Computer-aided screening for hallucinogenic and stimulant amphetamines with gas chromatography-Fourier transform infrared spectroscopy (GC-FTIR).
An expert system applied as a screening test for amphetamine analogues found in recreational-drug exhibits (tablets or powders) is described. The knowledge base defining the reference Fourier transform infrared spectroscopic (FTIR) spectral patterns has been built according to criteria encompassing toxicological, pharmacological, and neurochemical aspects. The class identity of a compound is determined within seconds using soft independent modeling of class analogy (SIMCA). The predictive value of the system, as assessed at a testing accuracy of 95%, is expressed by a total correct classification rate of 93.93% and by a 96.30% rate of true-positive amphetamines. The specificity and the selectivity of the screening test, evaluated by testing 159 toxicologically relevant compounds, are discussed, emphasizing the chemical and physical factors affecting these parameters. Medicinal amphetamines giving cross-reactions with traditional screening techniques produce a negative result. The specificity of the system characterizes the expert system as a highly sensitive, selective, fast, and user-friendly screening test that screens for amphetamines with prediction accuracy adequate for investigations in analytical toxicology.


Central nervous system involvement as a relapse of disseminated histoplasmosis in an Italian AIDS patient.
A case of an Italian AIDS patient who developed both meningitis and cerebral mass lesion as a final relapse of disseminated histoplasmosis is reported. Central nervous system (CNS) involvement occurred while the patient was receiving both amphotericin B and itraconazole as maintenance therapy, thus indicating the difficulty of eradicating histoplasmosis in patients with AIDS.


Dictionary-based matching graph network for biomedical named entity recognition.
Biomedical named entity recognition (BioNER) is an essential task in biomedical information analysis. Recently, deep neural approaches have become widely utilized for BioNER. Biomedical dictionaries, implemented through a masked manner, are frequently employed in these methods to enhance entity recognition. However, their performance remains limited. In this work, we propose a dictionary-based matching graph network for BioNER. This approach utilizes the matching graph method to project all possible dictionary-based entity combinations in the text onto a directional graph. The network is implemented coherently with a bi-directional graph convolutional network (BiGCN) that incorporates the matching graph information. Our proposed approach fully leverages the dictionary-based matching graph instead of a simple masked manner. We have conducted numerous experiments on five typical Bio-NER datasets. The proposed model shows significant improvements in F1 score compared to the state-of-the-art (SOTA) models: 2.8% on BC2GM, 1.3% on BC4CHEMD, 1.1% on BC5CDR, 1.6% on NCBI-disease, and 0.5% on JNLPBA. The results show that our model, which is superior to other models, can effectively recognize natural biomedical named entities.


Preferential expression of insulin-like growth factor binding proteins-1, -3, and -5 during early diabetic renal hypertrophy in rats.
The renal insulin-like growth factor-I (IGF-I) system has been implicated in the pathogenesis of renal hypertrophy, altered hemodynamics, and extracellular matrix expansion associated with early diabetes. The relative abundance of IGF binding proteins (IGFBPs) in the renal microenvironment may modulate IGF-I actions. However, the precise IGFBPs expressed in the glomerular and tubulointerstitial compartments during diabetic renal growth have not been characterized. In the present study, in situ hybridization studies were performed to examine the expression of IGFBP-1 to -6 messenger RNAs (mRNAs) 3, 7, and 14 days after streptozotocin (STZ) injection in rats. In control, nondiabetic kidneys, all six IGFBP mRNAs were differentially expressed with a predominance of IGFBP-5. The onset of renal hypertrophy in STZ-induced diabetes was associated with a rapid and site-specific induction of IGFBP-1, -3, and -5 mRNAs. In contrast, basal expression of IGFBP-2, -4, and -6 mRNAs was not altered in diabetic rats. IGFBP-5 mRNA expression increased in diabetic glomeruli, cortical, and inner medullary peritubular interstitial cells at days 3, 7, and 14. Although normal glomeruli failed to express IGFBP-3, it was induced concomitantly with IGFBP-5 in diabetic glomeruli and cortical peritubular interstitial cells. IGFBP-1 mRNA levels also increased in cortical tubular cells at each time point tested. Peak induction of IGFBP-3 and -5 was observed at day 3, whereas IGFBP-1 was delayed until day 7. IGFBP-1, -3, and -5 mRNA levels declined by day 14, but remained persistently elevated above control. By immunoperoxidase staining, similar alterations in the pattern of IGFBP-3 and -5 protein expression were observed at each time point. The preferential and site-specific increase in IGFBP-1, -3, and -5 suggest that these IGFBPs may regulate the local autocrine and/or paracrine actions of IGF-I and contribute to the pathogenesis of the early manifestations of diabetic nephropathy.


