A new rapid diagnostic test for detection of anti-Schistosoma mansoni and anti-Schistosoma haematobium antibodies.
Parasitological methods are widely used for the diagnosis of schistosomiasis. However, they are insensitive, particularly in areas of low endemicity, and labour-intensive. Immunoassays based on detection of anti-schistosome antibodies have the merit of high sensitivity and recently a rapid diagnostic test (RDT), incorporating Schistosoma mansoni cercarial transformation fluid (SmCTF) for detection of anti-schistosome antibodies in blood has been developed. Here, we assessed the diagnostic performance of the SmCTF-RDT for S. mansoni and S. haematobium infections by comparing it with microscopy for egg detection. A cross-sectional survey was carried out in Azaguié, south Côte d'Ivoire. 118 pre-school-aged children submitted two stool and two urine samples, which were subjected to the Kato-Katz and urine filtration methods for the detection of S. mansoni and S. haematobium eggs, respectively. Urine was also subjected to a commercially available cassette test for S. mansoni, which detects circulating cathodic antigen. A finger-prick blood sample was used for the SmCTF-RDT for detection of anti-S. mansoni and anti-S. haematobium antibodies. The prevalence of both anti-S. mansoni and anti-S. haematobium antibodies was more than three times higher than the prevalence of infection estimated by egg detection under a microscope. Using quadruplicate Kato-Katz as the reference standard for the diagnosis of S. mansoni infection, the sensitivity, negative predictive value (NPV), and positive predictive value (PPV) of the SmCTF-RDT was 75.0%, 84.2% and 22.5%, respectively. When two urine filtrations were considered as the reference standard for the diagnosis of S. haematobium infection, the sensitivity, NPV and PPV of SmCTF-RDT was 66.7%, 94.9% and 5.1%, respectively. The specificity of SmCTF-RDT, when using egg-detection as the reference standard, was estimated to be 34.4%. This low specificity may be a reflection of the relative insensitivity of the direct diagnostic approaches using microscopy. The SmCTF-RDT is at least as sensitive as duplicate Kato-Katz and a single urine filtration for detection of S. mansoni and S. haematobium, respectively. Further investigations into the specificity of the test for anti-schistosome antibodies are necessary, but our results suggest that it may be a useful tool for mapping the prevalence of anti-schistosome antibodies in a given population pending intervention.


Comparison of chemical composition and antioxidant capacity of commercially available blueberry and blackberry wines in Illinois.
Moderate wine consumption may reduce the incidence of certain age-related chronic diseases such as heart disease, hypertension, metabolic disease, and neurodegenerative disease. Blueberry and blackberry wines commercially available in Illinois were evaluated for chemical and quality components relevant to consumers in order to study their potential health benefits. Total polyphenolic content was measured by the Folin-Ciocalteu method, total anthocyanin content by the pH differential test, and in vitro antioxidant capacity (AC) by the oxygen radical absorbance capacity (ORAC) method. Color was measured using Hunter colorimetry and quality parameters including pH, °Brix, acid content, glucose-fructose, and percent alcohol were measured using Fourier transform infrared spectroscopy. Blackberry wines (n= 6) had an average total polyphenolic content of 2212.5 ± 1090.3 mg ellagic acid equivalents (EAE) per liter, total anthocyanin content of 75.56 ± 70.44 mg/L, and AC of 26.39 ± 17.95 mmol trolox equivalents (TEs) per liter. Blueberry wines (n= 4) had an average total polyphenolic content of 1623.3 ± 645.5 mg EAE per liter, total anthocyanin content of 20.82 ± 12.14 mg/L, and AC of 21.21 ± 7.71 mmol TE per liter. Strong positive correlations were found between °Brix and glucose-fructose concentration (r= 0.90), total acid and malic acid (r= 0.90), and between total polyphenols and AC (r= 0.88). The results suggest that fruit wines made from blueberries and blackberries may have potential health applications and therefore could contribute to the economy of the wine industry. The majority of wines are produced from grapes, but wine can also be produced from other fruits including blueberries and blackberries, which contain phenolic compounds that may contribute to human health. A comparative evaluation was conducted on commercial nongrape fruit wines and parameters related to their health benefits. Fruit wines made from blueberries and blackberries may have potential health applications and therefore could contribute to the economy of the wine industry.


Effects of cryopreservation on human mesenchymal stem cells attached to different substrates.
There is a need to preserve cell-seeded scaffolds or cell-matrix constructs for tissue-engineering and other applications. Cryopreservation is likely to be the most practical method. The aim of this study was to investigate how cryopreservation affects cells attached to different substrates and how they respond differently from those in suspension. Human mesenchymal stem cells (hMSCs) were studied for their close relevance to tissue-engineering and stem cell therapy applications, in particular how cryopreservation affects cell adherence, cell growth and the viability of hMSCs attached to different substrates, including glass, gelatin, matrigel and a matrigel sandwich. The effects of cryopreservation on F-actin organization, intracellular pH and mitochondrial localization of the adherent hMSCs were further investigated. It was found that cells attached to a glass surface could hardly survive the common cryopreservation protocol using 10% DMSO and a 1°C/min cooling rate. By contrast, cells attached to gelatin and matrigel could survive to a greater extent. Furthermore, cryopreservation affected the potential of cell attachment and proliferation, resulted in distortion of F-actin, led to alteration of intracellular pH of the hMSCs for all tested substrates and caused a change in the mitochondrial localization of hMSCs on a matrigel substrate and in a matrigel sandwich. Our results showed that cell attachment and cell viability could be improved by changing the interaction between cell and substrate through modification of the substrate properties, which has implications for scaffold design if cell-seeded scaffolds or engineered tissues need to be cryopreserved.


Cloned human polyomavirus JC DNA can transform human amnion cells.
The genome of the human polyomavirus JC (Mad-1 strain) was molecularly cloned in Escherichia coli by using the plasmid vector pBR322. Recombinant DNA molecules were constructed with the entire JC genome inserted either at its unique EcoRI site at 0.0 map units or at its unique BamHI site at 0.51 map units. Viral DNA from each of these recombinant plasmids was capable of transforming human amnion cells, and cell lines established from transformed foci were positive for JC tumor antigen as assayed by indirect immunofluorescence.


The Staphylococcus aureus cidAB operon: evaluation of its role in regulation of murein hydrolase activity and penicillin tolerance.
Recent studies have shown that expression of the Staphylococcus aureus lrgAB operon inhibits murein hydrolase activity and decreases sensitivity to penicillin-induced killing. It was proposed that the lrgAB gene products function in a manner analogous to an antiholin, inhibiting a putative holin from transporting murein hydrolases out of the cell. In the present study the cidAB operon was identified and characterized based on the similarity of the cidA and cidB gene products to the products of the lrgAB operon. Zymographic and quantitative analyses of murein hydrolase activity revealed that mutation of the cidA gene results in decreased extracellular murein hydrolase activity compared to that of S. aureus RN6390, the parental strain. Complementation of cidA expression restored the wild-type phenotype, indicating that expression of the cidAB operon has a positive influence on extracellular murein hydrolase activity. The cidA mutant also displayed a significant decrease in sensitivity to the killing effects of penicillin. However, complementation of the cidA defect did not restore penicillin sensitivity to wild-type levels. Reverse transcriptase PCR also revealed that cidAB is maximally expressed during early exponential growth, opposite of what was previously observed for lrgAB expression. Based on these results, we propose that the cidAB operon encodes the holin-like counterpart of the lrgAB operon and acts in a manner opposite from that of lrgAB by increasing extracellular murein hydrolase activity and increasing sensitivity to penicillin-induced killing.


Commonly used thiol-containing antioxidants reduce cardiac differentiation and alter gene expression ratios of sarcomeric isoforms.
Reactive oxygen species (ROS) scavengers such as beta-mercaptoethanol (BME) and monothiol glycerol (MTG) are extensively used in stem cell research to prevent cellular oxidative stress. However, how these antioxidant supplements impact stem cell cardiac differentiation, a process regulated by redox-signaling remains unknown. In this study, we found that removal of BME from the conventional high-glucose, serum-based differentiation medium improved cardiac differentiation efficiency by 2-3 fold. BME and MTG treatments during differentiation significantly reduced mRNA expression of cardiac progenitor markers (NKX2.5 and ISL1) as well as sarcomeric markers (MLC2A, MLC2V, TNNI3, MYH6 and MYH7), suggesting reduced cardiomyogenesis by BME or MTG. Moreover, BME and MTG altered the expression ratios between the sarcomeric isoforms. In particular, TNNI3 to TNNI1 ratio and MLC2V to MLC2A ratio were significantly lower in BME or MTG treated cells than untreated cells, implying altered cardiomyocyte phenotype and maturity. Lastly, BME and MTG treatments resulted in less frequent beating, slower contraction and relaxation velocities than untreated cells. Interestingly, none of the above-mentioned effects was observed with Trolox, a non-thiol based antioxidant, despite its strong antioxidant activity. This work demonstrates that commonly used antioxidant supplements may cause considerable changes to cellular redox state and the outcome of differentiation.


Accumulation of genetic alterations and progression of primary breast cancer.
In order to detect common regions of deletion, 219 breast tumors were examined for loss of heterozygosity at several loci on chromosomes 3p, 16q, and 17 by restriction fragment length polymorphism analysis. Allelic deletions of loci on chromosomes 3p, 13q, 16q, and 17, and amplification of the erbB2 oncogene, were analyzed and compared with histopathological and clinical features. Common regions of deletion were detected within chromosomal bands 3p13-14.3, 16q22-23, 17p13 (two separated loci), and 17q21. Concordant losses of alleles on chromosomes 3p, 13q, 16q, 17p, and 17q were observed. A significant association was detected between loss of heterozygosity on chromosomes 17p and 17q and amplification of the erbB2 oncogene (17p, P = 0.000721, by Fisher's exact test; 17q, P less than 0.001, chi 2 = 12.135). Furthermore, tumors showing highly malignant phenotypes had accumulated more genetic changes at the loci studied than those having less malignant phenotypes on the basis of histopathological classification, lymph node metastasis, and tumor size. These results suggested that accumulation of genetic alterations, including loss of function of tumor suppressor genes on chromosomes 3p, 13q, 16q, and 17, and amplification of the erbB2 oncogene, may contribute to tumor development and/or progression in primary breast cancer.


