Porcine IPEC-J2 intestinal epithelial cells in microbiological investigations.
IPEC-J2 cells are porcine intestinal columnar epithelial cells that were isolated from neonatal piglet mid-jejunum. This cell line forms polarized monolayers with high transepithelial electrical resistance when cultured on 0.4 μm pore-size filters. The cell line is unique in that it is derived from small intestinal tissue (compared to the common human colon-derived lines HT-29, T84, and Caco-2) and is not transformed (compared to the porcine small intestinal line, IPI-2I). Porcine intestinal epithelial cells more closely mimic human physiology than analogous rodent cell lines (e.g. IEC-6 or IEC-18), which is important in studies of zoonotic infections; in addition, they provide specificity to study porcine-derived infections. IPEC-J2 cells are increasingly being used in microbiological studies to examine the interactions of various animal and human pathogens, including Salmonella enterica and pathogenic Escherichia coli, with intestinal epithelial cells. The IPEC-J2 cell line has also been employed in some probiotic studies, in which the cells have been used as an initial screening tool for adhesiveness and anti-inflammatory properties of the potential probiotic microorganisms. The validity of these studies is not clear as follow-up studies to assess the efficacy of the probiotics in vivo have not been published to date. The aims of this review are to provide a comprehensive overview of the microbiological studies that have been conducted with IPEC-J2 cells and a reference guide of key cellular and immune markers that have been identified in this cell line that may prove to be useful in future studies.


Life course trajectories of systolic blood pressure using longitudinal data from eight UK cohorts.
Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from cross-sectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods. Data are from 30,372 individuals and comprise 102,583 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade. Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population. Please see later in the article for the Editors' Summary.


Understanding the Insight Mechanism of Chemical-Mechanical Degradation of Layered Co-Free Ni-Rich Cathode Materials: A Review.
Layered Cobalt (Co)-free Nickel (Ni)-rich cathode materials have attracted much attention due to their high energy density and low cost. Still, their further development is hampered by material instability caused by the chemical/mechanical degradation of the material. Although there are numerous doping and modification approaches to improve the stability of layered cathode materials, these approaches are still in the laboratory stage and require further research before commercial application. To fully exploit the potential of layered cathode materials, a more comprehensive theoretical understanding of the underlying issues is necessary, along with active exploration of previously unrevealed mechanisms. This paper presents the phase transition mechanism of Co-free Ni-rich cathode materials, the existing problems, and the state-of-the-art characterization tools employed to study the phase transition. The causes of crystal structure degradation, interfacial instability, and mechanical degradation are elaborated, from the material's crystal structure to its phase transition and atomic orbital splitting. By organizing and summarizing these mechanisms, this paper aims to establish connections among common research problems and to identify future research priorities, thereby facilitating the rapid development of Co-free Ni-rich materials.


Metabolite identification and profiling in drug design: current practice and future directions.
Drug metabolism and pharmacokinetics (DMPK) represents a critical component in support of drug discovery and development. This is because the therapeutic efficacy of a drug is dependent on its exposure which in turn is dictated in part by metabolic stability of the molecule. In addition, drug metabolism may lead to the formation of metabolites that can either be pharmacologically active or elicit adverse effect. On this basis, metabolite identification and profiling have become a routine exercise during lead optimization and subsequent development processes. The current communication provides an overview on the account of metabolite identification and profiling in support of drug design with an additional emphasis on the commonly used analytical techniques. The discussion is supported by case studies. Future directions are discussed in the context of newer platforms of technology and bioanalytical approaches enabling better operation efficiency in pharmaceutical research.


[Deteriorating factors on the outcome in patients with fair grade of subarachnoid hemorrhage (WFNS grade I and II)].
Although, the overall treatment results in aneurysmal subarachnoid hemorrhage (SAH) has been improving in recent years, more than 10% of the patients with WFNS grade I and II we have sought to determine the clinical variables for predicting poor functional outcome and symptomatic vasospasm (VS) in patients with individual WFNS grades. The eligible patient fulfilled the following conditions; (1) ruptured aneurysm located in the anterior part of the circle of Willis, (2) surgically clipped followed by craniotomy under microscope, (3) early surgery within 72 hours, (4) classified to WFNS grade I or II. The medical records were retrospectively reviewed in 119 patients (63 of grade I and 56 of grade II). Sex, age, Fisher's CT group, intraventricular hemorrhage (IVH), site of aneurysm, VS, hydrocephalus, premature bleeding and complications of various kinds were selected as the dependent variables. The contributions of these factors to outcome (Glasgow Outcome Scale, GOS) as well as VS were analyzed using the logistic regression method. Outcome was better in WFNS grade I (p=0.039), and VS occurred less often and responded well to various interventional techniques and drug delivery. No significant variables contributed to the poor outcome or VS in WFNS grade I. In WFNS grade II, logistic regression analysis showed that VS (OR 34.6, 95% CI, 30.8-38.9, p =0.012) and the complications (OR 52.4, 95% CI, 46.5-59.1, p=0.004) were significant predictors for a poor outcome. Fisher's group 3 was also the only significant factors in VS (OR 3.78, 95% CI, 3.35-4.28, p =0.039). The cause for the difference in outcome and VS were discussed in detail. The vasospasm and various kinds of complications were the predictive factors of poor clinical outcome, in patient of WFNS garde II. Therefore, careful management and meticulous/pertinent surgical maneuvers are mandatory to obtain better results in aneurysmal SAH, even in better WFNS grades.


A 27-bp region of the inducible nitric oxide synthase promoter regulates expression in glial cells.
The expression of inducible nitric oxide synthase (NOS2) in glial cells is inhibited by neurotransmitters such as norepinephrine (NE) which elevate cAMP levels. We examined the molecular basis for this effect using a 2.2-kb fragment of the rat NOS2 promoter transfected into rat C6 glioma cells. Promoter activation (up to six-fold) by lipopolysaccharide (LPS) and interferon-gamma (IFNgamma) was reduced by NE, which alone had no effect. However, a promoter construct extending to bp -130 and containing the proximal nuclear factor-kappa B (NF-kappaB) binding site was minimally activated by LPS and cytokines, but activated up to three-fold by NE. Deletion analysis identified a 27-bp region (bp -187 to -160) as critical for mediating this suppressive effect. This region also enhanced promoter activation by LPS and cytokines, and prevented activation by NE alone. Gel shift analysis revealed constitutive binding to this region, and induction by NE of additional complexes which could be blocked by an antibody against CREB. NE also increased levels of the IkappaBalpha protein which could contribute to its suppressive effects. These results identify a critical role for this 27-bp region in regulation of NOS2 promoter activation and suppression by cAMP.


The transmission/disequilibrium test and parental-genotype reconstruction for X-chromosomal markers.
Family-based association methods have recently been introduced that allow testing for linkage in the presence of linkage disequilibrium between a marker and a disease even if there is only incomplete parental-marker information. No such tests are currently available for X-linked markers. This report fills this methodological gap by presenting the X-linked sibling transmission/disequilibrium test (XS-TDT) and the X-linked reconstruction-combination transmission/disequilibrium test (XRC-TDT). As do their autosomal counterparts (S-TDT and RC-TDT), these tests make no assumption about the mode of inheritance of the disease and the ascertainment of the sample. They protect against spurious association due to population stratification. The two tests were compared by simulations, which show that (1) the X-linked RC-TDT is, in general, considerably more powerful than the X-linked S-TDT and (2) the lack of parental-genotype information can be offset by the typing of a sufficient number of sibling controls. A freely available SAS implementation of these tests allows the calculation of exact P values.


Mycobacterial disease in cats in Great Britain: I. Culture results, geographical distribution and clinical presentation of 339 cases.
This study investigated 339 cases of feline mycobacterial disease from cats with cutaneous lesions or masses found at exploratory laparotomy. Tissue samples were submitted to the Veterinary Laboratories Agency for mycobacterial culture over a 4-year period to December 2008. The study assessed which species of culturable mycobacteria were involved, where the cats lived, and their clinical presentation (physical findings, serum biochemistry, radiography, feline leukaemia virus and feline immunodeficiency virus status). Mycobacterium microti was cultured from 19%, Mycobacterium bovis 15%, Mycobacterium avium 7%, non-M avium non-tuberculous mycobacteria 6%, with no growth in 53% of samples. M microti, M bovis and M avium were found in almost mutually exclusive clusters within Great Britain (GB) (ie, M bovis in South-West England/Wales/Welsh Border, M avium in eastern England and M microti south of London and in South-West Scotland). While differences were seen in the clinical presentation and distribution of lesions caused by the different infections, these were not sufficiently different to be diagnostic. Cats commonly presented with single or multiple cutaneous lesions (74%), which were sometimes ulcerated or discharging, located most frequently on the head (54%). Lymph nodes were usually involved (47%); typically the submandibular nodes. Systemic or pulmonary signs were rarely seen (10-16%). When a cat is suspected of having mycobacteriosis, accurate identification of the species involved helps to determine appropriate action. Our findings show that knowing the cat's geographic location can be helpful, while the nature of the clinical presentation is less useful. Most cases of feline mycobacterial disease in GB are cutaneous.


Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics.
A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 μM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 μM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 μM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF3-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC50 ranged from 1.4 to >10 µM and increased with increasing lipophilicity.


