androgen metabolism in the organs studied from the 5th till the 23rd day of development was dozens of times that in the adult animals. Sexual dimorphism was also shown. 3H-5 alpha-androstan-3 beta, 17 beta-diol transforms in hypothalamuses and hypophyses of the rats of all age groups of both sexes into polar metabolites only. A suggestion is put forward to the effect that the extensive metabolism of androgens in the brain until the 23rd day of development is due to the development of the system hypothalamus-hypophysis-gonads, depends on the concentration of androgens circulating in the blood and is directed to control the secretion of gonadotropins. The above period of development is termed as "critical".


[Cytotoxic and complement-binding activity of rabbit antisera against the cortex and cerebral white matter of rats and humans].
The cytotoxicity and complement-fixation activity of rabbit antisera against rat and human brain cortex and white matter was tested against mouse and rat thymocytes and bone marrow cells. The cytotoxic test proved to be more sensitive and accurate. The cytotoxins to rodent thymocytes were found in the antisera against human brain cortex only. At the same time cytotoxic antibodies were revealed both in the antisera rat brain cortex and white matter; but the former contained much more cytotoxic antibodies than the letter. After absorption with the same antigen the antisera against rat brain cortex lost their cytotoxic effect, but retained it in case of absorption with the white matter.


Contacts between pigmented retina epithelial cells in culture.
The behaviour of primary cultures of dissociated embryonic chick pigmented retina epithelial (PRE) cells has been investigated. Isolated PRE cells have a mean speed of locomotion of 7-16 mum/h. Collisions between the cells normally result in the development of stable contacts between the cells involved. This leads to a gradual reduction in the number of isolated cells and an increase in the number of cells incorporated into islands. Ultrastructural observations of islands of cells after 24 h in culture show that junctional complexes are present between the cells. These complexes consist of 2 components: (a) an apically situated region of focal tight junctions and/or gap junctions, and (b) a more ventrally located zonula adhaerens with associated cytoplasmic filaments forming a band running completely around the periphery of each cell. The intermembrane gap in the region of the zonula is 6-0-12-0 nm. The junctional complexes become more differentiated with time and after 48 h in culture consist of an extensive region of tight junctions and/or gap junctions and a more specialized zonula adhaerens. It is suggested that the development of junctional complexes may be responsible for the stable contacts that the cells display in culture.


The future of varicella vaccine.
Based on conservative figures, an estimated 60 million varicella-zoster cases occur annually worldwide, highlighting the global significance of this disease. The development of a viable varicella vaccine, therefore, raises important questions as to the indications for its use in normal children, normal seropositive and seronegative adults, and immunocompromised patients. A review of the available data addresses the potential future role of the varicella vaccine in these groups.


Rho GTPase-phosphatidylinositol phosphate interplay in fungal cell polarity.
Rho G-proteins and phosphatidylinositol phosphates, which are important for exocytosis, endocytosis and cytoskeleton organization, are key regulators of polarized growth in a range of organisms. The aim of the present brief review is to highlight recent findings and their implications with respect to the functions and interplay between Rho G-proteins and phosphatidylinositol phosphates in highly polarized fungal filamentous growth.


[What does "pharmacognosy" mean for pharmacists?].
Pharmacists consider pharmacognosy to be a part of Kampo-related education. However, actually, pharmacists cannot generally apply pharmacognosy to their work in clinical settings because they do not have sufficient opportunities to learn about the relationship between pharmacognosy and Kampo in the Faculty of Pharmacy. Meanwhile, in the Faculty of Medicine, education in Kampo has spread at an accelerated rate since the amendment of the medical education core curriculum in 2001, leading to the present condition of 73 out of a total of 80 Faculties of Medicine in Japan already having adopted Kampo as a part of that curriculum. However, clinical education is often focused on, while items of pharmacognosy are hardly mentioned; therefore, pharmacognosy remains not as important in medical education. It is thus often very difficult for pharmacists who have only learned Kampo based on pharmacognosy to understand the prescription of a physician who has received Kampo education, and this remains a considerable problem for pharmacists who are required to explain how to take a drug to a patient in clinical practice. What role does pharmacognosy have to play to bridge the gap between such physicians and pharmacists? Here, I would like to describe what I believe is necessary regarding pharmacognosy education in the future, both from the perspectives of pharmacists and physicians who prescribe Kampo medicine.


Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation.
The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence the functional properties of midbrain dopamine neurons, midbrain inflammation may play a role in schizophrenia by contributing to presynaptic dopamine abnormalities. Thus, we quantified inflammatory markers in dopaminergic areas of the midbrain of people with schizophrenia and matched controls. We also measured these markers in midbrain of mice exposed to maternal immune activation (MIA) during pregnancy, an established risk factor for schizophrenia and other psychiatric disorders. We found diagnostic increases in SERPINA3, TNFα, IL1β, IL6, and IL6ST transcripts in schizophrenia compared with controls (p < 0.02-0.001). The diagnostic differences in these immune markers were accounted for by a subgroup of schizophrenia cases (~ 45%, 13/28) showing high immune status. Consistent with the human cohort, we identified increased expression of immune markers in the midbrain of adult MIA offspring (SERPINA3, TNFα, and IL1β mRNAs, all p ≤ 0.01), which was driven by a subset of MIA offspring (~ 40%, 13/32) with high immune status. There were no diagnostic (human cohort) or group-wise (mouse cohort) differences in cellular markers indexing the density and/or morphology of microglia or astrocytes, but an increase in the transcription of microglial and astrocytic markers in schizophrenia cases and MIA offspring with high inflammation. These data demonstrate that immune-related changes in schizophrenia extend to dopaminergic areas of the midbrain and exist in the absence of changes in microglial cell number, but with putative evidence of microglial and astrocytic activation in the high immune subgroup. MIA may be one of the contributing factors underlying persistent neuroimmune changes in the midbrain of people with schizophrenia.


Ischemic stroke in PAR1 KO mice: Decreased brain plasmin and thrombin activity along with decreased infarct volume.
Ischemic stroke is a common and debilitating disease with limited treatment options. Protease activated receptor 1 (PAR1) is a fundamental cell signaling mediator in the central nervous system (CNS). It can be activated by many proteases including thrombin and plasmin, with various down-stream effects, following brain ischemia. A permanent middle cerebral artery occlusion (PMCAo) model was used in PAR1 KO and WT C57BL/6J male mice. Mice were evaluated for neurological deficits (neurological severity score, NSS), infarct volume (Tetrazolium Chloride, TTC), and for plasmin and thrombin activity in brain slices. Significantly low levels of plasmin and thrombin activities were found in PAR1 KO compared to WT (1.6±0.4 vs. 3.2±0.6 ng/μl, p<0.05 and 17.2±1.0 vs. 21.2±1.0 mu/ml, p<0.01, respectively) along with a decreased infarct volume (178.9±14.3, 134.4±13.3 mm3, p<0.05). PAR1 KO mice have smaller infarcts, with lower thrombin and plasmin activity levels. These findings may suggest that modulation of PAR1 is a potential target for future pharmacological treatment of ischemic stroke.


Cefoxitin, N-formimidoyl thienamycin, clavulanic acid, and penicillanic acid sulfone as suicide inhibitors for different types of beta-lactamases produced by gram-negative bacteria.
Cefoxitin, N-formimidoyl thienamycin (MK0787), clavulanic acid, and penicillanic acid sulfone (CP45,899) were studied to determine their potency as suicide inhibitors of three very different kinds of beta-lactamases produced by Gram-negative bacteria: type Ib penicillinase (TEM-2 type), a typical cephalosporinase (the enzyme of Proteus morganii), and a cephalosporinase with broad substrate specificity (the enzyme of Proteus vulgaris). All these beta-lactams were confirmed to be quite stable to the three beta-lactamases. The absolute values of the turnover numbers (kcat) for these enzyme-catalyzed hydrolyses were determined, the values ranged from 0.25 minute-1 to 660 minute-1. All the beta-lactams studied, except cefoxitin, acted as suicide inhibitors of the typical cephalosporinase. Although cefoxitin did not exhibit such an effect, it was a powerful competitive inhibitor of this enzyme. Although the four beta-lactams acted as suicide inhibitors of the P. vulgaris cephalosporinase, the inactivated enzyme partially regained its activity after removing the effect of the free inhibitor. Type Ib penicillinase was also inactivated by the four beta-lactams, and the activity of the inactivated enzyme, except in the case of cefoxitin, was partially restored. The rate constants for enzyme inactivation or reactivation were calculated and are presented. The information obtained from this study suggests that the catalytic center of the P. vulgaris cephalosporinase is different not only from that of the penicillinase-type but also from that of the cephalosporinase-type beta-lactamases.