Mandibular dental arch changes associated with treatment of crowding using self-ligating and conventional brackets.
The purpose of this study was to investigate the effect of treatment of mandibular crowding with self-ligating and conventional brackets on dental arch variables. Fifty-six patients were selected from a pool of subjects satisfying the following inclusion criteria: non-extraction treatment in the mandibular or maxillary arches, eruption of all mandibular teeth, no spaces and an irregularity index greater than 2 mm in the mandibular arch, and no adjunct treatment such as etxra- or intraoral appliances. The patients were assigned to two groups: one group received treatment with the self-ligating bracket and the other with a conventional edgewise appliance, both with a 0.022 inch slot. Lateral cephalometric radiographs obtained at the beginning (T1) and end (T2) of treatment were used to assess the alteration in mandibular incisor inclination, and measurements of intercanine and intermolar widths were made on dental casts to investigate changes associated with the correction. The results were analysed with bivariate and multivariate linear regression analysis in order to examine the effect of the bracket systems on arch width or lower incisor inclination, adjusting for the confounding effect of demographic and clinical characteristics. An alignment-induced increase in the proclination of the mandibular incisors was observed for both groups; no difference was identified between self-ligating and conventional brackets with respect to this parameter. Likewise, an increase in intercanine and intermolar widths was noted for both bracket groups; the self-ligating group showed a higher intermolar width increase than the conventional group, whereas the amount of crowding and Angle classification were not significant predictors of post-treatment intermolar width.


Catalytic improvement and evolution of atrazine chlorohydrolase.
The atrazine chlorohydrolase AtzA has evolved within the past 50 years to catalyze the hydrolytic dechlorination of the herbicide atrazine. It is of wide research interest for two reasons: first, catalytic improvement of the enzyme would facilitate its application in bioremediation, and second, because of its recent evolution, it presents a rare opportunity to examine the early stages in the acquisition of new catalytic activities. Using a structural model of the AtzA-atrazine complex, a region of the substrate-binding pocket was targeted for combinatorial randomization. Identification of improved variants through this process informed the construction of a variant AtzA enzyme with 20-fold improvement in its k(cat)/K(m) value compared with that of the wild-type enzyme. The reduction in K(m) observed in the AtzA variants has allowed the full kinetic profile for the AtzA-catalyzed dechlorination of atrazine to be determined for the first time, revealing the hitherto-unreported substrate cooperativity in AtzA. Since substrate cooperativity is common among deaminases, which are the closest structural homologs of AtzA, it is possible that this phenomenon is a remnant of the catalytic activity of the evolutionary progenitor of AtzA. A catalytic mechanism that suggests a plausible mechanistic route for the evolution of dechlorinase activity in AtzA from an ancestral deaminase is proposed.


Large-scale fungal diversity assessment in the Andean Yungas forests reveals strong community turnover among forest types along an altitudinal gradient.
The Yungas, a system of tropical and subtropical montane forests on the eastern slopes of the Andes, are extremely diverse and severely threatened by anthropogenic pressure and climate change. Previous mycological works focused on macrofungi (e.g. agarics, polypores) and mycorrhizae in Alnus acuminata forests, while fungal diversity in other parts of the Yungas has remained mostly unexplored. We carried out Ion Torrent sequencing of ITS2 rDNA from soil samples taken at 24 sites along the entire latitudinal extent of the Yungas in Argentina. The sampled sites represent the three altitudinal forest types: the piedmont (400-700 m a.s.l.), montane (700-1500 m a.s.l.) and montane cloud (1500-3000 m a.s.l.) forests. The deep sequence data presented here (i.e. 4 108 126 quality-filtered sequences) indicate that fungal community composition correlates most strongly with elevation, with many fungi showing preference for a certain altitudinal forest type. For example, ectomycorrhizal and root endophytic fungi were most diverse in the montane cloud forests, particularly at sites dominated by Alnus acuminata, while the diversity values of various saprobic groups were highest at lower elevations. Despite the strong altitudinal community turnover, fungal diversity was comparable across the different zonal forest types. Besides elevation, soil pH, N, P, and organic matter contents correlated with fungal community structure as well, although most of these variables were co-correlated with elevation. Our data provide an unprecedented insight into the high diversity and spatial distribution of fungi in the Yungas forests.


The development of gender stereotype components.
Developmental research has been limited by a narrow concept of stereotypes. A more complex model is presented, and developmental changes in gender stereotypes were investigated using the new model. In 2 studies, children were told about several sex-unspecified children, each described as having 1 masculine or 1 feminine characteristic. The children then predicted the likelihood of each story child having other masculine and feminine characteristics. In Study 1, 56 children (4-6 years) were told about target children who liked either a masculine or feminine toy, and then children predicted the targets' interests in other toys. In Study 2, 76 older children (6, 8, 10 years) were told about target children with a masculine or feminine characteristic from 1 of 4 categories (appearance, personality, occupations, toys), and then they predicted the likelihood of targets having other masculine and feminine characteristics from the same and from different categories as the cue. 2 developmental trends emerged: (a) children appear first to learn associations among characteristics relevant to their own sex and, later, to learn them for the other sex, and (b) older children's stereotypic judgments are more extreme than those of younger children. The implications of these results for the development of stereotypes, assessing gender knowledge, and understanding social judgments are discussed.


Insights into the binding and covalent inhibition mechanism of PF-07321332 to SARS-CoV-2 Mpro.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the COVID-19 pandemic, resulting in several million deaths being reported. Numerous investigations have been carried out to discover a compound that can inhibit the biological activity of the SARS-CoV-2 main protease, which is an enzyme related to the viral replication. Among these, PF-07321332 (Nirmatrelvir) is currently under clinical trials for COVID-19 therapy. Therefore, in this work, atomistic and electronic simulations were performed to unravel the binding and covalent inhibition mechanism of the compound to Mpro. Initially, 5 μs of steered-molecular dynamics simulations were carried out to evaluate the ligand-binding process to SARS-CoV-2 Mpro. The successfully generated bound state between the two molecules showed the important role of the PF-07321332 pyrrolidinyl group and the residues Glu166 and Gln189 in the ligand-binding process. Moreover, from the MD-refined structure, quantum mechanics/molecular mechanics (QM/MM) calculations were carried out to unravel the reaction mechanism for the formation of the thioimidate product from SARS-CoV-2 Mpro and the PF-07321332 inhibitor. We found that the catalytic triad Cys145-His41-Asp187 of SARS-CoV-2 Mpro plays an important role in the activation of the PF-07321332 covalent inhibitor, which renders the deprotonation of Cys145 and, thus, facilitates further reaction. Our results are definitely beneficial for a better understanding of the inhibition mechanism and designing new effective inhibitors for SARS-CoV-2 Mpro.


[Cerebrospinal fluid syndrome in neuroschistosomiasis].
A study was made of 220 samples of cerebrospinal fluid (CSF) from patients who suffered from several diseases of the central nervous system. In all samples immunological reactions for syphilis, cysticercosis, toxoplasmosis, Chagas' disease and schistosomiasis were studied comparatively. Immunofluorescent reactions for schistosomiasis were made by indirect antiglobulin technic with two types of antigen: the worm and the liver granuloma of hamster infected by Schistosoma mansoni. Emphasis is given on data concerning to 16 cases in which these reactions were reagent. The importance of routine search in the CSF for schistosomiasis antibodies is discussed. The concept of a 'CSF neuroschistosomiasis syndrome' is discussed as the main aspect of diagnosis "in vivo" of the disease. It is supported by the demonstration of specific antibodies in the CSF. Hypercytosis of lymphomononuclear type associated to the presence of eosinophil cells, protein concentration increase and gamma globulins increase are other characteristics found in the CSF in this syndrome.


Preliminary investigations on a new disposable potentiometric biosensor for uric acid.
In this paper, uricase, catalase, and electron mediator were coimmobilized on the surface of the tin oxide (SnO2)/indium tin oxide (ITO) glass, to develop a disposable potentiometric uric acid biosensor. The SnO2/ITO glass was employed as a pH sensor, fabricated by sputtering SnO2 thin films on the ITO glass. 3-Glycidyloxypropyltrimethoxysilane (GPTS) was utilized to immobilize uricase, catalase and the electron mediator (ferrocenecarboxylic acid, FcA) on the sensing window. The experimental results reveal that the optimal weight ratio of uricase, FcA to catalase (CAT) is 4:1:2. The sensor responds linearly between 2 mg/dl and 7 mg/dl at pH 7.5, in 20 mM of test solution, with a correlation coefficient of 0.99213. Accordingly, no significant interference was observed when interfering substances, glucose, urea and ascorbic acid, were added to the uric acid solution. Moreover, the recorded voltage was relatively constant during the first 28 days of measurement. Consequently, a potentiometric uric acid biosensor was realized with the advantages of low cost and simple fabrication.


Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures.
This study compares generalized Born (GB) and Poisson (PB) methods for calculating electrostatic solvation energies of proteins. A large set of GB and PB implementations from our own laboratories as well as others is applied to a series of protein structure test sets for evaluating the performance of these methods. The test sets cover a significant range of native protein structures of varying size, fold topology, and amino acid composition as well as nonnative extended and misfolded structures that may be found during structure prediction and folding/unfolding studies. We find that the methods tested here span a wide range from highly accurate and computationally demanding PB-based methods to somewhat less accurate but more affordable GB-based approaches and a few fast, approximate PB solvers. Compared with PB solvation energies, the latest, most accurate GB implementations were found to achieve errors of 1% for relative solvation energies between different proteins and 0.4% between different conformations of the same protein. This compares to accurate PB solvers that produce results with deviations of less than 0.25% between each other for both native and nonnative structures. The performance of the best GB methods is discussed in more detail for the application for force field-based minimizations or molecular dynamics simulations.