Generation and Reactions of an Octacyclic Hindered Pyramidalized Alkene.
Octacyclo[10.6.1.01,10.03,7.04,9.08,19.011,16.013,17]nonadeca-5,8,14-triene (27), a hindered pyramidalized alkene, has been generated from a diiodide precursor. Contrary to the usual behavior of known pyramidalized alkenes, no Diels-Alder adducts were obtained from the present alkene when it was generated by different standard procedures in the presence of different dienes. However, products derived from the reduction, t-BuLi addition, condensation with the solvent, or dimerization were isolated from these reactions, depending on the conditions used to generate it. No [2 + 2] cross product among this pyramidalized alkene and tricyclo[3.3.1.03,7]non-3(7)-ene was formed when a mixture of the corresponding precursor diiodides was reacted with sodium amalgam. The analysis of selected geometrical and orbital parameters determined from quantum mechanical calculations indicates that the degree of pyramidalization of this alkene and its higher steric hindrance compared with other polycyclic pyramidalized alkenes may explain its peculiar reactivity.


Distinct contributions of the amygdala and hippocampus to fear expression.
The present study attempted to distinguish the independent contributions of the amygdala and hippocampus to fear expression. Rhesus monkeys (Macaca mulatta) with bilateral excitotoxic amygdala lesions (n = 4), bilateral excitotoxic hippocampal lesions (n = 8) and unoperated controls (n = 9) were allowed to reach over a neutral junk object or fear-provoking stimulus (i.e., a rubber snake or a jumping rubber spider) to retrieve a food reward. Monkeys were exposed to each stimulus for 30 s. On each trial we recorded the monkey's latency to retrieve the food reward and scored their whole-body reactions to the object. Confirming previous work we found that, relative to controls, both operated groups showed shorter food-retrieval latencies and exhibited fewer defensive and more approach behaviors when exposed to the fear-provoking stimuli. However, only monkeys with amygdala lesions showed an abnormal, excessive visual interest in the snake and spider. By contrast, monkeys with hippocampal lesions displayed behaviors that were unrelated to the presence of the fear stimuli, thereby indicating a lack of interest in, and emotional reactivity towards, the snake and spider. These data show that the hippocampus and amygdala contribute independently to the overall expression of defensive responses.


Introduction: the Traumatic Brain Injury Model Systems of Care.
The Traumatic Brain Injury Model Systems of Care (TBIMS) is a program that has been funded by the National Institute on Disability and Rehabilitation Research (US Department of Education) since 1987. The program is a collaborative effort of rehabilitation centers across the United States to further knowledge about the natural history of recovery and outcomes over the life course of individuals with traumatic brain injury, as well as to provide comprehensive services across the continuum of care and to foster innovative research programs. This introduction describes the underlying principles of the TBIMS program and the research initiatives carried out in the 1997/1998-2002 funding cycle.


Nitrophenylboronic acids as highly chemoselective probes to detect hydrogen peroxide in foods and agricultural products.
Hydrogen peroxide is commonly used in the food processing industry as a chlorine-free bleaching and sterilizing agent, but excessive amounts of residual hydrogen peroxide have led to cases of food poisoning. Here we describe the development of a novel nonenzymatic colorimetric method for the determination of residual hydrogen peroxide in foods and agricultural products. Nitrophenylboronic acids chemoselectively react with hydrogen peroxide under alkaline conditions to produce yellow nitrophenolates. Of the three nitrophenylboronic acid isomers tested, the p-isomer displayed the highest sensitivity for hydrogen peroxide and the fastest reaction kinetics. The reaction product, p-nitrophenolate, has an absorption maximum at 405 nm and a good linear correlation between the hydrogen peroxide concentration and the A(405) values was obtained. We successfully applied this convenient and rapid method for hydrogen peroxide determination to samples of dried bean curds and disposable chopsticks, thereby demonstrating its potential in foods and agricultural industries.


Structure and decomposition energies of high-energy open-chain carbon-nitrogen compounds N(x)C(2).
Molecules and ions consisting entirely or predominantly of nitrogen are of interest because of their energy release properties. Such molecules can decompose into N(2), a process that is very exothermic. Following a study predicting the stability properties of isomers of open-chain N(4)C(2), the current study involves calculations on a series of open-chain carbon-nitrogen molecules. Molecules with the general formulas N(x)C(2) are studied to determine their structure and bonding, as well as their energy release capabilities. Theoretical calculations are carried out on this series of molecules to determine geometries and heats of formation. The MP2 method is used for geometry optimizations and vibrational frequencies, with single energies calculated with coupled-cluster theory (CCSD(T)). Energetic and structural trends are calculated and discussed.


Level of Knowledge, Attitude, and Practice of Pregnant Women on Antenatal Care in Amatere Health Center, Massawa, Eritrea: A Cross-Sectional Study, 2019.
Proper antenatal care is one of great means of reducing maternal and child morbidity and mortality. However, determining level of knowledge and practice is vital, and the objective of this study was to evaluate this gap among pregnant women in Amatere Health Center, Massawa city, Eritrea, 2019. A cross-sectional study with systematic sampling was conducted. All pregnant mothers who were resident of Massawa city and visiting Amatere Health Center for their current pregnancy were included in the study. An interviewer-administered structured questionnaire was used as data collection tool. Results were presented using descriptive statistics, percent, and frequencies. A total of 289 pregnant mothers were enrolled in the study with a mean age of 27.7 years. Most mothers reported that high blood pressure (92.4%), maternal smoking (97.6%), alcohol consumption (97.2%), infection (92.7%), and medicines (98.3%) had affected fetal growth during pregnancy. Practically, two-thirds (59.4%) of the mothers were visiting the health facility during the first three months of their pregnancy. Majority of mothers had good knowledge (84.1%) and attitude (99%), but they had low level of practice (45%). Marital status, occupation, gravidity, and parity had showed statistically significant association to their comprehensive knowledge (p < 0.001). And their gravidity (p < 0.003) and parity (p < 0.001) had also showed statistically significant association to their level of practice. Even though majority of the pregnant mothers had high level of knowledge and attitude, their practice towards ANC was relatively low. Age, marital status, and occupation showed statistically significant association to their comprehensive knowledge. Moreover, multiparous and multigravida mothers were having higher level of knowledge and practice on antenatal care. Enhancing community awareness on early starting of antenatal care and improving their practice through proper counseling are highly recommended.


Living Fungi in an Opencast Limestone Mine: Who Are They and What Can They Do?
Opencast limestone mines or limestone quarries are considered challenging ecosystems for soil fungi as they are highly degraded land with specific conditions, including high temperature, prolonged sunlight exposure, and a lack of organic matter, moisture, and nutrients in soil. In such ecosystems, certain fungi can survive and have a crucial function in maintaining soil ecosystem functions. Unfortunately, we know very little about taxonomic diversity, potential functions, and the ecology of such fungi, especially for a limestone quarry in a tropical region. Here, we characterized and compared the living soil fungal communities in an opencast limestone mine, including mining site and its associated rehabilitation site (9 months post-rehabilitation), with the soil fungal community in a reference forest, using the amplicon sequencing of enrichment culture. Our results showed that living fungal richness in the quarry areas was significantly lower than that in the reference forest, and their community compositions were also significantly different. Living fungi in the mining sites mostly comprised of Ascomycota (Eurotiomycetes and Sordariomycetes) with strongly declined abundance or absence of Basidiomycota and Mucoromycota. After nine months of rehabilitation, certain taxa were introduced, such as Hypoxylon spp. and Phellinus noxius, though this change did not significantly differentiate fungal community composition between the mining and rehabilitation plots. The majority of fungi in these plots are classified as saprotrophs, which potentially produce all fifteen soil enzymes used as soil health indicators. Network analysis, which was analyzed to show insight into complex structures of living fungal community in the limestone quarry, showed a clear modular structure that was significantly impacted by different soil properties. Furthermore, this study suggests potential taxa that could be useful for future rehabilitation.


Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.
The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia. In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs). A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: -0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met. Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.


Oral Toxicokinetics, Tissue Distribution, and 28-Day Oral Toxicity of Two Differently Manufactured Food Additive Silicon Dioxides.
(1) Background: Synthetic amorphous silica (SAS) is widely used as a food additive and contains nano-sized particles. SAS can be produced by fumed and precipitated methods, which may possess different physiochemical properties, toxicokinetics, and oral toxicity. (2) Methods: The toxicokinetics of fumed SAS and precipitated SAS were evaluated following a single-dose oral administration in rats. The tissue distribution and fate of both SAS particles were assessed after repeated oral administration in rats for 28 d, followed by recovery period for 90 d. Their 28-d repeated oral toxicity was also evaluated. (3) Results: Precipitated SAS showed higher oral absorption than fumed SAS, but the oral absorption of both SAS particles was low (<4%), even at 2000 mg/kg. Our tissue-distribution study revealed that both SAS particles, at a high dose (2000 mg/kg), were accumulated in the liver after repeated administration for 28 d, but the increased concentrations returned to normal levels at 29 d, the first day of the recovery period. A higher distribution level of precipitated SAS than fumed SAS and decomposed particle fates of both SAS particles were found in the liver at 28 d. No significant toxicological findings were observed after 28-d oral administration, suggesting their low oral toxicity. (4) Conclusions: Different manufacturing methods of SAS can, therefore, affect its oral toxicokinetics and tissue distribution, but not oral toxicity.


Validity of the lagged normal density function as a model for pulmonary indicator dispersion.
The aim of this study was to investigate whether the lagged normal density function is a useful model for the dispersion of intravascular and diffusible indicators in the lungs. In 18 mongrel dogs anesthetized with N2O-piritramide, 221 sets of thermal-indocyanine green dye kinetics were recorded in the pulmonary artery and in the aorta after central venous indicator injection. A model-free deconvolution technique was used to compute the pulmonary transport functions for dye and heart from the measured indicator kinetics (reference method). The lagged normal density function was used to model pulmonary indicator transport. Its parameters were computed by a nonlinear least-squares procedure by iterative convolution. After baseline measurements in nine dogs, pulmonary edema was induced by central venous application of oleic acid. In nine other dogs, measurements were performed before and after postural changes from the horizontal to the vertical position. The mean transit times derived from the lagged normal density function were in good agreement with those obtained after model-free deconvolution. Although the shape (relative dispersion, skewness) of the transport function is less well described by the model, the authors conclude that the lagged normal density function is useful to determine indicator volumes of distribution that require only the correct mean transit times.