A Population-level Analysis of the Differing Effects of Rheumatoid Arthritis and Spondyloarthritis on Peripartum Outcomes.
The effects of rheumatoid arthritis (RA) and spondyloarthritis (SpA) on maternal and neonatal outcomes at a population level have not previously been well compared. A contemporary pregnancy cohort of 312,081 women and corresponding birth events was assembled for the province of Alberta from the random selection of 1 live birth event per woman. We identified 3 groups: (1) no inflammatory arthritis (no IA, n = 308,989), (2) RA (n = 631), and (3) SpA (n = 2461). We compared maternal and neonatal outcomes, comorbid conditions, and medication use among the 3 groups. Multivariable logistic regression models evaluated the independent association between RA and SpA, relative to no IA, and the outcomes of small for gestation age (SGA) and hypertensive disorders during pregnancy. Pregnant women with RA were significantly more likely to have preterm delivery (13.5%), cesarean delivery (33.9%), hypertensive disorders in pregnancy (10.5%), and SGA babies (15.6%), compared to pregnant women with either SpA or no IA. Nonsteroidal antiinflammatory drugs and corticosteroid use were significantly higher in pregnant women with RA compared to the other groups. Women with RA were significantly more likely to have an SGA baby (OR 1.51, 95% CI 1.21-1.88; p < 0.01), and hypertensive disorder in pregnancy (OR 1.51, 95% CI 1.16-1.97; p < 0.01), compared to women with no IA, while no difference was found between women with SpA and those with no IA. Women with RA have a higher risk of worse maternal and neonatal outcomes, whereas the risk of these events is similar between women with and without SpA.


Hydraulic and electric control of cell spheroids.
We use a theoretical approach to examine the effect of a radial fluid flow or electric current on the growth and homeostasis of a cell spheroid. Such conditions may be generated by a drain of micrometric diameter. To perform this analysis, we describe the tissue as a continuum. We include active mechanical, electric, and hydraulic components in the tissue material properties. We consider a spherical geometry and study the effect of the drain on the dynamics of the cell aggregate. We show that a steady fluid flow or electric current imposed by the drain could be able to significantly change the spheroid long-time state. In particular, our work suggests that a growing spheroid can systematically be driven to a shrinking state if an appropriate external field is applied. Order-of-magnitude estimates suggest that such fields are of the order of the indigenous ones. Similarities and differences with the case of tumors and embryo development are briefly discussed.


Bundling of cellulose microfibrils in native and polyethylene glycol-containing wood cell walls revealed by small-angle neutron scattering.
Wood and other plant-based resources provide abundant, renewable raw materials for a variety of applications. Nevertheless, their utilization would greatly benefit from more efficient and accurate methods to characterize the detailed nanoscale architecture of plant cell walls. Non-invasive techniques such as neutron and X-ray scattering hold a promise for elucidating the hierarchical cell wall structure and any changes in its morphology, but their use is hindered by challenges in interpreting the experimental data. We used small-angle neutron scattering in combination with contrast variation by poly(ethylene glycol) (PEG) to identify the scattering contribution from cellulose microfibril bundles in native wood cell walls. Using this method, mean diameters for the microfibril bundles from 12 to 19 nm were determined, without the necessity of cutting, drying or freezing the cell wall. The packing distance of the individual microfibrils inside the bundles can be obtained from the same data. This finding opens up possibilities for further utilization of small-angle scattering in characterizing the plant cell wall nanostructure and its response to chemical, physical and biological modifications or even in situ treatments. Moreover, our results give new insights into the interaction between PEG and the wood nanostructure, which may be helpful for preservation of archaeological woods.