A radial basis function neural network (RBFNN) approach for structural classification of thyroid diseases.
The thyroid is a gland that controls key functions of body. Diseases of the thyroid gland can adversely affect nearly every organ in human body. The correct diagnosis of a patient's thyroid disease clarifies the choice of drug treatment and also allows an accurate assessment of prognosis in many cases. This study investigates Multilayer Perceptron Neural Network (MLPNN) and Radial Basis Function Neural Network (RBFNN) for structural classification of thyroid diseases. A data set for 487 patients having thyroid disease is used to build, train and test the corresponding neural networks. The structural classification of this data set was performed by two expert physicians before the input variables and results were fed into the neural networks. Experimental results show that the predictions of both neural network models are very satisfying for learning data sets. Regarding the evaluation data, the trained RBFNN model outperforms the corresponding MLPNN model. This study demonstrates the strong utility of an artificial neural network model for structural classification of thyroid diseases.


The Effect of Menstrual Cycle Phase on the Prognostic Factors in Patients with Premenopausal Breast Tumors.
Background: Estrogen receptor and progesterone receptor positivity and c-erbB2 gene expression levels are important in determining breast cancer development and aggression. Although the importance of hormonal factors in tumor cell proliferation, migration and differentiation is increasing, it needs more evidence. The effect of BC surgery timing during the menstrual cycle on prognosis remains controversial. In order to clarify this hypothesis, we aimed to determine the importance of adjusting the timing of surgery according to the menstrual cycle by examining the relationship between estrogen receptor, progesterone receptor, c-erbB2 gene and the menstrual cycle phase in patients with premenopausal breast cancer. Method: Our study was designed retrospectively. 50 patients with premenopausal breast cancer who were operated were included in the study. Results: Our results showed that the patients in the luteal phase had higher ER positivity, PR positivity and c-erbB2 negativity, and the number of metastatic axillary lymph nodes was lower than the patients in follicular phase. Conclusions: BC surgery during the luteal phase in pre-menopausal women is associated with a better clinical outcome. Although larger-scale studies are needed, our results suggest that better results can be achieved by performing surgery in luteal phase in BC patients during premenopausal period.


The association of ethnic minority density with late entry into antenatal care in the Netherlands.
In the Netherlands, non-Western ethnic minority women make their first antenatal visit later than native Dutch women. Timely entry into antenatal care is important as it provides the opportunity for prenatal screening and the detection of risk factors for adverse pregnancy outcomes. In this study we explored whether women's timely entry is influenced by their neighborhood. Moreover, we assessed whether ethnic minority density (the proportion of ethnic minorities in a neighborhood) influences Western and non-Western ethnic minority women's chances of timely entry into care differently. We hypothesized that ethnic minority density has a protective effect against non-Western women's late entry into care. Data on time of entry into care and other individual-level characteristics were obtained from the Netherlands Perinatal Registry (2000-2008; 97% of all pregnancies). We derived neighborhood-level data from three other national databases. We included 1,137,741 pregnancies of women who started care under supervision of a community midwife in 3422 neighborhoods. Multi-level logistic regression was used to assess the associations of individual and neighborhood-level determinants with entry into antenatal care before and after 14 weeks of gestation. We found that neighborhood characteristics influence timely entry above and beyond individual characteristics. Ethnic minority density was associated with a higher risk of late entry into antenatal care. However, our analysis showed that for non-Western women, living in high ethnic minority density areas is less detrimental to their risk of late entry than for Western women. This means that a higher proportion of ethnic minority residents has a protective effect on non-Western women's chances of timely entry into care. Our results suggest that strategies to improve timely entry into care could seek to create change at the neighborhood level in order to target individuals likely of entering care too late.


Phase Behaviors in Compressible Polymer Blends.
We study phase behaviors in compressible polymer blends by using an equation of state in the framework of classical density-functional theory. The phase behaviors are explored by decomposing the compressible mixing of polymers into two steps: incompressible mixing as holding the volume and density relaxation at the given pressure. There exists both upper consolute pressure (UCP) and lower consolute pressure (LCP). LCP-type behaviors are driven by the entropy effect of asymmetric size of molecules, while UCP-type behaviors are driven by energetic interactions. The value of LCP follows a scaling of O(N-2), which can be improved to O(N-1.8) by taking into account the effects of random chain conformation. The volume of LCP-type polymers expands upon mixing, while that of UCP-type polymers contracts. A closed-loop phase coexisting curve may appear because of the interplay between UCP- and LCP-type behaviors. At the UCP/LCP boundary, the mixing free energy of density relaxation is much smaller than that of both UCP- and LCP-type behaviors. The contribution from incompressible mixing step always dominates the phase behaviors, while that from density relaxation step could distinguish UCP-type between LCP-type behaviors.


Comparative aspects of placental efficiency.
Litter size is often proposed as the trait that could have the greatest impact in improving reproductive efficiency of pigs. Efforts to select directly for increased litter size have generally been unsuccessful and highly variable. As a result, several attempts have been made to identify critical physiological components that control litter size, with the underlying assumption that augmenting these components would improve this important trait. One attempt at improving physiological components has involved the selection of animals for increased uterine capacity, as measured by the number of fetuses or piglets that a female can carry successfully to term. Recent evidence indicates that one critical component of the uterine capacity in pigs is placental efficiency, or the body weight of a piglet divided by the mass of its placenta. It is easy to determine the average placental efficiency in a litter, but variation among conceptuses within a litter for this trait can be substantial, leading to the conclusion that placental efficiency is an individual conceptus trait. It is suggested that the limited success of selection for an increased uterine capacity results, at least in part, from a misguided view that 'uterine capacity' is strictly a maternal trait. Uterine capacity is better defined as the mass of placental tissue that a pregnant female can support to term, and involves phenotypic variation in both the dam and her offspring. This definition of uterine capacity allows maximization of both uterine size and placental efficiency in future attempts to increase litter size in pigs.


Feasibility, safety, and primary efficacy of DermaStream: a novel continuously streaming device for chronic wounds.
Chronic wounds are associated with significant morbidity, mortality, and economic burden. Once a wound has settled into a senescent phase, outside factors must be used to convert that wound back to a more acute phase. Traditional methods, such as surgical debridement or biologic debridement, can cause removal of healthy tissue as well as pain to the patient. Enzymatic debridement has been under much scrutiny lately as popular drugs have been pulled by the Food and Drug Administration. The purpose of this study was to test feasibility, safety, and primary efficacy of 5 control subjects and 10 treatment subjects to the DermaStream system. It is a device that uses a continuously streaming infusion to create a stable, granular wound bed in a relatively short amount of time. The device provides for continuously streaming of therapeutic solutions to the wound while removing exudates by vacuum-assisted drainage throughout the treatment cycle.


Biosynthesis of silver nanoparticles using Euglena gracilis, Euglena intermedia and their extract.
Extracellular and intracellular biosynthesis of silver nanoparticles (AgNPs) by Euglena gracilis (EG) strain and Euglena intermedia (EI) strain are reported in this study. The obtained nanoparticles showed an absorption peak approximates 420 nm in the UV-visible spectrum, corresponding to the plasmon resonance of AgNPs. According to the result of inductively coupled plasma-atomic emission spectrometer, the intakes of silver ions by EI and EG are roughly equal. The transmission electron microscope (TEM) analysis of the successful in vivo and in vitro synthesised AgNPs indicated the sizes, ranging from 6 to 24 nm and 15 to 60 nm in diameter, respectively, and a spherical-shaped polydispersal of the particles. The successful formation of AgNPs has been confirmed by energy dispersive X-ray analysis connected to the TEM. The Fourier transform infrared spectroscopy measurements reveal the presence of bioactive functional groups such as amines are found to be the capping and stabilising agents of nanoparticles. To our knowledge, this is the first report where two kinds of Euglena microalga were used as the potential source for in vivo and in vitro biosynthesis of AgNPs.


The impact of pyrethroid resistance on the efficacy and effectiveness of bednets for malaria control in Africa.
Long lasting pyrethroid treated bednets are the most important tool for preventing malaria. Pyrethroid resistant Anopheline mosquitoes are now ubiquitous in Africa, though the public health impact remains unclear, impeding the deployment of more expensive nets. Meta-analyses of bioassay studies and experimental hut trials are used to characterise how pyrethroid resistance changes the efficacy of standard bednets, and those containing the synergist piperonyl butoxide (PBO), and assess its impact on malaria control. New bednets provide substantial personal protection until high levels of resistance, though protection may wane faster against more resistant mosquito populations as nets age. Transmission dynamics models indicate that even low levels of resistance would increase the incidence of malaria due to reduced mosquito mortality and lower overall community protection over the life-time of the net. Switching to PBO bednets could avert up to 0.5 clinical cases per person per year in some resistance scenarios.


Effect of recording-beam ratio on diffraction efficiency of polarization holographic gratings in dye-doped liquid-crystal films.
The +1 order diffraction of polarization holographic gratings generated by two linear orthogonally polarized writing beams in dye-doped liquid-crystal films were increased by using two recording beams with unequal intensity. The maximum diffraction efficiency of the polarization holograms in our experimental sample can reach 23% when the intensity ratio of two recording beams is 7:1, and this value is almost triple that when the intensity ratio of two recording beams is 1:1.


Aclidinium bromide/formoterol fumarate fixed-dose combination for the treatment of chronic obstructive pulmonary disease.
Combining a long-acting β(2)-agonist (LABA) and a long-acting antimuscarinic agent (LAMA) is potentially a good pharmacological approach to improve clinical results in stable moderate chronic obstructive pulmonary disease (COPD) patients when symptoms are not adequately controlled with tiotropium monotherapy. Consequently, there is a strong interest in developing a LABA/LAMA fixed-dose combination therapy in an attempt to simplify the treatment. An aclidinium bromide/formoterol fumarate fixed-dose combination is under development. The few clinical data at our disposal suggest that the addition of formoterol fumarate to aclidinium bromide results in greater bronchodilation than formoterol fumarate or aclidinium bromide alone. However, a large Phase III program is involving a huge number of patients with moderate-to-severe COPD and consists of large long-term (from 24 to 52 weeks) pivotal clinical trials that have been designed to fulfil both European Medicines Agency (EMA) and Food and Drug Administration (FDA) requirements and are evaluating the efficacy and safety of this fixed-dose combination. Studies assessing the impact of aclidinium bromide/formoterol fumarate fixed-dose combination on COPD exacerbations, exercise capacity and hospitalisations are clearly needed to better detect its potential effects of disease modification in COPD. Moreover, it seems pragmatic to proceed with its introduction in the market at a highly competitive price.