Herpes Simplex Virus Type 2 Mucin-Like Glycoprotein mgG Promotes Virus Release from the Surface of Infected Cells.
The contribution of virus components to liberation of herpes simplex virus type 2 (HSV-2) progeny virions from the surface of infected cells is poorly understood. We report that the HSV-2 mutant deficient in the expression of a mucin-like membrane-associated glycoprotein G (mgG) exhibited defect in the release of progeny virions from infected cells manifested by ~2 orders of magnitude decreased amount of infectious virus in a culture medium as compared to native HSV-2. Electron microscopy revealed that the mgG deficient virions were produced in infected cells and present at the cell surface. These virions could be forcibly liberated to a nearly native HSV-2 level by the treatment of cells with glycosaminoglycan (GAG)-mimicking oligosaccharides. Comparative assessment of the interaction of mutant and native virions with surface-immobilized chondroitin sulfate GAG chains revealed that while the mutant virions associated with GAGs ~fourfold more extensively, the lateral mobility of bound virions was much poorer than that of native virions. These data indicate that the mgG of HSV-2 balances the virus interaction with GAG chains, a feature critical to prevent trapping of the progeny virions at the surface of infected cells.


6-Mercaptopurine-induced potentiation of active immunotherapy in L1210-bearing mice treated with concanavalin A-bound leukemia cell vaccine.
While the combination of L1210 murine leukemia cell vaccine (L1210 vaccine) with 6-mercaptopurine (6-MP) or 6-thioguanine produces a therapeutic response greater than that induced by either of these agents alone, its combination with cyclophosphamide, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, or 5-fluorouracil does not produce such a response. The administration of cyclophosphamide, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, or 5-fluorouracil alone resulted in a response as great as, or greater than, that induced by 6-MP alone. This and the finding that the 6-MP-induced response was more pronounced upon its delayed rather than its early administration indicate that 6-MP-induced reduction of the tumor burden does not explain this augmentation. The combination of 6-MP and L1210 vaccine was not effective in mice bearing 6-MP-resistant L1210 leukemia; however, an augmented response occurred when the tumor burden was reduced by N4-behenoyl-1-beta-D-arabinofuranosylcytosine, indicating that reduction of the tumor burden by 6-MP was only partially associated with augmentation of the therapeutic response. Augmentation was associated with vaccine-induced antitumor immunity because it was induced by the combination of 6-MP and concanavalin A-bound, but not concanavalin A-free L1210 vaccine. This augmentation was dependent on the timing of the L1210 vaccine administration. The combination was not effective in mice bearing P388 leukemia, indicating the tumor specificity of the augmentation. These results show that 6-MP not only reduced the tumor burden but also potentiated the vaccine-dependent antitumor immunity, resulting in the induction of an augmented therapeutic response.


The road to the first, fully active and more stable human insulin variant with an additional disulfide bond.
Insulin, a small peptide hormone, is crucial in maintaining blood glucose homeostasis. The stability and activity of the protein is directed by an intricate system involving disulfide bonds to stabilize the active monomeric species and by their non-covalent oligomerization. All known insulin variants in vertebrates consist of two peptide chains and have six cysteine residues, which form three disulfide bonds, two of them link the two chains and a third is an intra-chain bond in the A-chain. This classical insulin fold appears to have been conserved over half a billion years of evolution. We addressed the question whether a human insulin variant with four disulfide bonds could exist and be fully functional. In this review, we give an overview of the road to engineering four-disulfide bonded insulin analogs. During our journey, we discovered several active four disulfide bonded insulin analogs with markedly improved stability and gained insights into the instability of analogs with seven cysteine residues, importance of dimerization for stability, insulin fibril formation process, and the conformation of insulin binding to its receptor. Our results also open the way for new strategies in the development of insulin biopharmaceuticals.


Indatraline: synthesis and effect on the motor activity of Wistar rats.
A new approach for the synthesis of indatraline was developed using as the key step an iodine(III)-mediated ring contraction of a 1,2-dihydronaphthalene derivative. Behavioral tests were conducted to evaluate the effect of indatraline and of its precursor indanamide on the motor activity of Wistar rats. Specific indexes for ambulation, raising and stereotypy were computed one, two and three hours after i.p. drug administration. Indatraline effects on motor activity lasted for at least three hours. On the other hand, no significant differences in motor activity were observed using indanamide. The results suggest that indatraline has a long lasting effect on motor activity and add evidence in favor of the potential use of that compound as a substitute in cocaine addiction.


[Application of the HLA system to forensic medicine--from serology to DNA polymorphism].
HLA antigens are highly polymorphic and therefore considered useful for personal identification in forensic medicine. The HLA system was first applied to forensic medicine for serological typing and is currently being applied to DNA typing. We first applied the HLA system to serological typing for paternity testing. Exclusion of paternity was confirmed in 39 of 93 cases. While serological HLA typing and other testing yielded consistent results in 37 of these 39 cases, exclusion of paternity could be confirmed only by serological HLA typing in 1 case and only by other testing in 1 case. Even in cases where exclusion could not be confirmed, it was possible to increase the probability of paternity. Bloodstains with known HLA types were then subjected to lymphocytotoxic inhibition tests to detect HLA antigens using one of the following methods: a two-stage method using an antibody and a bloodstain extract; a one-stage method where a bloodstain was allowed to react directly with an antiserum; or a washing method where washing was combined with one of the two above methods. Although HLA antigen detection was possible using any of these methods, some antisera yielded false-positive reactions, which limited the range of usable antisera. With the exception of cross-reactions, the washing method eliminated false-positive reactions. Antigens were detectable in bloodstains that were left to stand for up to 42 days. DNA typing based on the HLA system was investigated by determining DR and DQB1 types using the Hot Start PCR-SSP method with various samples of known HLA types and tissue samples collected from unidentified corpses. With bloodstains, DR typing was possible in all 61 cases, while DQB1 typing was possible in 31 of 33 cases. DR typing was possible even when bloodstains had been stored for 10 to 20 years. With saliva stains, typing was possible in all cases by purifying DNA using a Microcon 100 microconcentrator. With hair samples, typing was possible with all hair root samples and about half of hair shaft samples. With mixed stains, the detection of minor components was possible even at a low mixing ratio of 10:1. With cigarette butts, as was the case with saliva stains, typing was possible using purified DNA. Lipstick did not affect the results of DNA typing. Although DNA typing was possible in many cases using tissue samples collected from unidentified corpses, the results were affected by factors such as status of corpse, postmortem interval, postmortem change and tissue type. With some aorta samples, for example, typing was possible up to one year after death. The results of typing were also fairly favorable using bone samples.


Monitoring collaborative practice guideline access: initial steps to define effect on patient outcomes.
Over the past decade Intermountain Healthcare (Intermountain) developed the Collaborative Practice Guidelines (CPGs) as an e resource to direct bedside care delivery. The intent was to decrease care variability and improve patient outcomes. The CPGs provide pertinent clinical knowledge at the point of care. Intermountain clinicians are responsible to deliver care based on the best level of evidence available as reflected in the CPGs. Data regarding access was requested by Intermountain leaders to begin answering the question whether the CPGs have any effect on improving patient outcomes.


Structured visualization of expert nursing--An educational program for stoma self-care.
To provide an adequate educational program for patients with a stoma, we have developed an algorithm which was divided into three parts according to the period, i.e., the preoperative period, postoperative period, and rehabilitation period. It was composed of action nodes, thinking nodes, choice branches, assessment item tables, reference tables, and candidate logic tables. Wound Ostomy Continence Nurses (WOCNs) used this algorithm. The results indicated that the algorithm did not omit any important points involved in stoma care, and that it could therefore be successfully applied to patients with a stoma.


The Effect of Lower Body Anaerobic Pre-Loading on Upper Body Ergometer Time Trial Performance.
Pre-competitive conditioning has become a substantial part of successful performance. In addition to temperature changes, a metabolic conditioning can have a significant effect on the outcome, although the right dosage of such a method remains unclear. The main goal of the investigation was to measure how a lower body high-intensity anaerobic cycling pre-load exercise (HIE) of 25 s affects cardiorespiratory and metabolic responses in subsequent upper body performance. Thirteen well-trained college-level male cross-country skiers (18.1 ± 2.9 years; 70.8 ± 7.6 kg; 180.6 ± 4.7 cm; 15.5 ± 3.5% body fat) participated in the study. The athletes performed a 1000-m maximal double-poling upper body ergometer time trial performance test (TT) twice. One TT was preceded by a conventional low intensity warm-up (TTlow) while additional HIE cycling was performed 9 min before the other TT (TThigh). Maximal double-poling performance after the TTlow (225.1 ± 17.6 s) was similar (p > 0.05) to the TThigh (226.1 ± 15.7 s). Net blood lactate (La) increase (delta from end of TT minus start) from the start to the end of the TTlow was 10.5 ± 2.2 mmol L-1 and 6.5 ± 3.4 mmol L-1 in TThigh (p < 0.05). La net changes during recovery were similar for both protocols, remaining 13.5% higher in TThigh group even 6 min after the maximal test. VCO2 was lower (p < 0.05) during the last 400-m split in TThigh, however during the other splits no differences were found (p < 0.05). Respiratory exchange ratio (RER) was significantly lower in TThigh in the third, fourth and the fifth 200 m split. Participants individual pacing strategies showed high relation (p < 0.05) between slower start and faster performance. In conclusion, anaerobic metabolic pre-conditioning leg exercise significantly reduced net-La increase, but all-out upper body performance was similar in both conditions. The pre-conditioning method may have some potential but needs to be combined with a pacing strategy different from the usual warm-up procedure.