'Regularly licensed and properly educated practitioners': professionalisation 1860-1910.
This chapter explores the later professionalisation of medicine at the Cape, particularly after the discovery of diamonds and gold, when the number of doctors increased. As the demand for an improved public health system grew, and the Colonial Medical Committee was unable to cope with the more complex demands of the colony, legislation was gradually set in place to transform the practice of medicine. This legislation included a Public Health Act, improved censuses, the registration of births and deaths, and a more effective registration of nurses as well as doctors and pharmacists. By the time the Cape entered the Union in 1910, it possessed modern, well-organised medical structures.


Latent profile approach to duration of stalking.
Stalking behavior and victim-stalker relationship are often the principal known factors in a stalking case. Thus, they are of great importance when trying to identify factors contributing to stalking duration. The present study aims to identify distinct subgroups of stalking victims based on measures of behavioral stalking dimensions. These victim subgroups, stalking dimensions, and victim-stalker relationship are examined in relation to stalking duration. Using a sample of 137 university students, latent profile analysis (LPA) revealed five distinct victim subgroups based on stalker behavior dimensions: surveillance, low-profile, social lurker, wide scope, and baseline stalkers. The subgroups were significantly related to stalking duration and explained a considerable amount of the variance along with the stalking dimensions and victim-stalker relationship. Connections to stalking literature and utility of person-orientated methods in stalking research are discussed.


A Palaeogene perspective on climate sensitivity and methane hydrate instability.
The Palaeocene-Eocene thermal maximum (PETM), a rapid global warming event and carbon-cycle perturbation of the early Palaeogene, provides a unique test of climate and carbon-cycle models as well as our understanding of sedimentary methane hydrate stability, albeit under conditions very different from the modern. The principal expression of the PETM in the geological record is a large and rapid negative excursion in the carbon isotopic composition of carbonates and organic matter from both marine and terrestrial environments. Palaeotemperature proxy data from across the PETM indicate a coincident increase in global surface temperatures of approximately 5-6 degrees C. Reliable estimates of atmospheric CO(2) changes and global warming through past transient climate events can provide an important test of the climate sensitivities reproduced by state-of-the-art atmosphere-ocean general circulation models. Here, we synthesize the available carbon-cycle model estimates of the magnitude of the carbon input to the ocean-atmosphere-biosphere system, and the consequent atmospheric pCO(2) perturbation, through the PETM. We also review the theoretical mass balance arguments and available sedimentary evidence for the role of massive methane hydrate dissociation in this event. The plausible range of carbon mass input, approximately 4000-7000 PgC, strongly suggests a major alternative source of carbon in addition to any contribution from methane hydrates. We find that the potential range of PETM atmospheric pCO(2) increase, combined with proxy estimates of the PETM temperature anomaly, does not necessarily imply climate sensitivities beyond the range of state-of-the-art climate models.


Reassessment of gamma-ray doses in Hiroshima and Nagasaki.
Reassessment of gamma-ray doses from the atomic bombs in Hiroshima and Nagasaki has been carried out with the thermoluminescent measurements of bricks and decorative tiles which were collected from the buildings that remain as they were at the time of the explosions. The thermoluminescent measurements were performed using a dating technique generally used in archaeology. Annual background dose rates from natural radionuclides in the brick and tile samples and from environmental radiations around the samples were determined with commercially available thermoluminescent detectors. The resultant gamma-ray doses in Hiroshima and Nagasaki are given as a function of distance from the hypocenters and are compared with the DS86 (Dosimetry System 1986) and the T65D (Tentative 1965 Dose).