Pursuing the Promise of Preschool: An Exploratory Investigation of the Perceptions of Parents Experiencing Homelessness.
Rates of homelessness are worsening in the United States, with a third of individuals experiencing homelessness being families with children. These families face many challenges, including limited social supports, insufficient access to services, and mental health concerns. These challenges inform a nuanced worldview, leading parents experiencing homelessness to understand their child's school life in unique ways. The purpose of this study is to explore how parents experiencing homelessness understand their children's participation in Head Start and publicly funded 4 K programs. We utilized semi-structured interviews with parents of 4 K students and applied an iterative approach for analysis to identify emergent themes and concepts. Results suggest families enter homelessness through several avenues and struggle with many aspects of homelessness, including stigma directed at parents and children. Parents identified many strengths in their children's school programs, including education and support from faculty, as well as areas for growth, such as more comprehensive transportation and meal services. Overall, these results suggest families experiencing homelessness encounter many barriers to finding stable housing. Additionally, parents of children experiencing homelessness value their child's education and access to resources in schools while still fearing the potential for their child to experience stigmatization and discrimination in schools.


A Pilot Randomized Trial of a Brief Intervention to Prevent Suicide After Inpatient Psychiatric Discharge.
Risk for suicide is high after psychiatric hospitalization. The World Health Organization's Brief Intervention and Contact (BIC) program has shown efficacy in preventing suicide. A version adapted for the U.S. Department of Veterans Affairs (VA) was studied to determine preliminary effects. Patients receiving psychiatric hospitalization because of acute risk for self-harm were randomly assigned to the VA BIC or standard care alone. Effect sizes (Hedges' g) for suicidal ideation (primary outcome), social connectedness (measured as thwarted belongingness and perceived burdensomeness), hopelessness, and engagement were calculated at 1 and 3 months. Patients were randomly assigned to the VA BIC (N=10) or standard care (N=9). The VA BIC had a medium or large effect on most measures at 1 month (suicidal ideation, g=0.45). Effects diminished at 3 months, except for thwarted belongingness (g=0.81). The VA BIC had meaningful effects on suicide-related outcomes. The largest effect was seen in the first month.


A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions.
Benign familial neonatal convulsions (BFNC) is a rare dominantly inherited epileptic syndrome characterized by frequent brief seizures within the first days of life. The disease is caused by mutations in one of two recently identified voltage-gated potassium channel genes, KCNQ2 or KCNQ3. Here, we describe a four-generation BFNC family carrying a novel mutation within the distal, unconserved C-terminal domain of KCNQ2, a 1-bp deletion, 2513delG, in codon 838 predicting substitution of the last seven and extension by another 56 amino acids. Three family members suffering from febrile but not from neonatal convulsions do not carry the mutation, confirming that febrile convulsions and BFNC are of different pathogenesis. Functional expression of the mutant channel in Xenopus oocytes revealed a reduction of the potassium current to 5% of the wild-type current, but the voltage sensitivity and kinetics were not significantly changed. To find out whether the loss of the last seven amino acids or the C-terminal extension because of 2513delG causes the phenotype, a second, artificial mutation was constructed yielding a stop codon at position 838. This truncation increased the potassium current by twofold compared with the wild type, indicating that the pathological extension produces the phenotype, and suggesting an important role of the distal, unconserved C-terminal domain of this channel. Our results indicate that BFNC is caused by a decreased potassium current impairing repolarization of the neuronal cell membrane, which results in hyperexcitability of the central nervous system.


Feasibility of increasing childhood outdoor play and decreasing television viewing through a family-based intervention in WIC, New York State, 2007-2008.
Active Families is a program developed to increase outdoor play and decrease television viewing among preschool-aged children enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). Our objective was to assess its feasibility and efficacy. We implemented Active Families in a large WIC clinic in New York State for 1 year. To this end, we incorporated into WIC nutrition counseling sessions a community resource guide with maps showing recreational venues. Outcome measures were children's television viewing and time playing outdoors and parents' behaviors (television viewing, physical activity), self-efficacy to influence children's behaviors, and parenting practices specific to television viewing. We used a nonpaired pretest and posttest design to evaluate the intervention, drawing on comparison data from 3 matched WIC agencies. Compared with the children at baseline, the children at follow-up were more likely to watch television less than 2 hours per day and play outdoors for at least 60 minutes per day. Additionally, parents reported higher self-efficacy to limit children's television viewing and were more likely to meet physical activity recommendations and watch television less than 2 hours per day. Results suggest that it is feasible to foster increased outdoor play and reduced television viewing among WIC-enrolled children by incorporating a community resource guide into WIC nutrition counseling sessions. Future research should test the intervention with a stronger evaluation design in multiple settings, with more diverse WIC populations, and by using more objective outcome measures of child behaviors.


Thyroid hormones in the regulation of brown adipose tissue thermogenesis.
A normal thyroid status is crucial for body temperature homeostasis, as thyroid hormone regulates both heat loss and conservation as well as heat production in the thermogenic tissues. Brown adipose tissue (BAT) is the major site of non-shivering thermogenesis and an important target of thyroid hormone action. Thyroid hormone not only regulates the tissue's sensitivity to sympathetic stimulation by norepinephrine but also the expression of uncoupling protein 1, the key driver of BAT thermogenesis. Vice versa, sympathetic stimulation of BAT triggers the expression of deiodinase type II, an enzyme that enhances local thyroid hormone availability and signaling. This review summarizes the current knowledge on how thyroid hormone controls BAT thermogenesis, aiming to dissect the direct actions of the hormone in BAT and its indirect actions via the CNS, browning of white adipose tissue or heat loss over body surfaces. Of particular relevance is the apparent dose dependency of the observed effects, as we find that minor or moderate changes in thyroid hormone levels often have different effects as compared to high pharmacological doses. Moreover, we conclude that the more recent findings require a reevaluation of older studies, as key aspects such as heat loss or central BAT activation may not have received the necessary attention during the interpretation of these early findings. Finally, we provide a list of what we believe are the most relevant questions in the field that to date are still enigmatic and require further studies.


Laparoscopy-assisted resection of complicated Meckel's diverticulum in adults.
The era of videoendoscopic surgery in emergency surgery practice has facilitated a wide range of endoscopic operative procedures. In our unit the diagnosis of acute abdomen is made after sequential clinical and laboratory examination, and diagnostic laparoscopy is advocated. Laparoscopy-assisted resection of complicated Meckel's diverticulum in two adult patients was performed, and the results are discussed. Between December 1996 and June 2000, 98 patients underwent diagnostic laparoscopy at the Cerrahpasa Medical Faculty Emergency Surgery Unit of Istanbul University because of signs and symptoms of acute abdomen. Among these, we have diagnosed one case of intestinal obstruction due to a volvulus around Meckel's diverticulum and one of acute abdomen masquerading as acute appendicitis but actually involving omphalomesenteric duct cyst torsion. Both of these patients underwent diagnostic laparoscopy and laparoscopy-assisted Meckel's diverticulectomy. Diagnostic laparoscopies were performed on 46 male (47%) and 52 female (53%) patients. In all cases, laparoscopy successfully confirmed the diagnosis. Although in 27 patients the interventions were converted to open procedures, the operations were completed laparoscopically in 71 patients. Two of these patients underwent laparoscopy-assisted Meckel's diverticulectomy and their postoperative periods were uneventful. Both patients were discharged from the hospital on their fourth postoperative day. Diagnostic laparoscopy is a safe and effective method for diagnosis of acute abdomen. In emergency surgery practices in developing countries, advanced laparoscopy should be performed to reduce expenses. Laparoscopy-assisted Meckel's diverticulectomy is a safe and economic procedure and can be performed in adults for treatment of complicated cases without staplers.


On the near-wall accumulation of injectable particles in the microcirculation: smaller is not better.
Although most nanofabrication techniques can control nano/micro particle (NMP) size over a wide range, the majority of NMPs for biomedical applications exhibits a diameter of ~100 nm. Here, the vascular distribution of spherical particles, from 10 to 1,000 nm in diameter, is studied using intravital microscopy and computational modeling. Small NMPs (≤100 nm) are observed to move with Red Blood Cells (RBCs), presenting an uniform radial distribution and limited near-wall accumulation. Larger NMPs tend to preferentially accumulate next to the vessel walls, in a size-dependent manner (~70% for 1,000 nm NMPs). RBC-NMP geometrical interference only is responsible for this behavior. In a capillary flow, the effective radial dispersion coefficient of 1,000 nm particles is ~3-fold larger than Brownian diffusion. This suggests that sub-micron particles could deposit within diseased vascular districts more efficiently than conventional nanoparticles.


Luteolin suppresses oral carcinoma 3 (OC3) cell growth and migration via modulating polo-like kinase 1 (PLK1) expression and cellular energy metabolism.
Oral squamous cell carcinoma (OSCC) is a prevalent malignant tumor affecting the head and neck region (Leemans et al., 2018). It is often diagnosed at a later stage, leading to a poor prognosis (Muzaffar et al., 2021; Li et al., 2023). Despite advances in OSCC treatment, the overall 5-year survival rate of OSCC patients remains alarmingly low, falling below 50% (Jehn et al., 2019; Johnson et al., 2020). According to statistics, only 50% of patients with oral cancer can be treated with surgery. Once discovered, it is more frequently at an advanced stage. In addition, owing to the aggressively invasive and metastatic characteristics of OSCC, most patients die within one year of diagnosis. Hence, the pursuit of novel therapeutic drugs and treatments to improve the response of oral cancer to medication, along with a deeper understanding of their effects, remains crucial objectives in oral cancer research (Johnson et al., 2020; Bhat et al., 2021; Chen et al., 2023; Ruffin et al., 2023).