Stereospecific Formation of E- and Z-Disubstituted Double Bonds by Dehydratase Domains from Modules 1 and 2 of the Fostriecin Polyketide Synthase.
The dehydratase domain FosDH1 from module 1 of the fostriecin polyketide synthase (PKS) catalyzed the stereospecific interconversion of (3R)-3-hydroxybutyryl-FosACP1 (5) and (E)-2-butenoyl-FosACP1 (11), as established by a combination of direct LC-MS/MS and chiral GC-MS. FosDH1 did not act on either (3S)-3-hydroxybutyryl-FosACP1 (6) or (Z)-2-butenoyl-FosACP1 (12). FosKR2, the ketoreductase from module 2 of the fostriecin PKS that normally provides the natural substrate for FosDH2, was shown to catalyze the NADPH-dependent stereospecific reduction of 3-ketobutyryl-FosACP2 (23) to (3S)-3-hydroxybutyryl-FosACP2 (8). Consistent with this finding, FosDH2 catalyzed the interconversion of the corresponding triketide substrates (3R,4E)-3-hydroxy-4-hexenoyl-FosACP2 (18) and (2Z,4E)-2,4-hexadienoyl-FosACP2 (21). FosDH2 also catalyzed the stereospecific hydration of (Z)-2-butenoyl-FosACP2 (14) to (3S)-3-hydroxybutyryl-FosACP2 (8). Although incubation of FosDH2 with (3S)-3-hydroxybutyryl-FosACP2 (8) did not result in detectable accumulation of (Z)-2-butenoyl-FosACP2 (14), FosDH2 catalyzed the slow exchange of the 3-hydroxy group of 8 with [18O]-water. FosDH2 unexpectedly could also support the stereospecific interconversion of (3R)-3-hydroxybutyryl-FosACP2 (7) and (E)-2-butenoyl-FosACP2 (13).


[A comparison of propofol and midazolam in sedation of mechanically-ventilated postoperative patients].
To compare the quality of sedation using propofol (n = 8) vs midazolam (n = 7) we evaluated their effectiveness, safety, and recovery time after their continuous infusion in patients who required mechanical ventilation after cervical spine surgery. We also calculated the cost of drugs used during the mechanical ventilation. In addition, processed electroencephalogram (pEEG) was monitored employing spectral edge frequency 90 (SEF 90) as an indicator of sedation. Both drugs produced good sedation without any complication. The patients who had received propofol were extubated significantly earlier than those who had received midazolam (P; 35 +/- 18 mins, M; 97 +/- 55 mins). However, the mean drug cost in the propofol group was five times higher than that in the midazolam group (P; yen 15,881 +/- 7,788, M; yen 3,355 +/- 1,187). There was no correlation between the value of SEF 90 and the depth of sedation during mechanical ventilation. In conclusion, propofol exhibited the shorter recovery time after cessation of the continuous infusion than midazolam, but it costed five times compared with midazolam. SEF 90 failed to indicate the depth of sedation during mechanical ventilation.


[High-frequency pressure ventilation with high positive end-expiratory pressure in the treatment of respiratory failure in neonates].
The authors present results of group of 13 neonates treated with high frequency positive pressure ventilation (HFPPV) with high positive end-expiratory pressure (PEEP) for severe respiratory failure. The ventilatory protocol was based on the following principles: a) higher mean airway pressure (MAP) to achieve adequate oxygenation, b) MAP titrated mainly with PEEP, c) fraction of inspired oxygen (FiO2) below 0.6, d) small tidal volumes 3-6 ml/kg, e) ventilatory rates to achieve normocapnia in newborns with persistent pulmonary hypertension and to allow permissive hypercapnia in others. During HFPPV, the maximum values for respiratory rate, PEEP, MAP and peak inspiratory pressures (PIP), the incidence of airleak and the need for inotropic support were recorded. The values for arterial partial pressure of oxygen (paO2), FiO2, paO2/FiO2 and MAP during conventional ventilation and 30 minutes after initiation of HFPPV were statistically analyzed. paO2 increased from 8.0 kPa (3.3-10.4) to 11.8 kPa (7.3-16.2, p < 0.001) and paO2 (torr)/FiO2 increased from 62.2 (24.7-101.2) to 157.5 (62.2-275.2, p < 0.001) 30 minutes after institution of HFPPV when MAP was increased from 11.8 cmH2O (9-13.8,) to 17.2 H2O (14.8-22.2) p < 0.001. This allowed turning down FiO2 from 1 (0.6-1) to 0.6 (0.4-1 p < 0.001). Maximal ventilatory rates used were in average 60/min (50-105), PEEP 8 cmH2O (6-10), PIP 30 cmH2O (26-45), MAP 18.8 cmH2O (14.8-22.2). Air leak did not occur in any patient. Catecholamines were used in 8 patients. The duration of ventilatory support lasted in average 6 days (2-18). All patients were successfully extubated. 5 of them required nasal continuous positive airway pressure (14 hours--7 days). (Tab. 3, Fig. 3, Ref. 19.)


Spanish-language measures of mania and depression.
Efforts to better understand bipolar spectrum disorders across ethnic groups are often hampered by the lack of commonly used self-report instruments to assess mania and depression in individuals who speak languages other than English. This article describes the translation into Spanish of 2 self-report measures of manic symptoms (i.e., the Internal State Scale and the Hypomanic Personality Scale) and 2 self-report measures of depression (i.e., the Inventory to Diagnose Depression and the Inventory to Diagnose Depression, Lifetime version). The authors translated these measures into Spanish and assessed their psychometric properties among bilingual college students (N = 88). Results suggest that the Spanish versions have psychometric properties comparable to the English versions of the instruments.


[Study of CO2 spectroscopic parameters at high temperature near 1.57 microm].
Measurements strategies based on absorption spectroscopy techniques, especially the measurements in high temperature, require accurate values of important spectroscopic parameters of the probed species. Sometimes the parameters listed in widely used HITRAN and HITEMP2004 database are uncertain to some extent. In order to validate the spectroscopic parameters of 9 selected CO2 lines which should be used in combustion diagnosis, spectra of those lines were recorded in a high temperature experiment setup as a function of temperature (in the range of 300-800 K) and pressure (in the range of 9-450 torr) using a distributed feed-back (DFB) diode laser. The recorded absorption spectra were fitted to Voigt profile. Line intensity, air-broadening coefficient and temperature exponent of each line were deduced from those data. Through comparison of experimental results and those listed in HITRAN and HITEMP2004 database, the discrepancies of most line intensities, air-broadening coefficients and their temperature exponents are less than 3%, 5% and 2% respectively. Those results show good consistency between the experimental data and that in HITRAN and HITEMP2004 database. The discrepancy in line intensities may be caused by the fitting of absorption spectra, the reading of thermocouple and pressure gage, uniformity of temperature in the heated cell, and uncertainty of the optical path. Those factors also cause the discrepancy in air-broadening coefficients and their temperature exponent. CO2 contained in air also introduces error in air-broadening coefficients and their temperature exponent beside those factors. Though we have deducted them in data-processing, the little change of CO2 in partial region also exists. Those results will be helpful to the measurement of CO2 concentration in combustion diagnosis in the future.


Multifunctional porous graphene for nanoelectronics and hydrogen storage: new properties revealed by first principle calculations.
The lack of an obvious "band gap" is a formidable hurdle for making a nanotransistor from graphene. Here, we use density functional calculations to demonstrate for the first time that porosity such as evidenced in recently synthesized porous graphene ( http://www.sciencedaily.com/releases/2009/11/091120084337.htm ) opens a band gap. The size of the band gap (3.2 eV) is comparable to most popular photocatalytic titania and graphitic C(3)N(4) materials. In addition, the adsorption of hydrogen on Li-decorated porous graphene is much stronger than that in regular Li-doped graphene due to the natural separation of Li cations, leading to a potential hydrogen storage gravimetric capacity of 12 wt %. In light of the most recent experimental progress on controlled synthesis, these results uncover new potential for the practical application of porous graphene in nanoelectronics and clean energy.


Mevalonate kinase deficiency: a survey of 50 patients.
The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD). This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations. Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients. MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.


LC-MS guided isolation of phenolic glycosides from Viburnum luzonicum Rolfe leaves and their α‑amylase and α-glucosidase inhibitory activities.
Viburnum luzonicum Rolfe is widely used in China as folk medicine. The bioactivity evaluation indicated that the n-BuOH fraction of V. luzonicum leaves (VLLB) could significantly inhibit α‑amylase and α-glucosidase. In order to clarify its active constituents, the phytochemical analysis on VLLB was first performed using HPLC-QTOF-MS/MS, and three new phenolic compounds, viburosides A-C (1-3), along with seven known analogues (4-10) were isolated through preparative HPLC. The undescribed compounds were determined by extensive spectroscopic analyses (1H and 13C NMR, HSQC, HMBC, HRESIMS, and ORD) and enzymatic hydrolysis. In the in vitro enzyme assays, compounds 1-8 showed potent α‑amylase and α-glucosidase inhibitory activities. The enzymatic kinetics and molecular docking of the strongest inhibitors 2 and 3 against the corresponding target enzyme were also performed.


Multiswarm comprehensive learning particle swarm optimization for solving multiobjective optimization problems.
Comprehensive learning particle swarm optimization (CLPSO) is a powerful state-of-the-art single-objective metaheuristic. Extending from CLPSO, this paper proposes multiswarm CLPSO (MSCLPSO) for multiobjective optimization. MSCLPSO involves multiple swarms, with each swarm associated with a separate original objective. Each particle's personal best position is determined just according to the corresponding single objective. Elitists are stored externally. MSCLPSO differs from existing multiobjective particle swarm optimizers in three aspects. First, each swarm focuses on optimizing the associated objective using CLPSO, without learning from the elitists or any other swarm. Second, mutation is applied to the elitists and the mutation strategy appropriately exploits the personal best positions and elitists. Third, a modified differential evolution (DE) strategy is applied to some extreme and least crowded elitists. The DE strategy updates an elitist based on the differences of the elitists. The personal best positions carry useful information about the Pareto set, and the mutation and DE strategies help MSCLPSO discover the true Pareto front. Experiments conducted on various benchmark problems demonstrate that MSCLPSO can find nondominated solutions distributed reasonably over the true Pareto front in a single run.