Tunable Chirality of Self-Assembled Dipeptides Mediated by Bipyridine Derivative.
Supramolecular peptide assemblies have been widely used for the development of biomedical, catalytical, and optical materials with chiral nanostructures in view of the intrinsic chirality of peptides. However, the assembly pathway and chiral transformation behavior of various peptides remain largely elusive especially for the transient assemblies under out-of-equilibrium conditions. Herein, the N-fluorenylmethoxycarbonyl-protected phenylalanine-tyrosine dipeptide (Fmoc-FY) was used as a peptide assembly platform, which showed that the assembly proceeds multistep evolution. The original spheres caused by liquid-liquid phase separation (LLPS) can nucleate and elongate into the formation of right-handed helices which were metastable and easily converted into microribbons. Interestingly, a bipyridine derivative can be introduced to effectively control the assembly pathway and induce the formation of thermodynamically stable right-handed or left-handed helices at different stoichiometric ratios. In addition, the chiral assembly can also be regulated by ultrasound or enzyme catalysis. This minimalistic system not only broadens the nucleation-elongation mechanisms of protein aggregates but also promotes the controllable design and development of chiral biomaterials.


Transition state analogue structures of human phosphoglycerate kinase establish the importance of charge balance in catalysis.
Transition state analogue (TSA) complexes formed by phosphoglycerate kinase (PGK) have been used to test the hypothesis that balancing of charge within the transition state dominates enzyme-catalyzed phosphoryl transfer. High-resolution structures of trifluoromagnesate (MgF(3)(-)) and tetrafluoroaluminate (AlF(4)(-)) complexes of PGK have been determined using X-ray crystallography and (19)F-based NMR methods, revealing the nature of the catalytically relevant state of this archetypal metabolic kinase. Importantly, the side chain of K219, which coordinates the alpha-phosphate group in previous ground state structures, is sequestered into coordinating the metal fluoride, thereby creating a charge environment complementary to the transferring phosphoryl group. In line with the dominance of charge balance in transition state organization, the substitution K219A induces a corresponding reduction in charge in the bound aluminum fluoride species, which changes to a trifluoroaluminate (AlF(3)(0)) complex. The AlF(3)(0) moiety retains the octahedral geometry observed within AlF(4)(-) TSA complexes, which endorses the proposal that some of the widely reported trigonal AlF(3)(0) complexes of phosphoryl transfer enzymes may have been misassigned and in reality contain MgF(3)(-).


A review on computational systems biology of pathogen-host interactions.
Pathogens manipulate the cellular mechanisms of host organisms via pathogen-host interactions (PHIs) in order to take advantage of the capabilities of host cells, leading to infections. The crucial role of these interspecies molecular interactions in initiating and sustaining infections necessitates a thorough understanding of the corresponding mechanisms. Unlike the traditional approach of considering the host or pathogen separately, a systems-level approach, considering the PHI system as a whole is indispensable to elucidate the mechanisms of infection. Following the technological advances in the post-genomic era, PHI data have been produced in large-scale within the last decade. Systems biology-based methods for the inference and analysis of PHI regulatory, metabolic, and protein-protein networks to shed light on infection mechanisms are gaining increasing demand thanks to the availability of omics data. The knowledge derived from the PHIs may largely contribute to the identification of new and more efficient therapeutics to prevent or cure infections. There are recent efforts for the detailed documentation of these experimentally verified PHI data through Web-based databases. Despite these advances in data archiving, there are still large amounts of PHI data in the biomedical literature yet to be discovered, and novel text mining methods are in development to unearth such hidden data. Here, we review a collection of recent studies on computational systems biology of PHIs with a special focus on the methods for the inference and analysis of PHI networks, covering also the Web-based databases and text-mining efforts to unravel the data hidden in the literature.