Age-related changes in the activities of epoxide hydrolases in different tissues of mice.
Age-related changes in epoxide hydrolase (EH) activity in the liver, kidney, lung, and intestine were studied in male C57BL/6 mice of 1 through 30 months of age. Hepatic cytosolic EH activity increased until 15 months after which there was a decline of 59% during senescence (30 months). Hepatic EH activity in the mitochondrial fraction increased until 4 months and decreased thereafter with a 43% decline by 30 months. The hepatic microsomal EH activity increased until 6 months followed by decline of 32% by 30 months. All of these increases and declines were statistically significant. Renal cytosolic EH showed maximum activity at 6 months after which the activity decreased significantly with age. However, renal EH activity in the mitochondrial fraction, in general, did not change substantially with age. Although changes in renal microsomal EH activity were small, the decrease in activity at 9-18 months was significantly lower than at 1 month and 23-30 months. EH activity in the cytosolic, mitochondrial and microsomal fractions of kidney was 2.5-, 2-, and 10-fold less, respectively, than that found in similar subcellular fractions of liver. Cytosolic EH activity in lung and intestine and lung microsomal EH showed variations with age. The intestinal microsomal EH was not detectable under the experimental conditions used.


Trochanteric repair and reconstruction in revision total hip arthroplasty.
Repair and reconstruction of the greater trochanter in revision total hip arthroplasty requires a system that achieves rigid fixation of fragile bone stock that often is nothing but a fragmented cortical shell. This fixation must be done with a mechanism that does not disrupt the blood supply and soft tissue attachments to the bone fragments and also does not require extensive stripping of muscle from the femoral shaft. The implants must be absolutely smooth in the region of the trochanter so they can glide under the fascia lata or else be minimally invasive so that they lie under the soft tissues of the femur and thus avoid abrading the overlying fascia. The technique described here uses a cable around the femur and 2 cables over the top of the greater trochanter. The results have been good in 10 of 11 hips. One required reoperation and bone grafting.


Early quantitative evaluation of indocyanine green angiography in patients with critical limb ischemia.
Patients requiring lower extremity revascularization are increasingly complex. Traditional means of evaluating perfusion before and after revascularization are often limited by the presence of medial calcinosis, open wounds, prior toe or forefoot amputations, and infection. We evaluated the initial application of indocyanine green angiography (ICGA) to patients with severe lower extremity ischemia to develop quantitative, reproducible parameters to assess perfusion. ICGA uses a charge-coupled device camera, a laser, and intravenous contrast to visually assess skin surface perfusion. From January 2011 to April 2012, we performed ICGA within 5 days of 31 revascularization procedures in patients with Rutherford class 5 and 6 ischemia. We also compared ICGA before and after revascularization in a subset of 13 patients. We evaluated multiple, quantitative parameters to assess perfusion. Twenty-four patients underwent ICGA associated with 31 revascularization procedures (26 endovascular, four open, one hybrid) for 26 lower limb wounds; 92% were diabetic and 20% were dialysis-dependent. In 50% of these patients, it was not possible to measure ankle-brachial indexes due to medial calcinosis. Paired analysis of ingress (increase in pixel strength [PxS]), ingress rate (slope of increase in PxS), curve integral (area under the curve in PxS over time), end intensity (PxS at end of study), egress (decrease in PxS from maximum), and egress rate (slope of decrease in PxS) increased significantly (P < .05) after revascularization. ICGA provides rapid visual and quantitative information about regional foot perfusion. We believe this is the first report describing quantification of foot perfusion before and after lower extremity revascularization for severe limb ischemia. Further study is warranted to help define the utility of this intriguing new technology to assess perfusion, response to revascularization, and potentially, to predict likelihood of wound healing.


Metabolism of L-(U-14C)valine, L-(U-14C)leucine, L-(U-14C)histidine and L-(U-14C) phenylalanine by the isolated perfused lactating guinea-pig mammary gland.
1. The incorporation of L-[U-14C]leucine, L[U-14C]histidine and L-[U-14C]phenylalanine into casein secreted during perfusion of isolated guinea-pig mammary glands was demonstrated. 2. The extent of incorporation of label into casein residues was consistent with their being derived from free amino acids of the perfusate plasma. 3. The mean transit time of the amino acids from perfusate into secreted casein was approx. 100 min. 4. Whereas radioactive histidine and phenylalanine were incorporated solely into milk protein, radioactivity from [U-14C]valine was also transferred to CO2 and to an unidentified plasma component, and from [U-14C]leucine to plasma glutamic acid. 5. Evidence from experiments with [U-14C]phenylalanine suggests that, as in rats, but in contrast with ruminant species, guinea-pig mammary tissue does not possess phenyl alanine hydroxylase activity. 6. The results are discussed in relation to the possible role of essential amino acid catabolism in the control of milk-protein synthesis.


What the Heck?-Automated Regioselectivity Calculations of Palladium-Catalyzed Heck Reactions Using Quantum Chemistry.
We present a quantum chemistry (QM)-based method that computes the relative energies of intermediates in the Heck reaction that relate to the regioselective reaction outcome: branched (α), linear (β), or a mix of the two. The calculations are done for two different reaction pathways (neutral and cationic) and are based on r 2SCAN-3c single-point calculations on GFN2-xTB geometries that, in turn, derive from a GFNFF-xTB conformational search. The method is completely automated and is sufficiently efficient to allow for the calculation of thousands of reaction outcomes. The method can mostly reproduce systematic experimental studies where the ratios of regioisomers are carefully determined. For a larger dataset extracted from Reaxys, the results are somewhat worse with accuracies of 63% for β-selectivity using the neutral pathway and 29% for α-selectivity using the cationic pathway. Our analysis of the dataset suggests that only the major or desired regioisomer is reported in the literature in many cases, which makes accurate comparisons difficult. The code is freely available on GitHub under the MIT open-source license: https://github.com/jensengroup/HeckQM.


Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid-Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario.
Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism are not understood. Our previous studies uncovered alterations in the ATPase H+/K+ Transporting Subunit Alpha (ATP4A) proton pump that triggered an internal cell acid-base imbalance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid-base balance. Thus, we built a custom gene panel with 12 genes based on the suggested mechanism to evaluate a new series of 69 APS patients. In total, 64 filtered putatively damaging variants in the 12 genes of the panel were found in 54.17% of the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, proposing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for polyautoimmunity that explains not only gastric disease, but also thyrogastric pathology and disease co-occurrence in APS that are different from clinical incidental findings. This opens a new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients.


Capsaicin sensitive-sensory nerves and blood pressure regulation.
Capsaicin (8-methyl-N-vannillyl-6-nonenamide), via binding to the vanilloid receptor subtype 1 (VR1), stimulates a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicin-sensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a "sensory-effector" function. Regarding the latter, these neurons release stored neuropeptides through a calcium-dependent mechanism via the binding of capsaicin to the VR1. A subset of capsaicin-sensitive sensory nerves contains calcitonin gene-related peptide (CGRP) and substance P (SP). These sensory neuropeptides are potent vasodilators and natriuretic/diuretic factors. Neonatal degeneration of capsaicin-sensitive sensory nerves has revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms are reviewed, which include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neuro-hormonal systems to maintain normal blood pressure when challenged with salt loading. Mechanisms underlying pneumotoxicity and pulmonary hypertension as revealed by degeneration of capsaicin-sensitive nerves are also discussed. Finally, the therapeutic utilities of capsaicin, endogenous anandamide, and CGRP agonists are assessed.


Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols.
Historically, adolescents with acute lymphoblastic leukemia (ALL) have had inferior outcomes when compared with younger children. We report the outcome of adolescents treated on Dana-Farber Cancer Institute (DFCI; Boston, MA) ALL Consortium Protocols conducted between 1991 and 2000. A total of 844 patients aged 1 to 18 years, with newly diagnosed ALL were enrolled onto two consecutive DFCI-ALL Consortium Protocols. We compared outcomes in three age groups: children aged 1 to 10 years (n = 685), young adolescents aged 10 to 15 years (n = 108), and older adolescents aged 15 to 18 years (n = 51). With a median follow-up of 6.5 years, the 5-year event-free survival (EFS) for those aged 1 to 10 years was 85% (SE, 1%), compared with 77% (SE, 4%) for those aged 10 to 15 years, and 78% (SE, 6%) for those aged 15 to 18 years (P = .09). Adolescents were more likely to present with T-cell phenotype (P < .001) and less likely to have the TEL-AML1 fusion (P = .05). The incidence of pancreatitis and thromboembolic complications, but not asparaginase allergy, was higher in patients 10 years of age compared with those younger than 10 years. However, there was no difference in the rate of treatment-related complications between the 10- to 15-year and 15- to 18-year age groups. Adolescents were more likely to present at diagnosis with biologically higher risk disease (T-cell phenotype and absence of the TEL-AML1 fusion) and more likely to experience treatment-related complications than younger children. However, the 5-year EFS for older adolescents was 78% +/- 6%, which is superior to published outcomes for similarly aged patients treated with other pediatric and adult ALL regimens. Based on this experience, we currently are piloting our regimen in patients aged 18 to 50 years.


Benefit evaluation in multiple sclerosis relapse treatment from the patients' perspective - Development and validation of a new questionnaire.
Little is known on how to measure patient-relevant benefit of relapse treatment in relapsing-remitting multiple sclerosis (MS). The objective of this study was to develop and validate a new method for monitoring recovery from MS relapses and patient-relevant treatment benefits. A 27-item questionnaire was developed using a multi-step approach comprising open item collection, multidisciplinary expert panel and cognitive debriefing. It was evaluated regarding psychometric properties and feasibility in a longitudinal validation study with 100 patients with MS undergoing relapse treatment. Construct validity was tested by correlations with patient and physician global impressions of change as well as disease-specific and generic health-related quality of life (HRQoL) measures. Results of the feasibility survey indicated high patient acceptance. Reliability was high (Cronbach's α = 0.90). While the Expanded Disability Status Scale (EDSS) was not sensitive to change, Patient Benefit Index for Multiple Sclerosis (PBI-MS) showed a high correlation cross-sectionally with patient global impression of change (PaGIC) (r = 0.60, p < 0.001). Significant moderate to high correlations were found with change in generic HRQoL (r = 0.55-0.61, p < 0.001) and lower correlations with change in disease-specific HRQoL (r = -0.36, p < 0.01). The PBI-MS is a reliable and valid instrument for ascertaining patient-relevant benefits of acute relapse treatment; it appears suited for use in routine care and in clinical or health care studies.