Familial Risk of Gout and Interaction With Obesity and Alcohol Consumption: A Population-Based Cohort Study in Korea.
Population-based studies of the familial aggregation of gout are scarce, and gene/environment interactions are not well studied. This study was undertaken to evaluate the familial aggregation of gout as well as assess interactions between family history and obesity or alcohol consumption on the development of gout. Using the Korean National Health Insurance database, which includes information regarding familial relationships and risk factor data, we identified 5,524,403 individuals from 2002 to 2018. Familial risk was calculated using hazard ratios (HRs) with 95% confidence intervals (95% CIs) to compare the risk in individuals with and those without affected first-degree relatives. Interactions between family history and obesity/alcohol consumption were assessed on an additive scale using the relative excess risk due to interaction (RERI). Individuals with a gout-affected first-degree relative had a 2.42-fold (95% CI 2.39, 2.46) increased risk of disease compared to those with unaffected first-degree relatives. Having both a family history of gout and being either overweight or having moderate alcohol consumption was associated with a markedly increased risk of disease, with HRs of 4.39 (95% CI 4.29, 4.49) and 2.28 (95% CI 2.22, 2.35), respectively, which exceeded the sum of their individual risks but was only statistically significant in overweight individuals (RERI 0.96 [95% CI 0.85, 1.06]). Obese individuals (RERI 1.88 [95% CI 1.61, 2.16]) and heavy drinkers (RERI 0.36 [95% CI 0.20, 0.52]) had a more prominent interaction compared to overweight individuals and moderate drinkers, suggesting a dose-response interaction pattern. Our findings indicate the possibility of an interaction between gout-associated genetic factors and obesity/alcohol consumption.


Autologous stem cell transplantation in treatment of aggressive non-Hodgkin's lymphoma.
There is no doubt that autologous stem cell transplantation is useful for patients with relapsed aggressive non-Hodgkin s lymphoma if they are responsive to the chemotherapy given before the transplantation. A small subset of patients with primary refractory disease still profits from this high dose chemotherapy regimen, but only if chemosensitive and if presenting with favorable risk factors at the moment of transplant eligibility. Autologous stem cell transplantation as upfront first line therapy for patients with aggressive non-Hodgkin s lymphoma does not contribute to a better outcome, most certainly not if it concerns patients with a favorable risk profile. There is still some doubt whether there is any place for autologous stem cell transplantation as first line therapy for patients with an unfavorable risk profile. Most randomized studies do not show an advantage, but more data are needed to definitely assess the place for this therapy option.


Instance theory predicts information theory: Episodic uncertainty as a determinant of keystroke dynamics.
How does prior experience shape skilled performance in structured environments? We use skilled typing of natural text to evaluate correspondence between performance (keystroke timing) and structure in the environment (letter uncertainty). We had ∼350 typists copy-type English text. We reproduced Ostry's (1983) analysis of interkeystroke interval as a function of letter position and word length, that showed prominent first-letter and midword slowing effects. We propose a novel account that letter position and word length effects on keystroke dynamics reflect informational uncertainty about letters in those locations, rather than resource limited planning/buffering processes. We computed positional uncertainty for letters in all positions of words from length one to nine using Google's n-gram database. We show that variance in interkeystroke interval by letter position and word length tracks natural variation in letter uncertainty. Finally, we provide a model showing how a general learning and memory process could acquire sensitivity to patterns of letter uncertainty in natural English. In doing so, we draw an equivalence between Logan's (1988) instance theory of automatization and Shannon's measure of entropy (H) from information theory. Instance theory's predictions for automatization as a function of experience follow exactly the uncertainty in the choice set being automatized. As a result, instance theory stands as a general process model explaining how context-specific experiences in a structured environment tune skilled performance. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Fatigue and depression in children with multiple sclerosis and monophasic variants.
Fatigue is an important symptom in adult multiple sclerosis (MS) and it is likely to occur in children with MS. It is currently unknown whether children who experienced a monophasic inflammatory demyelinating event of the central nervous system in the past also suffer from fatigue. We studied the presence and severity of fatigue in 32 children (18 boys, 14 girls) between 11-17 years old (mean: 14 years, 10 months) with a monophasic inflammatory demyelinating disease (n=22) or definite MS (n=10). This was measured with the Checklist Individual Strength. A score of >or=40 on the severity of fatigue subscale indicated the presence of severe fatigue. We also examined the relation between fatigue and depression (assessed by the Child Depression Inventory). Additionally we measured the health-related quality of life (HRQoL), using the TNO-AZL Child Quality of Life child form. We compared the scores of the MS and monophasic patients with the scores of healthy Dutch children. The highest scores on the fatigue scales subjective fatigue and physical activity were found in the children with MS. Only 1 of the monophasic patients suffered from severe fatigue in contrast to 4 of the MS patients. In the MS group fatigue and depression were correlated. MS patients experienced a lower HRQoL on the scales locomotor functioning, cognitive functioning and interaction with peers. The occurrence of fatigue is very rare after a monophasic inflammatory demyelinating event in the past. As expected, fatigue occurs more frequent in paediatric MS patients.


Theory of damped quantum rotation in NMR spectra. I. Fundamental aspects.
The damped quantum rotation (DQR) theory, formulated originally for methyl-like atomic groupings, is now extended to hindered (N>3)-fold molecular rotors, such as the cyclopentadienyl, benzene, and cycloheptatrienyl rings in solid phase environments. It heightens the significance of the Pauli principle in shaping up the stochastic dynamics of such objects, reflected in NMR line shapes. The corresponding NMR line-shape equation is derived; its stochastic part is shown for the first time to have the double commutator form for any values of the quantum-mechanical (coherence-damping) rate constants entering it. Constraints on the relative magnitudes of such constants are determined under which the DQR line-shape equation is converted into the phenomenological Alexander-Binsch equation describing classical jumps of the rotor. When all the quantum rate constants happen to be equal, the phenomenological model of equal jump rates between any two of the N (equivalent) orientations of the rotor is reproduced. On the other hand, the seemingly most plausible (for N>3) nearest-neighbor hopping model does not have any peculiar grounds in the DQR approach. For the special instances of stochastic molecular motions addressed in this work, the extended DQR formalism affords a quantification of the "degree of classicality" represented by a complete set of the relevant quantum rate constants. In view of our earlier experimental findings for the methyl rotors, the very occurrence of the nonclassical DQR effects seems unquestionable even for the objects of the size of benzene. The question of under what circumstances such effects can be big enough to be detected experimentally will be addressed in Part II of this work.


Cytotoxic Effects on HL-60 Cells of Myosin Light Chain Kinase Inhibitor ML-7 Alone and in Combination with Flavonoids.
Uncontrolled cell growth and increased cell proliferation are major features of cancer that are dependent on the stable structure and dynamics of the cytoskeleton. Since stable cytoskeleton structure and dynamics are partly regulated by myosin light chain kinase (MLCK), many current studies focused on MLCK inhibition as a chemotherapeutic target. As a potent and selective MLCK inhibitor, ML-7 [1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazapine hydrochloride] is a promising candidate for an anticancer agent, which would induce apoptosis as well as prevents invasion and metastasis in certain types of cancer cells. This study assessed cytotoxic effects of ML-7 against HL-60 cells and therapeutic efficacy of ML-7 as a potential antileukemia agent. Trypan-blue exclusion assays showed dose- and time- dependent decreases in ML-7 treated HL-60 cells (p < 0.05). Comet assays revealed a significant increase in DNA damage in HL-60 cells after treatment with 40 µM ML-7 for 2 h. Sub-G1 fractions, analyzed by flow cytometry increased in a dose-dependent manner, suggesting that ML-7 can induce apoptotic cell death in HL-60 cells. ML-7 was selectively cytotoxic towards HL-60 cells; not affecting normal human lymphocytes. That selective effect makes it a promising potential anti-leukemia agent. In addition, anticancer efficacy of ML-7 in combination with flavonoids (genistein or quercetin) or anticancer drugs (cisplatin or AraC) against HL-60 cells was assessed. Combination of ML-7 with flavonoids increased the anticancer effect of ML-7 to a greater extent than combination with the anticancer drugs. This implies that ML-7 in combination with flavonoids could increase the efficacy of anticancer treatment, while avoiding side effects cansed by conventional anticancer drug-containing combination chemotherapy.


Hot Electrons in TiO2-Noble Metal Nano-Heterojunctions: Fundamental Science and Applications in Photocatalysis.
Plasmonic photocatalysis enables innovation by harnessing photonic energy across a broad swathe of the solar spectrum to drive chemical reactions. This review provides a comprehensive summary of the latest developments and issues for advanced research in plasmonic hot electron driven photocatalytic technologies focusing on TiO2-noble metal nanoparticle heterojunctions. In-depth discussions on fundamental hot electron phenomena in plasmonic photocatalysis is the focal point of this review. We summarize hot electron dynamics, elaborate on techniques to probe and measure said phenomena, and provide perspective on potential applications-photocatalytic degradation of organic pollutants, CO2 photoreduction, and photoelectrochemical water splitting-that benefit from this technology. A contentious and hitherto unexplained phenomenon is the wavelength dependence of plasmonic photocatalysis. Many published reports on noble metal-metal oxide nanostructures show action spectra where quantum yields closely follow the absorption corresponding to higher energy interband transitions, while an equal number also show quantum efficiencies that follow the optical response corresponding to the localized surface plasmon resonance (LSPR). We have provided a working hypothesis for the first time to reconcile these contradictory results and explain why photocatalytic action in certain plasmonic systems is mediated by interband transitions and in others by hot electrons produced by the decay of particle plasmons.