Conformational change of glyceraldehyde-3-phosphate dehydrogenase induced by acetylleucine chloromethyl ketone is followed by unique enzymatic degradation.
We have previously reported that acetylleucine chloromethyl ketone (ALCK), an inhibitor of acylpeptidehydrolase, induces the inhibition and degradation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the U937 cell extract. In the present study, the process of ALCK-induced GAPDH degradation was investigated. A kinetic study revealed that GAPDH was irreversibly inhibited by ALCK. ALCK treatment induced a change in the signal intensity of GAPDH in the near-UV region of the circular dichroism (CD) spectrum, and the fluorescence intensity of GAPDH at 330 nm increased to about 10% when excited at 280 nm, suggesting that a significant conformational change of GAPDH was induced by ALCK. When the U937 cell extract was incubated with ALCK and the products were separated by SDS-polyacrylamide gel electrophoresis (PAGE), a 23-kDa fragment from GAPDH was detected by Western blotting using anti-GAPDH serum. When ALCK-treated GAPDH was incubated with protease fractions from the U937 cell extract, a 17-kDa fragment was also detected. Sequence analysis showed that the N-terminal amino acid sequence of the 23-kDa fragment was GKVKVG and that of 17-kDa fragment was RDGRGAL. Therefore, ALCK-modified GAPDH is deduced to be digested at the peptide bond Trp(195)-Arg(196). The protease activity liberating a 23-kDa fragment from ALCK-treated GAPDH was effective under the basic condition. Results suggested that ALCK binds to GAPDH to modulate the conformation of enzyme, which is susceptible to chymotrypsin-like protease activity.


Feasibility and Implementation Determinants of a Structured Goal Setting and Goal Management System.
There is no evidence-based system to guide occupational therapists in implementing theory-based, client-engaged goal setting and goal management. A new system is needed to support high-quality goal setting and goal management. To determine the acceptability, appropriateness, feasibility, credibility, and expectancy of a new structured theory-based, client-engaged goal setting and goal management system, called MyGoals, for occupational therapists. We explored MyGoals' implementation determinants, potential positive outcomes, and comparative advantages. This was a mixed-methods feasibility study. Community. Occupational therapists (N = 7). Acceptability, appropriateness, and feasibility were assessed using the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM). Credibility and expectancy were assessed with the Credibility and Expectancy Questionnaire (CEQ). Semistructured 1:1 interviews were conducted to explore occupational therapy perspectives on MyGoals and its implementation-related factors. MyGoals had high AIM (M = 18.1, SD = 1.9), IAM (M = 17.9, SD = 2.2), FIM (M = 17.3, SD = 2.1) scores and high CEQ Credibility (M = 22.1, SD = 5.0) and Expectancy (M = 20.6, SD = 4.3) scores. Interview data revealed suggestions to improve MyGoals, implementation determinants across the individuals involved, inner setting, and intervention characteristic domains, client- and clinician-related potential positive outcomes, and comparative advantages. MyGoals is an acceptable, appropriate, feasible, credible, and promising system to guide occupational therapists in implementing theory-based, client-engaged goal setting and goal management for adults with chronic conditions in community-based rehabilitation. What This Article Adds: MyGoals is an easy-to-use, appealing, and helpful system to support occupational therapists in delivering theory-based goal setting and goal management components and to enable adults with chronic conditions to actively engage in their rehabilitation. This study supports the usefulness of MyGoals in community-based rehabilitation to improve goal setting and goal management quality and personally meaningful rehabilitation goal achievement in this population.


Temporal similarity perfusion mapping: A standardized and model-free method for detecting perfusion deficits in stroke.
Interpretation of the extent of perfusion deficits in stroke MRI is highly dependent on the method used for analyzing the perfusion-weighted signal intensity time-series after gadolinium injection. In this study, we introduce a new model-free standardized method of temporal similarity perfusion (TSP) mapping for perfusion deficit detection and test its ability and reliability in acute ischemia. Forty patients with an ischemic stroke or transient ischemic attack were included. Two blinded readers compared real-time generated interactive maps and automatically generated TSP maps to traditional TTP/MTT maps for presence of perfusion deficits. Lesion volumes were compared for volumetric inter-rater reliability, spatial concordance between perfusion deficits and healthy tissue and contrast-to-noise ratio (CNR). Perfusion deficits were correctly detected in all patients with acute ischemia. Inter-rater reliability was higher for TSP when compared to TTP/MTT maps and there was a high similarity between the lesion volumes depicted on TSP and TTP/MTT (r(18) = 0.73). The Pearson's correlation between lesions calculated on TSP and traditional maps was high (r(18) = 0.73, p<0.0003), however the effective CNR was greater for TSP compared to TTP (352.3 vs 283.5, t(19) = 2.6, p<0.03.) and MTT (228.3, t(19) = 2.8, p<0.03). TSP maps provide a reliable and robust model-free method for accurate perfusion deficit detection and improve lesion delineation compared to traditional methods. This simple method is also computationally faster and more easily automated than model-based methods. This method can potentially improve the speed and accuracy in perfusion deficit detection for acute stroke treatment and clinical trial inclusion decision-making.