Diagnosing coeliac disease and the potential for serological markers.
The diagnosis of coeliac disease has advanced in the past decade owing to increased clinical awareness and improved tests. Coeliac disease is now regarded as a common disease presenting at any age with a broad spectrum of symptoms. Previous guidelines on diagnosis relied on the histological analysis of duodenal biopsy samples. However, contemporary antibody analysis is a diagnostic tool with a comparatively high accuracy that has reduced reliance on performing biopsies. Furthermore, determination of HLA-based genetic susceptibility to coeliac disease has become routine. European and North American guidelines utilize symptoms, coeliac antibodies (primarily tissue transglutaminase 2 IgA and endomysial IgA antibodies), HLA determination and histological analysis of biopsy tissue for diagnosis. Some guidelines conclude that the diagnostic accuracy of tissue transglutaminase 2 IgA antibodies is sufficient to omit duodenal biopsies in selected children with very high antibody levels, in the presence of clear symptom response as well as a positive endomysial antibody test and confirmation of genetic susceptibility. This Review discusses if such a strategy is appropriate for children and adults in all populations. The performance characteristics of antibody tests (particularly of the tissue transglutaminase 2 IgA test) including quality control and characterisation of the population in whom testing is performed are also discussed.


Enteric neuropathy in horses with grass sickness.
The degeneration of enteric neurones has been recorded in grass sickness, but the distribution of the lesions in the gut and their possible relationship with the severity of the clinical signs has not been established. Samples obtained from 11 anatomically defined sites along the gastrointestinal tract of eight control horses without gastrointestinal disease, five horses with acute grass sickness and three horses with chronic grass sickness were examined histologically. The organisation of the enteric ganglia was similar to that in other large mammalian species. Minor exceptions included the presence of fundic mucosal nerve cell bodies and blood vessels within submucosal ganglia. All the horses with grass sickness had severe enteric neuropathy, widespread in the acute cases but localised to the distal small intestine in the chronic cases. These neuronal lesions are consistent with, and may explain the intractable gastrointestinal propulsive deficit that characterises grass sickness.


Species life-history strategies affect population responses to temperature and land-cover changes.
Human-induced environmental changes have a direct impact on species populations, with some species experiencing declines while others display population growth. Understanding why and how species populations respond differently to environmental changes is fundamental to mitigate and predict future biodiversity changes. Theoretically, species life-history strategies are key determinants shaping the response of populations to environmental impacts. Despite this, the association between species life histories and the response of populations to environmental changes has not been tested. In this study, we analysed the effects of recent land-cover and temperature changes on rates of population change of 1,072 populations recorded in the Living Planet Database. We selected populations with at least 5 yearly consecutive records (after imputation of missing population estimates) between 1992 and 2016, and for which we achieved high population imputation accuracy (in the cases where missing values had to be imputed). These populations were distributed across 553 different locations and included 461 terrestrial amniote vertebrate species (273 birds, 137 mammals, and 51 reptiles) with different life-history strategies. We showed that populations of fast-lived species inhabiting areas that have experienced recent expansion of cropland or bare soil present positive populations trends on average, whereas slow-lived species display negative population trends. Although these findings support previous hypotheses that fast-lived species are better adapted to recover their populations after an environmental perturbation, the sensitivity analysis revealed that model outcomes are strongly influenced by the addition or exclusion of populations with extreme rates of change. Therefore, the results should be interpreted with caution. With climate and land-use changes likely to increase in the future, establishing clear links between species characteristics and responses to these threats is fundamental for designing and conducting conservation actions. The results of this study can aid in evaluating population sensitivity, assessing the likely conservation status of species with poor data coverage, and predicting future scenarios of biodiversity change.


G541R within the 4070A TM protein regulates fusion in murine leukemia viruses.
The mutation G541R within the ectodomain of TM was isolated in three independent chimeric enveloped murine leukemia virus (MuLV) viral populations originally impaired in viral passage and in wild-type 4070A. Isolation of G541R in multiple populations suggested it played a critical role in viral envelope function. Using a viral vector system, the observed effects of the G541R mutation within MuLV envelope proteins were pleiotropic and included effects on the regulation of SU-TM interactions and membrane fusion. G541R suppresses enhanced cell-cell fusion events attributable to the absence of the R-peptide yet does not adversely affect virus titers. The ability to suppress cell-cell fusion is dependent on the presence of the C terminus of the amphotropic 4070A SU protein. Within the wild-type 4070A envelope background, the mutation results in a decreased level of Env at the cell surface that is mirrored in the virion. The TM mutation alters recognition of the SU C terminus by a monoclonal antibody, suggestive of an altered conformation. The presence of G541R allowed the virus to achieve a balance between cytopathogenicity and replication and restored productive viral entry.


Intravenous Acetaminophen vs. Ketorolac in Terms of Pain Management in Prehospital Emergency Services: A Randomized Clinical Trial.
Although pain management in EDs has been fully addressed in clinical trials, prehospital settings have rarely been investigated. The present study was conducted to compare the effectiveness of intravenous acetaminophen with that of ketorolac in pre-hospital pain control. This randomized clinical trial (RCT) was performed at a prehospital setting during EMS missions in Tehran, Iran. The eligible candidates comprised all patients over the age of 7 years with a complaint of moderate to severe pain. The patients were randomly assigned to two groups, one receiving 30 mg of intravenous (IV) ketorolac and the other 1 g of IV acetaminophen. The pain intensity was measured using a visual analog scale (VAS) before administering the analgesic and upon admission to the ED. The present study was conducted on 150 patients aged 8-81 years with a mean age of 40.4 ± 17.7, including 84 (56%) males. The mean reduction in the pain score was 14.9±8.6 in the acetaminophen group and 16.0±8.8 in the ketorolac group. Univariate analyses suggested no statistically significant differences between the two groups in terms of delta pain score (pain reduction) (P=0.429). Based on the obtained findings, both ketorolac and acetaminophen could be administered for pain management in prehospital settings in both traumatic and non-traumatic patients in case their contraindications are considered.


Sensing the Messenger: Potential Roles of Cyclic-di-GMP in Rickettsial Pathogenesis.
Pathogenic bacteria causing human rickettsioses, transmitted in nature by arthropod vectors, primarily infect vascular endothelial cells lining the blood vessels, resulting in 'endothelial activation' and onset of innate immune responses. Nucleotide second messengers are long presumed to be the stimulators of type I interferons, of which bacterial cyclic-di-GMP (c-di-GMP) has been implicated in multiple signaling pathways governing communication with other bacteria and host cells, yet its importance in the context of rickettsial interactions with the host has not been investigated. Here, we report that all rickettsial genomes encode a putative diguanylate cyclase pleD, responsible for the synthesis of c-di-GMP. In silico analysis suggests that although the domain architecture of PleD is apparently well-conserved among different rickettsiae, the protein composition and sequences likely vary. Interestingly, cloning and sequencing of the pleD gene from virulent (Sheila Smith) and avirulent (Iowa) strains of R. rickettsii reveals a nonsynonymous substitution, resulting in an amino acid change (methionine to isoleucine) at position 236. Additionally, a previously reported 5-bp insertion in the genomic sequence coding for pleD (NCBI accession: NC_009882) was not present in the sequence of our cloned pleD from R. rickettsii strain Sheila Smith. In vitro infection of HMECs with R. rickettsii (Sheila Smith), but not R. rickettsii (Iowa), resulted in dynamic changes in the levels of pleD up to 24 h post-infection. These findings thus provide the first evidence for the potentially important role(s) of c-di-GMP in the determination of host-cell responses to pathogenic rickettsiae. Further studies into molecular mechanisms through which rickettsial c-di-GMP might regulate pathogen virulence and host responses should uncover the contributions of this versatile bacterial second messenger in disease pathogenesis and immunity to human rickettsioses.


Does the subtype of acute coronary syndrome treated by percutaneous coronary intervention predict long-term clinical outcomes?
The prognosis of patients undergoing percutaneous coronary intervention (PCI) for different subtypes of acute coronary syndromes (ACS) remains unclear. We compared short- and long-term mortality in patients undergoing PCI for unstable angina (UA), non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). This was a retrospective cohort study of 13 184 patients (5966 STEMI, 5307 NSTEMI, and 1911 UA) undergoing PCI between 1 January 2005 and 30 November 2013 in a multi-centre registry. Clinical and procedural characteristics, as well as outcomes, were compared by ACS subtype. Long-term all-cause mortality data were obtained via linkage to the National Death Index (NDI). Patients with STEMI compared with NSTEMI and UA were younger (62.9 ± 12.8 vs. 64.7 ± 12.5 vs. 65.5 ± 11.8 years; P < 0.01), had fewer comorbidities including diabetes, heart failure, and previous myocardial infarction (all P < 0.01). Procedural success was similar across all groups (P = 0.54). In-hospital, 30-day and 1-year all-cause mortality increased significantly from UA to NSTEMI to STEMI patients (1-year mortality 2.5% vs. 4.5% vs. 8.7%; P < 0.01). Kaplan-Meier survival estimates showed increased early mortality in the STEMI group (log-rank P < 0.01). However, after approximately 8.2 years, survival was similar across all groups. In a proportional-odds model using flexible parametric survival modelling, ACS subtype was not an independent predictor of NDI-linked mortality [UA: odds ratio (OR) 0.85, 95% CI 0.71-1.02; STEMI: OR 1.01, 95% confidence interval (CI) 0.88-1.16; NSTEMI as reference category]. Despite disparate baseline characteristics and differences in short-term mortality, long-term mortality was similar across the spectrum of ACS treated by PCI and contemporary medical therapy.