WS-9659 A and B, novel testosterone 5 alpha-reductase inhibitors isolated from a Streptomyces. II. Structural elucidation of WS-9659 A and B.
On the basis of spectroscopic and chemical evidence, the structures of WS-9659 A and B isolated as inhibitors of testosterone 5 alpha-reductase from a Streptomyces have been established as 1 and 2, respectively. The reductase inhibitory activities of the derivatives 5 and 6, and degradation products 3 and 8 were considerably less active and substantially inactive, respectively.


Mammary-Enriched Transcription Factors Synergize to Activate the Wap Super-Enhancer for Mammary Gland Development.
Super-enhancers are large clusters of enhancers critical for cell-type-specific development. In a previous study, 440 mammary-specific super-enhancers, highly enriched for an active enhancer mark H3K27ac; a mediator MED1; and the mammary-enriched transcription factors ELF5, NFIB, STAT5A, and GR, were identified in the genome of the mammary epithelium of lactating mice. However, the triggering mechanism for mammary-specific super-enhancers and the molecular interactions between key transcription factors have not been clearly elucidated. In this study, we investigated in vivo protein-protein interactions between major transcription factors that activate mammary-specific super-enhancers. In mammary epithelial cells, ELF5 strongly interacted with NFIB while weakly interacting with STAT5A, and it showed modest interactions with MED1 and GR, a pattern unlike that in non-mammary cells. We further investigated the role of key transcription factors in the initial activation of the mammary-specific Wap super-enhancer, using CRISPR-Cas9 genome editing to introduce single or combined mutations at transcription factor binding sites in the pioneer enhancer of the Wap super-enhancer in mice. ELF5 and STAT5A played key roles in igniting Wap super-enhancer activity, but an intact transcription factor complex was required for the full function of the super-enhancer. Our study demonstrates that mammary-enriched transcription factors within a protein complex interact with different intensities and synergize to activate the Wap super-enhancer. These findings provide an important framework for understanding the regulation of cell-type-specific development.


Genetic control of natural resistance in mouse macrophages regulating intracellular Legionella pneumophila multiplication in vitro.
It is known that Legionella pneumophila proliferates in peritoneal macrophage cultures derived from A/J mice but not in macrophage cultures derived from many other strains, including C57BL/6 mice. To analyze the genetic control of this trait and the location of the Legionella resistance-susceptibility gene, we prepared segregating progeny of A/J and C57BL/6 mice and determined the levels of susceptibility of individual mice. Peritoneal macrophages were collected by injecting thioglycolate medium, and macrophage monolayers were infected in vitro with L. pneumophila Philadelphia-1. Counting of colonies on buffered charcoal yeast extract agar plates and Gimenez staining of macrophage monolayers were carried out daily. There was a 10-fold increase in bacterial burden 1 day after infection and a 100-fold increase after 2 days in A/J (susceptible) macrophages. The increase in bacterial burden was always less than 10-fold in macrophages from C57BL/6 (resistant) progenitors, A/J x C57BL/6 F1 hybrids, and C57BL/6 x F1 backcross progeny. The ratios of resistant individuals to susceptible individuals were 22:6 for F2 progeny and 20:22 for A/J x F1 backcross progeny. The fact that the organism did not proliferate in macrophages from B10.A mice demonstrated that major histocompatibility antigens did not regulate the macrophage resistance of C57BL/6-derived mice. The sex and coat color genes of mice were not linked to the resistance-susceptibility gene. We suggest that resistance and susceptibility are controlled by a single gene or closely linked genes which are autosomal and that the resistance allele is dominant. The results of a comparison of the strain distribution pattern of this trait with the distribution pattern of 185 allelic markers in A/J x C57BL/6 and C57BL/6 x A/J recombinant inbred strains suggest that this susceptibility-resistance gene is located in the proximal part of chromosome 15.


Atypical bleeding in hemophilia: application of the conversion model to the case study of a child.
Although it has been suggested that psychosocial events may trigger bleeding in patients with hemophilia, few specific instances have been described. In this report we interpret a series of atypical bleeding episodes in a child with a factor VIII deficiency. Although the specific pathophysiologic events that led to bleeding into the elbow are unknown in this child, they are probably similar to those of "psychogenic purpura." It is likely that these episodes of atypical bleeding can be interpreted in terms of conversion model and that conversion reactions in children required involvement by at least one parent.


An automatic polarimeter for space applications.
Under a NASA contract, a compact automatic polarimeter was developed as a pilot model for lunar and planetary missions by spacecraft. The polarimeter simultaneously analyzes linearly polarized light into four intensities from which the Stokes parameters I, Q, and U can be determined. The measurements are made automatically by an electronic observation sequencer and an automatic gain selector. Five wavelength bands between 1900 A and 6000A can be used, and each measurement is calibrated automatically. The successful operation during three high altitude balloon flights indicates that the design is sound, and that with modifications for rocket vibration it can be used in space missions. The feature of making simultaneous measurements makes it particularly useful on planetary scans with fly-by probes. Preliminary results on the wavelength dependence of the polarization of the whole lunar disk, obtained ground-based, between 2850 A and 5100 A are presented.


Predicting the Recurrence of Gastric Cancer Using the Textural Features of Perigastric Adipose Tissue on [18F]FDG PET/CT.
This study aimed to assess the relationship between the histopathological and textural features of perigastric adipose tissue (AT) on 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) and to evaluate the prognostic significance of perigastric AT textural features in predicting recurrence-free survival (RFS) in patients with gastric cancer. Sixty-nine patients with gastric cancer who underwent staging [18F]FDG PET/CT and subsequent curative surgery were retrospectively reviewed. Textural features of perigastric AT were extracted from PET images. On histopathological analysis, CD4, CD8, and CD163 cell infiltration and matrix metalloproteinase-11 and interleukin-6 (IL-6) expression in perigastric AT were graded. The degree of CD163 cell infiltration in perigastric AT was significantly correlated with the mean standardized uptake value (SUV), SUV histogram entropy, grey-level co-occurrence matrix (GLCM) energy, and GLCM entropy of perigastric AT. The degree of IL-6 expression in the perigastric AT was significantly correlated with the mean and median SUVs of perigastric AT. In multivariate survival analysis, GLCM entropy, GLCM dissimilarity, and GLCM homogeneity of perigastric AT were significant predictors of RFS. The textural features of perigastric AT on [18F]FDG PET/CT significantly correlated with inflammatory response in perigastric AT and were significant prognostic factors for predicting RFS in patients with gastric cancer.


Alliin lyase (Alliinase) from garlic (Allium sativum). Biochemical characterization and cDNA cloning.
The garlic plant (Allium sativum) alliinase (EC 184.108.40.206), which catalyzes the synthesis of allicin, was purified to homogeneity from bulbs using various steps, including hydrophobic chromatography. Molecular and biochemical studies showed that the enzyme is a dimer of two subunits of MW 51.5 kDa each. Its Km using synthetic S-allylcysteine sulfoxide (+ isomer) as substrate was 1.1 mM, its pH optimum 6.5, and its isoelectric point 6.35. The enzyme is a glycoprotein containing 6% carbohydrate. N-terminal sequences of the intact polypeptide chain as well as of a number of peptides obtained after cyanogen bromide cleavage were obtained. Cloning of the cDNAs encoding alliinase was performed by a two-step strategy. In the first, a cDNA fragment (pAli-1-450 bp) was obtained by PCR using a mixed oligonucleotide primer synthesized according to a 6-amino acid segment near the N-terminal of the intact polypeptide. The second step involved screening of garlic lambda gt11 and lambda ZAPII cDNA libraries with pAli-1, which yielded two clones; one was nearly full length and the second was full length. These clones exhibited some degree of DNA sequence divergence, especially in their 3' noncoding regions, suggesting that they were encoded by separate genes. The nearly full length cDNA was fused in frame to a DNA encoding a signal peptide from alpha wheat gliadin, and expressed in Xenopus oocytes. This yielded a 50 kDa protein that interacted with the antibodies against natural bulb alliinase. Northern and Western blot analyses showed that the bulb alliinase was highly expressed in bulbs, whereas a lower expression level was found in leaves, and no expression was detected in roots. Strikingly, the roots exhibited an abundant alliinase activity, suggesting that this tissue expressed a distinct alliinase isozyme with very low homology to the bulb enzyme.


Coexistence of hepatitis B surface antigen (HBs Ag) and anti-HBs antibodies in chronic hepatitis B virus carriers: influence of "a" determinant variants.
In chronic hepatitis B (CHB), the persistence of hepatitis B surface antigen (HBs Ag) is sometimes associated with antibodies (Ab) to HBs (anti-HBs). To assess the hypothesis of the selection of HBs Ag immune escape variants in CHB patients, the variability of the HBV S gene was determined for patients persistently carrying both HBs Ag and anti-HBs antibodies and patients solely positive for HBs Ag. We selected 14 patients who presented both markers (group I) in several consecutive samples and 12 patients positive for HBs Ag only (group II). The HBs Ag-encoding gene was amplified and cloned, and at least 15 clones per patient were sequenced and analyzed. The number of residue changes within the S protein was 2.7 times more frequent for group I than for group II patients and occurred mostly in the "a" determinant of the major hydrophilic region (MHR), with 9.52 versus 2.43 changes per 100 residues (P = 0.009), respectively. Ten patients (71%) from group I, but only three (25%) from group II, presented at least two residue changes in the MHR. The most frequent changes in group I patients were located at positions s145, s129, s126, s144, and s123, as described for immune escape variants. In CHB patients, the coexistence of HBs Ag and anti-HBs Ab is associated with an increase of "a" determinant variability, suggesting a selection of HBV immune escape mutants during chronic carriage. The consequences of this selection process with regard to vaccine efficacy, diagnosis, and clinical evolution remain partially unknown.