Influence of self-care advice on patient satisfaction and healthcare utilization.
The aim of this study is to explore the influence of nurse-led self-care advice on healthcare utilization and patients' satisfaction with telephone nursing. Many consultations in high-cost settings are for conditions that are manageable through self-care and callers with greater satisfaction with the nurse interaction are nearly four times more likely to engage in self-care. Cross-sectional study. Questionnaires were sent out to 500 randomly selected callers to the Swedish Healthcare Direct in Northern Sweden during March 2014. Callers were asked about their satisfaction with the consultation, their intended actions prior to consultation, the recommendation given by the nurse and the action undertaken after the call. Young callers and persons recommended watchful waiting or recurrence if no improvements were significantly less satisfied with their care. When calling on their own behalf, both men and women rated the severity of their symptoms equally and were advised to self-care to the same extent. Self-care advice had a constricting influence on self-reported healthcare utilization, with 66·1% of cases resulting in a lower level of care than first intended. Feeling reassured after the call was the aspect of nursing care that influenced satisfaction the most. Receiving self-care advice rather than referral to a general practitioner influences patient satisfaction negatively. Feeling reassured after consultation is strongly related to satisfaction, which in turn has been found to increase the likelihood of engaging in self-care behaviour.


Attributes of effective disaster responders: focus group discussions with key emergency response leaders.
An effective disaster response requires competent responders and leaders. The purpose of this study was to ask experts to identify attributes that distinguish effective from ineffective responders and leaders in a disaster. In this qualitative study, focus groups were held with jurisdictional medical directors for the 9-1-1 emergency medical services systems of the majority of the nation's largest cities. These sessions were recorded with audio equipment and later transcribed. The researchers identified themes within the transcriptions, created categories, and coded passages into these categories. Overall interrater reliability was excellent (κ = .8). The focus group transcripts yielded 138 codable passages. Ten categories were developed from analysis of the content: Incident Command System/Disaster Training/Experience, General Training/Experience, Teamwork/Interpersonal, Communication, Cognition, Problem Solving/Decision Making, Adaptable/Flexible, Calm/Cool, Character, and Performs Role. The contents of these categories included knowledge, skills, attitudes, behaviors, and personal characteristics. Experts in focus groups identified a variety of competencies for disaster responders and leaders. These competencies will require validation through further research that involves input from the disaster response community at large.


Persistence of highly pathogenic avian influenza virus (H7N1) in infected chickens: feather as a suitable sample for diagnosis.
Selection of an ideal sample is a vital element in early detection of influenza infection. Rapid identification of infectious individuals or animals is crucial not only for avian influenza virus (AIV) surveillance programmes, but also for treatment and containment strategies. This study used a combination of quantitative real-time RT-PCR with an internal positive control and a cell-titration system to examine the presence of virus in different samples during active experimental AIV infection and its persistence in the infected carcasses. Oropharyngeal/cloacal swabs as well as feather pulp and blood samples were collected from 15-day-old chicks infected with H7N1 highly pathogenic AIV (HPAIV) and the kinetics of virus shedding during active infection were evaluated. Additionally, several samples (muscle, skin, brain, feather pulp and oropharyngeal and cloacal swabs) were examined to assess the persistence of virus in the HPAIV-infected carcasses. Based on the results, feather pulp was found to be the best sample to detect and isolate HPAIV from infected chicks from 24 h after inoculation onwards. Kinetic studies on the persistence of virus in infected carcasses revealed that tissues such as muscle could potentially transmit infectious virus for 3 days post-mortem (p.m.), whilst other tissues such as skin, feather pulp and brain retained their infectivity for as long as 5-6 days p.m. at environmental temperature (22-23 degrees C). These results strongly favour feather as a useful sample for HPAIV diagnosis in infected chickens as well as in carcasses.


[Role of histamine as an intermediary in the action of estradiol on the rat uterus: inhibition of the hormonal induction of enzymes using histamine antagonists].
The administration of methiamide, a blocker of histamine H2-receptors, to rats was shown to prevent the induction of hexokinase (HK) and glucose-6-phosphate dehydrogenase (G-6PD) caused by both histamine and estradiol. An inhibitory effect of methiamide remained stable up to 16 h after histamine and estradiol administration. Diphenhydramine, a blocker of histamine H1-receptors, produces a short-term inhibitory effect on the HK and G-6PD activity stimulated by histamine and estradiol. The short-term nature of the diphenhydramine effect may be attributed to a low affinity to histamine H2-receptors and histamine fast dissociation. It may be concluded that some of the estradiol effects, particularly the HK and G-6PD induction in the uterus are histamine-mediated, apparently by means of H2-receptors. The administration of histamine to rats increases the uterus mass causing its inundation, and H1- and H2-blockers prevent this effect of histamine. However, the above histamine antagonists do not inhibit uterus inundation caused by estradiol. A conclusion is made that estradiol stimulates the uterus inundation not only by means of histamine but also by some other means.