Acute effects of superimposed electromyostimulation during cycling on myokines and markers of muscle damage.
The purpose of the present study was to evaluate the effects of superimposed electromyostimulation (E) during cycling on myokines and markers of muscle damage, as E might be a useful tool to induce a high local stimulus to skeletal muscle during endurance training without performing high external workloads. 13 subjects participated in three experimental trials each lasting 60 min in a randomized order. 1) Cycling (C), 2) Cycling with superimposed E (C+E) and 3) E. Interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), creatine kinase (CK) and myoglobin were determined before (pre) and 0', 30', 60', 240' and 24h after each intervention. Only C+E caused significant increases in levels of CK and myoglobin. BDNF and IL-6 significantly increased after C and C+E, however increases for IL-6 were significantly higher after C+E compared to C. The present study showed that superimposed E during cycling might be a useful tool to induce a high local stimulus to skeletal muscle even when performing low to moderate external workloads. This effect might be due the activation of additional muscle fibers and mild eccentric work due to the concomitant activation of agonist and antagonist. However the higher load to skeletal muscle has to be taken into account.


A sodium channel variant in Aedes aegypti as a candidate pathogen sensor for viral-associated molecular patterns.
Recent work demonstrated that a splice variant of a human macrophage voltage-gated sodium channel expressed on endosomes acts as an intracellular sensor for dsRNA, a viral-associated molecular pattern. Here our goal was to identify a candidate gene in a clinically relevant invertebrate model with related cellular and pattern recognition properties. The para gene in drosophila and other insects encodes voltage-gated sodium channels with similar electrophysiological properties to those found in vertebrate excitable membranes. A database search revealed that the AAEL006019 gene in Aedes aegypti, the yellow fever mosquito, encodes a voltage-gated sodium channel that is distinct from genes that encode para-like sodium channels. As compared to para-like channels, the protein products from this gene have deletions in the N-terminus and in the DII-DIII linker region. When over-expressed in an Aedes aegypti cell line, CCL-125, the AAEL006019 channel demonstrated cytoplasmic expression on vesicular-like organelles. Electrophysiologic analysis revealed that the channel mediates small inward currents that are enhanced by synthetic mimics of viral-derived ssRNA, R848 and ORN02, but not the dsRNA mimic, poly I:C. R848 treatment of CCL-125 cells that express high levels of the channels led to increased expression of RelA and Ago2, two mediators of insect innate immunity. These results suggest that the AAEL006019 channel acts as an intracellular pathogen sensor for ssRNA molecular patterns.


Identification of epicatechin as one of the key bioactive constituents of polyphenol-enriched extracts that demonstrate an anti-allergic effect in a murine model of food allergy.
Polyphenols are naturally derived bioactive compounds with numerous reported health benefits. We have previously reported on the beneficial effect of a polyphenol-enriched apple extract in a murine model of food allergy. The objectives of the present study were to elucidate the class of bioactive polyphenols that exhibit a beneficial anti-allergic effect and to assess whether the protective effect matches the in vivo bioavailable metabolite concentrations. Female BALB/c mice were sensitised to ovalbumin (OVA) following the protocol of a well-established murine model of food allergy. They were fed diets containing polyphenol-enriched extracts or purified epicatechin for 8 d after the last sensitisation. The sensitised mice were orally challenged with OVA after the intervention. The allergy symptoms, in addition to allergen-specific serum Ig concentrations and gene expression profiles in the intestine, of the control and treated mice were compared. Plasma samples were collected to compare the concentrations of bioavailable epicatechin metabolites in the treatment groups. Polyphenol-enriched fruit extracts containing epicatechin exhibited a significant anti-allergic effect in vivo. This effect was unambiguously attributed to epicatechin, as oral administration of this purified polyphenol to sensitised mice by inclusion in their diet modulated allergy symptoms in a dose-dependent manner. Immune parameters were also affected by the administration of epicatechin. Bioavailability measurements in plasma indicated that the attenuation of allergy symptoms could be due to the higher concentrations of bioavailable epicatechin metabolites. In conclusion, epicatechin is a key bioactive polyphenol that has the ability to modulate allergy outcomes in sensitised mice.


Estimating glomerular filtration rate in youth with obesity and type 2 diabetes: the iCARE study equation.
The validity of pediatric estimated glomerular filtration rate equations (eGFRs) in early stages of CKD including hyperfiltration is unknown. The purpose of this study was to develop an eGFR equation for adolescents with obesity and type 2 diabetes (T2D). eGFRs were developed from iohexol-derived GFRs (iGFRs) in 26 overweight/obese (BMI > 85th percentile) youth and 100 with T2D from the iCARE (Improving renal Complications in Adolescents with T2D through REsearch) cohort. Twenty percent of the cohort was withheld as a validation dataset. Linear regression analyses were used to develop the best formula based on body size, sex, creatinine, urea, ± cystatin C. Comparable validity of commonly used eGFR equations was assessed. Mean age 15.4 + 2.4 years, BMI Z-score 2.5 + 1.2, 61% female, and mean iGFR 129.0 + 27.7 ml/min/ 1.73 m2. The best adjusted eGFR formula (ml/min/1.73 m2) was 50.7 × BSA0.816 × (height (cm)/creatinine)0.405 × 0.8994 if sex = female | 1 otherwise. It resulted in 53.8% of eGFRs within 10% of measured iGFR and 96.2% within 30%. Bland-Altman 95% limits of agreement in the external dataset were - 37.6 to 45.5 ml/min/1.73m2 (bias = 3.96), and the correlation was 0.62. This equation performed better than all previously published creatinine-based eGFRs. cystatin C did not significantly improve results; however, some other cystatin C formulas also performed well. The iCARE equation provides a more accurate creatinine-based eGFR in obese youth with and without T2D. Further studies are warranted to evaluate within-subject variability and applicability to lower GFRs and other populations.


Cell growth of BG-1 ovarian cancer cells is promoted by di-n-butyl phthalate and hexabromocyclododecane via upregulation of the cyclin D and cyclin-dependent kinase-4 genes.
Endocrine-disrupting chemicals (EDCs) are environmentally persistent exogenous compounds released from various industrial products such as plastics, pesticides, drugs, detergents and cosmetics. They can cause a variety of adverse effects to the reproductive, developmental, immune and nervous systems in humans and wildlife. Di-n-butyl phthalate (DBP) is the main compound of phthalates and is reported to inhibit estrogen receptor (ER)-mediated gene expression and to interfere with normal fetal development of the male reproductive system. Hexabromocyclododecane (HBCD or HBCDD) is one of the brominated flame retardants (BFRs) which have been widely used in plastic, electronic and textile applications and are known to cause endocrine disruption with toxicity of the nervous system. In the present study, the estrogenic effects of DBP and HBCD were examined in an ovarian cancer cell line, BG-1, expressing high levels of ER via MTT assay and semi-quantitative reverse-transcription PCR. Treatment with DBP (10(-8)-10(-5) M) or HBCD (2 x 10(-8) -2 x 10(-6) M) resulted in increased cell proliferation of BG-1 cells as observed with 17-β estradiol (E2). In addition, both DBP and HBCD upregulated the expression levels of cell cycle-regulatory genes, such as cyclin D and cyclin-dependent kinase-4 (cdk-4), which are downstream target genes of ER, at 6 h after treatment. However, the expression of the p21 gene was not altered by DBP or HBCD at any time as with E2. Taken together, these results suggest that DBP and HBCD are EDCs which have apparent estrogenic activities by stimulating the cell proliferation of BG-1 cells and by inducing the expression of cyclin D and cdk-4. Our results suggest that DBP and HBCD have sufficient potency to disrupt the endocrine system and to stimulate cell growth in ER-positive cancer cells.


Acute effects of caffeine ingestion at rest in humans with impaired epinephrine responses.
Caffeine ingestion has been demonstrated to increase circulating epinephrine (Epi) and norepinephrine (NE), elevate free fatty acids (FFAs), and alter heart rate, blood pressure (BP), and ventilation in humans. Whether these physiological responses are a result of caffeine acting through direct stimulation of specific tissues via adenosine receptors or secondary to Epi increases is not known. In the present experiment, six tetraplegics (level of spinal cord lesions C4-C6) were tested at rest for 3 h to investigate the effects of 6 mg/kg caffeine in capsule form on subjects with impaired Epi responses. Ventilatory, cardiovascular, metabolic, and hormonal data were collected every 15-20 min after caffeine ingestion. There were no significant (P > 0.05) increases in plasma Epi after caffeine ingestion [0.19 +/- 0.04 (SE) nM (preingestion); 0.20 +/- 0.04 nM (80 min postingestion)] or in plasma NE [0.53 +/- 0.16 nM (preingestion); 0.49 +/- 0.09 nM (80 min postingestion; P > 0.05)]. However, significant increases were found in serum FFAs [0.53 +/- 0.08 nM (preingestion); 1.03 +/- 0.20 mM (40 min postingestion; P < 0.05] and in glycerol. These concentrations remained elevated throughout the experiment. BP increased in the first hour postingestion. These data demonstrate that caffeine in physiological doses directly stimulates specific tissues, i.e., adipose and peripheral vascular tissue, and these effects are not secondary to increases in Epi after caffeine ingestion.


Incidence of enhancement of the trigeminal nerve on MRI in patients with multiple sclerosis.
The purpose of this study is to review the incidence of contrast enhancement of the trigeminal nerve on magnetic resonance imaging (MRI) in a large cohort of patients with multiple sclerosis (MS). MRI scans of 851 MS patients participating in a phase III clinical trial were reviewed for the presence of gadolinium enhancement on postcontrast T1-weighted images. If enhancement was present, it was documented whether this involved only the proximal or also the distal part of the fifth nerve, and whether the abnormality was unilateral or bilateral. In 24 (2.8%) patients, enhancement of the trigeminal nerve was observed, and was bilateral in 16 (66.7%) of those. In 19 (79.2%) patients with abnormal nerves, enhancement extended to the distal part of the trigeminal nerve (into Meckel's cave). The results of this study indicate a high, probably clinically silent, incidence of trigeminal nerve demyelination in MS and frequent involvement of the peripheral type of myelin in MS.