Processing and degradation of exogenous prion protein by CD11c(+) myeloid dendritic cells in vitro.
The immune system plays an important role in facilitating the spread of prion infections from the periphery to the central nervous system. CD11c(+) myeloid dendritic cells (DC) could, due to their subepithelial location and their migratory capacity, be early targets for prion infection and contribute to the spread of infection. In order to analyze mechanisms by which these cells may affect prion propagation, we studied in vitro the effect of exposing such DC to scrapie-infected GT1-1 cells, which produce the scrapie prion protein PrP(Sc). In this system, the DC efficiently engulfed the infected GT1-1 cells. Unexpectedly, PrP(Sc), which is generally resistant to protease digestion, was processed and rapidly degraded. Based on this observation we speculate that CD11c(+) DC may play a dual role in prion infections: on one hand they may facilitate neuroinvasion by transfer of the infectious agent as suggested from in vivo studies, but on the other hand they may protect against the infection by causing an efficient degradation of PrP(Sc). Thus, the migrating and highly proteolytic CD11c(+) myeloid DC may affect the balance between propagation and clearance of PrP(Sc) in the organism.


Fast glucocorticoid feedback inhibition of ACTH secretion in the ovariectomized rat: effect of chronic estrogen and progesterone.
The purpose of this study was to determine whether estrogen and progesterone influence fast glucocorticoid negative feedback regulation of the ACTH and corticosterone (CORT) responses to stress. Mature rats were ovariectomized and 6 weeks later implanted with 17 beta-estradiol (E2, 0.5 mg), E2 and progesterone (P, 100 mg; E2 + P group) or placebo pellets (OVX). Seven days later rats were subjected to a single or repeated intermittent footshock stress (0.2 mA, 15 s duration, 0.5 s on). The repeated stress was of the same intensity and duration, and was applied either during the time domain of the rate-sensitive fast glucocorticoid feedback when plasma CORT levels are rising (5 min after the onset of the first stress), or at the time of peak CORT response (15 min) to the initial stress. Plasma ACTH and CORT were measured from serial samples. Estrogen replacement alone or in combination with progesterone lowered the immediate (t = 5) ACTH and CORT response to a single stress in ovariectomized animals. The second stress applied 5 min after the initial stress produced net ACTH responses similar to those obtained after a single stress in the OVX and E2 + P-replaced hormone groups, while total ACTH responses were lower in the E2-treated group. In ovariectomized animals, a facilitation of ACTH response by a prior stress is apparent in response to a footshock 15 min later, when the integrated ACTH secretion is significantly greater than the response measured after a single shock, or after a repeated shock 5 min apart. Anterior pituitary proopiomelanocortin (POMC) mRNA levels were lower in groups with E2 or E2 + P replacement compared to OVX animals. In contrast, hypothalamic corticotropin-releasing factor (CRF) mRNA levels did not increase significantly. However, hypothalamic glucocorticoid receptor (GR) mRNA levels increased after 17 beta-estradiol treatment, and this increase was reversed by progesterone. These results suggest that prior stress leads to both a fast-feedback inhibition and a facilitation of the subsequent stress response. In the absence of gonadal hormones this facilitation is balanced by fast-feedback inhibition during the glucocorticoid fast-feedback time domain, and is unmasked outside of this time domain. Estrogen suppresses POMC mRNA synthesis leading to a decrease in the availability of releasable ACTH, thereby reducing the facilitation. Progesterone may counter this effect of estrogen by decreasing the efficacy of the fast rate-sensitive glucocorticoid negative feedback.


Spectral mixing of rhythmic neuronal signals in sensory cortex.
The ability to compute the difference between two frequencies depends on a nonlinear operation that mixes two periodic signals. Behavioral and psychophysical evidence suggest that such mixing is likely to occur in the mammalian nervous system as a means to compare two rhythmic sensory signals, such as occurs in human audition, and as a means to lock an intrinsic rhythm to a sensory input. However, a neurological substrate for mixing has not been identified. Here we address the issue of nonlinear mixing of neuronal activity in the vibrissa primary sensory cortex of rat, a region that receives intrinsic as well as sensory-driven rhythmic input during natural whisking. In our preparation, the intrinsic signal originates from cortical oscillations that were induced by anesthetics, and the extrinsic input is introduced by periodic stimulation of vibrissae. We observed that the local extracellular current in vibrissa primary sensory cortex contained oscillatory components at the sum and difference of the intrinsic and extrinsic frequencies. In complementary experiments, we observed that the simultaneous stimulation of contralateral and ipsilateral vibrissae at different frequencies also led to current flow at the sum and difference frequencies. We show theoretically that the relative amplitudes of the observed mixture terms can be accounted for by a threshold nonlinearity in the input-output relation of the underlying neurons. In general, our results provide a neurological substrate for the modulation and demodulation of rhythmic neuronal signals for sensory coding and feedback stabilization of motor output.


PRO: osmotherapy for the treatment of acute intracranial hypertension.
Persisting severe brain edema causes intracranial hypertension and is associated with poor patient outcome. The treatment of acute intracranial hypertension is complex and multimodal. The most important options for medical treatment include controlled ventilation and osmotherapy, maintenance of brain and body homeostasis, and sedation. Osmotherapy is recommended in all relevant guidelines. The 2 osmotic agents most frequently used are mannitol and hypertonic saline. Both reduce intracranial pressure and improve cerebral perfusion and cerebral oxygen delivery. However, hypertonic saline seems advantageous over mannitol in many situations. In multitrauma patients, hypertonic saline contributes to hemodynamic stabilization and to the prevention of secondary insults. In addition, hypertonic saline has neurohumoral and immunologic effects, which may be beneficial in cerebral resuscitation.


Incidence of febrile neutropenia and myelotoxicity of chemotherapy: a meta-analysis of biosimilar G-CSF studies in breast cancer, lung cancer, and non-Hodgkin's lymphoma.
The aim of this meta-analysis of 3 clinical studies, conducted with breast cancer, lung cancer, and non-Hodgkin's lymphoma patients, was to compare a new granulocyte colony-stimulating factor (G-CSF) biosimilar, XM02, with filgrastim in terms of its prophylactic effect on the development of febrile neutropenia (FN) during the first chemotherapy cycle in relation to the myelotoxic potency of the applied chemotherapy regimen. Overall, 608 patients (363 under XM02 and 245 under filgrastim) were included in the meta-analysis. The majority of patients were allocated to the chemotherapy categories docetaxel-doxorubicin (45.4%) and cyclophosphamide-hydroxy daunomycin (adriamycin)-oncovin (vincristine)-prednisolone (CHOP)/platinum(Pt)-vinorelbine or Pt-vinblastine/ Pt-etoposide (43.1%); another 11.5% were allocated to the category Pt-gemcitabine/Pt-docetaxel or Pt-paclitaxel. FN in the XM02 and filgrastim groups was reported for 12.1 and 12.5% of patients, respectively, under docetaxeldoxorubicin, for 13.5 and 11.9% under CHOP/Pt-vinorelbine or Pt-vinblastine/Pt-etoposide, and for 15.6 and 12.0% under Pt-gemcitabine/Pt-docetaxel or Pt-paclitaxel. The incidence of FN in the first cycle of chemotherapy under primary G-CSF prophylaxis is low (in the range of 12-16%) and not directly correlated with the myelotoxic potency of the applied chemotherapy regimen. XM02 demonstrated to be non-inferior to filgrastim regarding the incidence of FN, irrespective of the myelotoxicity of the chemotherapy regimen.


Inhibition of tonic spinal glutamatergic activity induces antinociception in the rat.
Inhibition of tonic activity in spino-supraspinal projection neurons induces heterosegmental antinociception that is mediated by opioid receptors in nucleus accumbens. To investigate the origin of this tonic activity, we evaluated the ability of inhibiting neurotransmission in the spinal cord to produce heterosegmental antinociception in the trigeminal nociceptive jaw-opening reflex (JOR) in the rat. Spinal intrathecal administration of calcium channel blockers attenuated the JOR, suggesting that the tonic spinal activity depends on synaptic input. To identify the excitatory neurotransmitter receptors involved, selective antagonists for AMPA/kainate, mGluR1, NMDA or NK1 receptors were administered intrathecally to the spinal cord. The AMPA/kainate and mGluR1 receptor antagonists, but not the NMDA or NK1 receptor antagonists, induced antinociception, which was antagonized by intra-accumbens administration of the selective micro -opioid receptor antagonist CTOP. Thus, inhibition of tonic spinal glutamatergic activity resulted in supraspinally mediated antinociception. As this antinociception occurred in the absence of interventions that would produce a facilitated nociceptive state, this tonic glutamatergic activity is important in setting nociceptive threshold.


Suppressive ability of defatted rice bran against lipid oxidation in cookies containing iron.
Cookies containing iron, defatted rice bran, and several oils were prepared, and their oxidative stability evaluated. Oxidation was suppressed by the defatted rice bran, but a limit to the suppressive effect was observed. The maximum peroxide values obtained with defatted rice bran were low, and similar, regardless of the degree of unsaturation of the oils. A chemical analysis suggested that proteins and polyphenols in the defatted rice bran contributed to the suppressive effect. Cookies without the defatted rice bran showed decreasing maximum peroxide value as the relative humidity increased. No such dependence was observed for the cookies containing defatted rice bran. The water sorption isotherm of defatted rice bran indicated that the weak dependence was due to low water sorption.