Evidence based radiation therapy for locally advanced resectable and unresectable gastric cancer.
Despite the fact that gastric cancer is decreasing in incidence in the United States, it remains one of the most commonly diagnosed and most fatal cancers worldwide. In localised disease, surgery remains the cornerstone of treatment. Nevertheless, the low overall survival rates at 5 years due to locoregional and distant recurrences has led to a large debate regarding the role of radiation therapy and chemotherapy in addition to curative resection. Recent data have shown that, even with improved surgical techniques, locoregional failure rates in these patients ranged between 57% and 88%. Failures were noted in the gastric bed, regional nodes, gastric remnant, anastomosis and duodenal stump, all of which can be encompassed in a regional radiation field, indicating the need of further locoregional treatment. In this article, a comprehensive literature review of the reliable medical databases of PubMed and Cochrane is made and we present all available information on the role of radiation therapy in the preoperative and postoperative setting of gastric cancer. Data reported show that in locally advanced gastric cancer the addition of radiation therapy post surgery has significantly improved disease-free survival as well as overall survival. Moreover, in unresectable gastric cancer, the combination of radiation therapy with chemotherapy has significantly improved mean and overall survival rates. The role of radiation therapy in patients with resectable gastric cancer is being further evaluated in ongoing phase III trials.


Cardiovascular effects of lepadiformine, an alkaloid isolated from the ascidians Clavelina lepadiformis (Müller) and C. moluccensis (Sluiter).
The effects of lepadiformine, a natural marine alkaloid isolated from the ascidians Clavelina lepadiformis (Müller) and C. moluccensis (Sluiter), were studied in vivo by arterial blood pressure (aBP) recordings and electrocardiograms (ECG) in anaesthetised rats and in situ by peripheral vascular pressure recordings on perfused rabbit ear. Transmembrane resting (RP) and action (AP) potentials were also recorded by intracellular microelectrodes on electrically stimulated left ventricular papillary muscle and spontaneously beating atrium isolated from rat and frog hearts, respectively. Intravenous injection of lepadiformine (6mg/kg) produced marked bradycardia and a lengthening of ECG intervals as well as a transient decrease of aBP, which rapidly returned to normal. The decrease of aBP may have been related to a vasoconstrictor effect observed in the perfused ear experiment. Lepadiformine did not alter RP, but significantly lengthened the repolarising phase of AP in rat papillary muscle and frog atrium. Lepadiformine also mimicked the effect of Ba(2+) (0.2mM) on the rat AP repolarising phase. Moreover, the lengthening of the AP in frog atrium induced by lepadiformine still developed after the delayed outward K(+) current (I(K)) was blocked by tetraethylammonium (10mM). These observations suggest that lepadiformine-induced lengthening of AP duration was not due to a decrease of I(K), but may reasonably be attributed to a reduction of the inward rectifying K(+) current (I(K1)). This blockade of I(K1) could account for the cardiovascular effects of lepadiformine in vivo and in vitro and suggests that lepadiformine has antiarrhythmic properties.