Phosphodiesterase inhibitors in the treatment of erectile dysfunction.
Based on knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation and the development of new and selective pharmacological agents, selective phosphodiesterase (PDE) inhibitors were recently introduced in the treatment of erectile dysfunction. The presence of mRNAs specific for 13 different human phosphodiesterase isoenzymes and isoforms in human cavernous tissue was shown by RT-PCR. We detected an expression of the following genes encoding for both cAMP and cGMP hydrolyzing PDEs: all three isogenes of PDE I and PDE IIa, which do hydrolyze cAMP as well as cGMP; the specific cAMP hydrolyzing PDEs PDE IIIa, the four isogenes of PDE IV, PDE VIIa and PDE VIIIa and the cGMP-specific PDEs PDE Va and PDE IXa. By protein chemical methods, PDE-isoenzymes III, IV and V were characterized in the human cavernous smooth muscles. In functional organ bath studies using precontracted human cavernous tissue strips, PDE III and V inhibitors showed the most pronounced relaxant responses. In clinical studies, the use of the orally active PDE V inhibitor sildenafil induced a pronounced and significant erectogenic effect in patients both with predominantly psychogenic and organogenic etiology of erectile dysfunction. The first promising clinical data of the use of an orally active PDE inhibitor for the treatment of erectile dysfunction are well supported by consistent basic scientific findings. Further research will possibly allow to identify diagnostic tools for erectile dysfunction and for even more selective drugs in its therapy.


A pre-partum lift in ewe nutrition from a high-energy lick or maize or by grazing Lotus uliginosus pasture, increases colostrum production and lamb survival.
This experiment tested the hypothesis that a lift in the nutrition of ewes, before lambing, to increase colostrum production would enhance lamb survival. In all, 261 mature Corriedale ewes, each with a single fetus from a synchronised mating, grazed native pasture to day 130 after mating; at which point they were weighed, condition scored and allocated to graze either native pasture or a pasture dominant with Lotus uliginosus. Five days later (14 days before the expected start of lambing) the ewes were allocated to one of four treatments and fed: (i) native pasture alone, (ii) native pasture plus a commercial high-energy lick, (iii) L. uliginosus pasture alone or (iv) L. uliginosus pasture plus whole maize. The weight, viscosity and concentration of components and immunoglobulin G in the colostrum that had accumulated at parturition, were measured for 10 ewes in each treatment. The lambs that survived to 20 days of age from the 221 ewes that were not milked, were recorded. The ewes supplemented with the lick or maize grain and those that grazed the L. uliginosus pasture alone accumulated two to three times more colostrum at birth than the ewes that grazed native pasture alone (396, 635 and 662 g v. 206 g; P < 0.01). The colostrum from the ewes that grazed only native pasture was more viscous (lower score) than that from the ewes supplemented with the lick or maize grain or the ewes that grazed the L. uliginosus pasture alone (scores of 4.1 v. 6.2, 6.5 and 6.4, P < 0.001) and, not surprisingly, the concentration of lactose in the colostrum of the ewes fed only native pasture was also much lower (1.1% v. 3.0%, 2.8% and 2.6%; P < 0.001)he survival of lambs from the ewes fed only native pasture was less than that of the lambs from ewes fed native pasture plus the commercial lick (81.8% v. 95.5%; P < 0.05) or the L. uliginosus pasture alone (92.4%, P < 0.05), and also tended to be lower than that for lambs born to ewes fed L. uliginosus pasture plus maize (91.8%, P = 0.08). The concentration of glucose in the blood of the lambs from the ewes that grazed only native pasture was lower than that of the other lambs (42.1 v. 60.2 ng/ml, P = 0.012). We conclude that the marked increase in colostrum production associated with the lift in ewe nutrition, just prior to lambing, enhanced lamb survival.


Characteristics, sources, and health risks of PM2.5-bound trace elements in representative areas of Northern Zhejiang Province, China.
This study aimed to characterize PM2.5-bound trace elements in Northern Zhejiang Province (NZP), one of the most economically prosperous regions in China, and assess the associated health risks for the general populations. A year-long sampling campaign was conducted at four sites representative of urban, suburban, and rural areas of NZP. The average of the sum of twenty trace elements in PM2.5 was 2.8 ± 0.4 μg m-3, dominated by K, Al, Fe, Mg, Zn, and V (>100 ng m-3). The highest total elements' concentration occurred in winter, followed by autumn, spring, and summer. Enrichment factors and principal component analysis (PCA) revealed that the major sources of trace elements in NZP were fossil fuel combustion, biomass burning, crustal dust, traffic, and industrial emissions. Elevated concentrations of certain elements reflected featured sources in different areas, e.g., V and Ni from heavy oil combustion in the port city, and Cu, Fe and Ba from traffic emissions in urban areas. Arsenic (As) represented the major non-cancer risk driver as its hazard quotient was 8.7. The cumulative cancer risk from all the carcinogenic elements was 1.7 × 10-3 in NZP, exceeding the upper limit (10-4) of the acceptable risk range. As and Cr contributed 33% and 66%, respectively, and thus were regarded as cancer risk drivers. The high health risks from PM2.5-bound elements warrant future actions to control their emissions in this region. Priorities should target industrial operations and coal combustion emissions, as informed by the risk drivers.


Characterization of CD24 expression in intraductal papillary mucinous neoplasms and ductal carcinoma of the pancreas.
CD24 is a molecule involved in cell adhesion and tumor metastasis. The aims of this study were (1) to evaluate the association between CD24 expression and the progression of intraductal papillary mucinous neoplasms of the pancreas and (2) to investigate the association between CD24 expression in pancreatic cancer and the prognosis of patients who underwent curative pancreatectomy. Immunohistochemical analysis of CD24 was performed for 95 intraductal papillary mucinous neoplasms of the pancreas and 83 pancreatic cancers. We investigated the association between CD24 expression and the histologic grade of intraductal papillary mucinous neoplasms of the pancreas, the clinicopathologic parameters of pancreatic cancers, and the survival time of pancreatic cancer patients who underwent pancreatectomy. The positive rates of CD24 expression in intraductal papillary mucinous adenoma, borderline intraductal papillary mucinous neoplasm, noninvasive intraductal papillary mucinous carcinoma, and invasive intraductal papillary mucinous carcinoma were 5 (20%) of 24, 12 (48%) of 25, 10 (43%) of 23, and 15 (65%) of 23, respectively. The CD24-positive rates were significantly higher in borderline intraductal papillary mucinous neoplasm and intraductal papillary mucinous carcinoma compared with intraductal papillary mucinous adenoma (P = .046 and P = .007, respectively). The staining scores, which were determined from the percentage of stained cells and the staining intensity, were significantly higher in invasive intraductal papillary mucinous carcinoma than in noninvasive intraductal papillary mucinous carcinoma (P = .043). In the pancreatic cancers, higher tumor stage (P = .007), nodal metastasis (P = .021), and higher-grade tumors (P < .001) were more frequent in the CD24-positive group compared with the CD24-negative group. CD24 expression was associated with shorter survival in univariate analysis (P = .028) However, based on the multivariate analysis, the CD24 expression was not associated with survival. In conclusion, CD24 is involved in the progression of intraductal papillary mucinous neoplasms of the pancreas and in the malignant behavior of pancreatic cancers.


[Universal screening program and early intervention (USPEI) in congenital bilateral sensorineural hearing loss in Chile].
Congenital hearing loss is the total or partial inability to hear sounds through the ears. It is the most common disability in newborns in Chile and worldwide, and is a permanent condition. The direct impact on children who are not adequately diagnosed is the alteration in acquisition of language and cognitive skills and a decline in their social and school insertion, jeopardizing their professional and potentially productive life. Universal screening programs for hearing loss are essential for the diagnosis, since 50% of infants with hearing loss have no known risk factor. Screening before one month of age, confirmation before 3 months, and effective intervention before 6 months, allows the development of these children as if they had normal hearing. In Chile there is a selective program of screening for infants aged less than 32 weeks or 1,500 grams, as part of Explicit Health Guarantees, but it covers only 0.9% of newborns per year. Therefore, a large majority of children remain without diagnosis. The aim of this review is to compare the situation in Chile with other countries, raising the need to move towards a universal neonatal hearing loss screening program, and propose necessary conditions in terms of justification and implementation of a universal screening public policy.


Place learning by mechanical contact.
For some animals (e.g. the night-active wandering spider) the encounters with the habitat that result in place learning are predominantly mechanical. We asked whether place learning limited to mechanical contact, like place learning in general, entails vectors tied to individual landmarks and relations between landmarks. We constructed minimal environments for blindfolded human participants. Landmarks were raised steps. 'Home' was a mechanically indistinct location. Travel was linear. The mechanical contacts were those of walking, stepping, and probing with a soft-tipped cane. Home-orienting activities preceded tests of finding home from a given location with landmarks unchanged or (unbeknown to participants) shifted. In a one-landmark environment, perceived home shifted in the same direction, with the same magnitude, as the shifted landmark. In an environment of two landmarks located in the same direction from home, shifting the further landmark toward home resulted in a change in home's perceived location that preserved the original ratio of distances separating home, nearer landmark, and further landmark. Both findings were invariant over the travel route to the test location and repetitions of testing. It seems, therefore, that for humans (and, perhaps, for wandering spiders), mechanical contact can reveal the vectors and relations specifying places.


Reviewing Magnetic Particle Preparation: Exploring the Viability in Biosensing.
In this review article, we conceptually investigated the requirements of magnetic nanoparticles for their application in biosensing and related them to example systems of our thin-film portfolio. Analyzing intrinsic magnetic properties of different magnetic phases, the size range of the magnetic particles was determined, which is of potential interest for biosensor technology. Different e-beam lithography strategies are utilized to identify possible ways to realize small magnetic particles targeting this size range. Three different particle systems from 500 μm to 50 nm are produced for this purpose, aiming at tunable, vertically magnetized synthetic antiferromagnets, martensitic transformation in a single elliptical, disc-shaped Heusler Ni50Mn32.5Ga17.5 particle and nanocylinders of Co2MnSi-Heusler compound. Perspectively, new applications for these particle systems in combination with microfluidics are addressed. Using the concept of a magnetic on-off ratchet, the most suitable particle system of these three materials is validated with respect to magnetically-driven transport in a microfluidic channel. In addition, options are also discussed for improving the magnetic ratchet for larger particles.