Formation Mechanism of Di-N-ethyl-2-pyrrolidinone-Substituted Epigallocatechin Gallate during High-Temperature Roasting of Tea.
Four di-N-ethyl-2-pyrrolidinone-substituted epigallocatechin gallate (EGCG) and two di-N-ethyl-2-pyrrolidinone-substituted gallocatechin gallate (GCG) flavan-3-ols (di-EPSFs) were prepared by the thermal simulation reaction. The effects of reaction temperature and time, initial reactant ratios, and pH values on the content of di-EPSFs were studied. The formation of six di-EPSFs was most favored when the initial reactant ratio of EGCG and theanine was 1:2 and heated under 130 °C at pH 10 for 120 min. The contents of di-EPSF1, di-EPSF2, and di-EPSF5 in large-leaf yellow tea (LYT) increased with the increase of roasting degree. Through quantitative analysis, it was found that EGCG would interact with the Strecker degradation products of theanine to form EPSFs, which further combined with the Strecker degradation products of theanine to form di-EPSFs. This study further improved the understanding of the transformation pathways of EGCG and theanine during tea processing and contributed to exploring the flavor characteristics and health benefits of di-EPSFs.


A public health enhanced surveillance system for a mass gathering event.
From June 7 to June 9, 2018, a G7 Summit was held in the Canadian province of Quebec. This international political mass gathering event posed a number of potential risks to public health. To assess three additional monitoring strategies to detect public health threats during a mass gathering event. In addition to routine public health monitoring, a partnership was created and three monitoring strategies were put in place three days before, during and six days after the G7 event: the analysis of data on the presenting complaint and discharge diagnosis from 11 emergency departments in the area using the logical Early Aberration Reporting System; the daily polling of key health partners with an online questionnaire; and the analysis of calls to Info-Santé, a government-run telephone consultation service for the public regarding health and social issues. Emergency room data produced 78 alerts from the presenting complaints and 39 alerts from the discharge diagnoses. Of these 117 alerts, two were investigated (one in the respiratory and one in the neurological-muscular categories) and no other interventions were required. With a few exceptions, all of the health partners completed the online survey each day and no signal of concern was generated. Compared with historical data, no increase or differences in calls to Info-Santé were detected during the monitoring period. The three additional monitoring strategies developed to detect events of public health importance during the 2018 G7 Summit in Quebec were successful in gathering timely data for analysis. Close collaboration and good participation from the different partners were essential to this project. However, because no public health event occurred, it was not possible to determine whether the enhanced surveillance system had sufficient speed and sensitivity for timely detection and response.


How does the mandible grow after early high condylectomy?
The early high condylectomy (HC), removing the overgrowing area of the condyle, may be indicated for condylar hyperplasia. However, in young patients, when the HC removes the pathological overgrowing tissue the contralateral condyle is still growing. May this surgical procedure, in these growing patients, stop the operated side growth creating the conditions for an opposite asymmetry? Authors investigate the way the operated mandible develops after the early HC, both as a symmetry percentage and in an absolute value related to the unaffected side. A sample of 8 consecutive growing patients, 1 male and 7 females, referred to the Maxillofacial Surgery Department of Parma University for HC were investigated. Patients were longitudinally studied with 3 orthopantomographies at: T0 (diagnosis: mean age, 13 years; range, 11 years 2 months to 13 years 8 months), T1 (after surgery: mean age, 15; range, 13-18 years) and T2 (follow-up: mean age, 18 years; range, 17-20 years). The x-ray is used to study the condyle, ramus, and total vertical structures length by Mattila tracing method. The data were analyzed by the Student t test and Wilcoxon matched pairs test; P value was set at 0.5. The operated side was overcorrected by HC and; during the investigated period, its growth decreased from T0 to T1 and restarted from T1 to T2. The whole T0-T2 growth of the operated side was not statistically different from the one of the healthy side (P < 0.05). These results suggest that the operated side growth may continue in a more normal way after condylectomy.


Tracking the Endosomal Escape: A Closer Look at Calcein and Related Reporters.
Crossing the cellular membrane and delivering active pharmaceuticals or biologicals into the cytosol of cells is an essential step in the development of nanomedicines. One of the most important intracellular processes regarding the cellular uptake of biologicals is the endolysosomal pathway. Sophisticated nanocarriers are developed to overcome a major hurdle, the endosomal entrapment, and delivering their cargo to the required site of action. In parallel, in vitro assays are established analyzing the performance of these nanocarriers. Among them, the release of the membrane-impermeable dye calcein has become a popular and straightforward method. It is accessible for most researchers worldwide, allows for rapid conclusions about the release potential, and enables the study of release mechanisms. This review is intended to provide an overview and guidance for scientists applying the calcein release assay. It comprises a survey of several applications in the study of endosomal escape, considerations of potential pitfalls, challenges, and limitations of the assay, and a brief summary of complementary methods. Based on this review, it is hoped to encourage further research groups to take advantage of the calcein release assay for their own purposes and help to create a database for more efficient cross-correlations between nanocarriers.


Effects of treadmill speed on the mechanics of the back in the trotting saddlehorse.
Speed related changes in trunk mechanics have not yet been investigated, although high-speed training is currently used in the horse. To evaluate the effects of speed on back kinematics and trunk muscles activity, 4 saddle horses were recorded while trotting on a horizontal treadmill at speeds ranging from 3.5 to 6 m/s. The 3-dimensional (3-D) trajectories of skin markers on the left side of the horse and the dorsal midline of the trunk were established. Electrical activity was simultaneously obtained from the longissimus dorsi (LD) and rectus abdominis (RA) muscles using surface electrodes. Ten consecutive strides were analysed for each horse at each of the 5 velocity steps. Electromyographic and kinematic data were time-standardised to the duration of the stride cycle and compared using an analysis of variance. The back extended during the first part of each diagonal stance phase when the RA was active and the back flexed during the second part of each diagonal stance phase when the LD was active. The onset and end of muscle activity came earlier in the stride cycle and muscle activity intensity increased when speed increased. The amplitude of vertical movement of the trunk and the maximal angles of flexion decreased with increasing speed, whereas the extension angles remained unchanged. This resulted in a decreased range of back flexion-extension. This study confirms that the primary role of trunk muscles is to control the stiffness of the back rather than to induce movements. Understanding the effects of speed on the back of healthy horses is a prerequisite for the prevention and treatment of back pathology.


Comparative study on efficacy of different alcohol hand rubs and routine hand wash in a health-care setting, alexandria, egypt.
Antiseptic agents or plain soap and water are mainly used for hand hygiene in Egypt. The impact of hand hygiene depends not only on the regularity and thoroughness of the procedures used but also on the type of hand-washing agent selected. To compare the efficacy of alcohol-based hand rubs versus traditional hand washing with soap and water in reducing hand contamination during routine patient care. The study included 20 volunteered nurses in 3 intensive care units and the renal dialysis unit, in the Alexandria University Students' Hospital. A total of 200 samples were collected by direct finger-print of the dominant hand taken from all nurses before and after applying hand hygiene procedures. Three hand-rubs available in the Egyptian market (Brands A, B; alcohol-based liquid, and C; alcohol-based gel) were used and compared to a locally prepared hand-rubbing solution (D) and to hand washing with non-antiseptic soap and water (SW). Hand washing with non-antiseptic soap and water and all of the four used alcohol-based hand-rubs showed significant reduction of bacterial counts on the examined hands. The median percentage reductions were 99%, 94%, 77%, and 87% with brands A, B, C and D respectively and only 30% reduction with soap and water (x2: 23.023, p <0.001). Alcohol-based hand rub is far more efficient than traditional hand washing, and more convenient and time saving. Locally prepared hand rub is comparable to readymade ones. It is recommended as a hand hygiene practice in critical areas, particularly when sink and running water are inaccessible.


Metabolomic Markers of Ultra-Processed Food and Incident CKD.
High ultra-processed food consumption is associated with higher risk of CKD. However, there is no biomarker for ultra-processed food, and the mechanism through which ultra-processed food is associated with CKD is not clear. Metabolomics can provide objective biomarkers of ultra-processed food and provide important insights into the mechanisms by which ultra-processed food is associated with risk of incident CKD. Our objective was to identify serum metabolites associated with ultra-processed food consumption and investigate whether ultra-processed food-associated metabolites are prospectively associated with incident CKD. We used data from 3751 Black and White men and women (aged 45-64 years) in the Atherosclerosis Risk in Communities study. Dietary intake was assessed using a semiquantitative 66-item food frequency questionnaire, and ultra-processed food was classified using the NOVA classification system. Multivariable linear regression models were used to identify the association between 359 metabolites and ultra-processed food consumption. Cox proportional hazards models were used to investigate the prospective association of ultra-processed food-associated metabolites with incident CKD. Twelve metabolites (saccharine, homostachydrine, stachydrine, N2, N2-dimethylguanosine, catechol sulfate, caffeine, 3-methyl-2-oxovalerate, theobromine, docosahexaenoate, glucose, mannose, and bradykinin) were significantly associated with ultra-processed food consumption after controlling for false discovery rate <0.05 and adjusting for sociodemographic factors, health behaviors, eGFR, and total energy intake. The 12 ultra-processed food-related metabolites significantly improved the prediction of ultra-processed food consumption (difference in C statistics: 0.069, P <1×10 -16 ). Higher levels of mannose, glucose, and N2, N2-dimethylguanosine were associated with higher risk of incident CKD after a median follow-up of 23 years. We identified 12 serum metabolites associated with ultra-processed food consumption and three of them were positively associated with incident CKD. Mannose and N2, N2-dimethylguanosine are novel markers of CKD that may explain observed associations between ultra-processed food and CKD. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_03_08_CJN08480722.mp3.