Arginosuccinate synthetase, arginosuccinate lyase and NOS in canine gastrointestinal tract: immunocytochemical studies.
Nitric oxide synthase (NOS) requires the substrate L-arginine for NO production to support multiple gastrointestinal functions. We asked, 'Where do enzymes to regenerate L-arginine from L-citrulline exist?'. We examined loci of immunoreactivities in the canine gastrointestinal tract for arginosuccinate synthetase and arginosuccinate lyase, enzymes that resynthesize L-arginine from L-citrulline, in relation to the distribution of nNOS immunoreactivity or NADPH-diaphorase histochemistry. Arginosuccinate synthetase and lyase were present in many neurones and nerve fibres in the myenteric plexus of the lower oesophageal sphincter (LOS), antrum, pylorus, ileum and colon; in the submucosal plexus of ileum and colon; in longitudinal muscle of ileum and colon; and in nerve bundles in circular muscle everywhere. LOS muscle was also immunoreactive for both enzymes. Circular and longitudinal muscle cells of the ileum and colon and cells resembling interstitial cells of Cajal in the deep muscular plexus of the ileum and the submuscular plexus of the colon also appeared immunoreactive. In neurones, arginosuccinate synthetase and nNOS were usually co-localized. NADPH diaphorase activity was present in LOS and likely in pylorus, but not in muscularis externa of ileum or colon. We conclude that resynthesis of L-arginine probably occurs in enteric nerves, interstitial cells of Cajal (ICC) and LOS muscle; also apparently in some cells without NOS to utilize it.


[Peri-orbital oedema and therapy-resistant hypertension: unusual side-effects of clozapine].
A 49-year-old male, known to have been suffering from paranoid schizophrenia for 10 years, was treated twice with clozapine. Although the clozapine alleviated his psychosis, the patient developed peri-orbital oedema repeatedly. As a result he requested a switch to a different antipsychotic. Also, while the patient was on clozapine, it proved difficult to regulate his hypertension. A possible explanation for these two side-effects is that clozapine blocks the renal dopamine D4 receptor, preventing it from performing its normal natriuretic and diuretic function. In view of the high but largely unnoticed incidence of hypertension in patients on clozapine (4%), we advise that such patients should receive structured somatic screening in a clinical setting.


Thermal regelation of single particles and particle clusters in ice.
We investigate the migration by thermal regelation of single particles and clusters of particles surrounded by ice subjected to a temperature gradient. This phenomenon is relevant to the casting of porous materials, to cryopreservation of biological tissue, and to the degradation of paleoclimatic signals held in ice sheets, for example. Using carefully controlled laboratory experiments, we measure the migration rates of single particles and clusters as they approach the freezing front. We find that clusters migrate at a constant rate, while single particles accelerate towards the freezing front. This fundamental difference is attributed to the fact that, during regelation, melt water passes through the interstices of a cluster, limited by its constant permeability, but for a single particle must flow through a thin layer of pre-melted ice whose thickness diverges as the freezing temperature is approached, reducing the viscous resistance to migration. We extend existing theories of particle and cluster migration to include the influences of different thermal conductivities and of latent heat on the local temperature field in and around the particle or cluster. We find that if the specific latent heat is large or the viscous resistance to flow is sufficiently small then the migration rate is determined solely by heat transport.


A phase II study of weekly paclitaxel and epirubicin in recurrent or refractory squamous cell carcinoma of the head and neck.
The combination of taxanes and anthracyclines has been proved to be active for treatment of many cancers. We conducted a phase II study to determine the response and toxicity of paclitaxel and epirubicin (TE) in patients with incurable squamous cell carcinoma of the head and neck (SCCHN). Patients with metastatic or recurrent SCCHN and adequate hematologic, renal and hepatic function and a Karnofsky performance status >/=60% were enrolled. Prior chemotherapy and/or radiotherapy were permitted with 4-week interval. The regimen was paclitaxel 60 mg/m(2) and epirubicin 20 mg/m(2), on Days 1, 8 and 15, as an intravenous infusion, repeated every 28 days. Patients with disease progression or unacceptable toxicity were excluded from the study. The current study was intended to treat 43 patients but closed at the planned interim analysis due to early evidence of insufficient efficacy than expectation. Fifteen patients with a median age of 52 years (range, 37-72 years) were accrued. Previously, most patients had received radiotherapy and chemotherapy, and a majority (87%) of patients had treatment-free interval of <6 months. Median Karnofsky performance status was 70% (range, 60-90%). There was one clinical response (7%) and another three (20%) had stable disease. Median overall survival time was 4.5 months. The most common major toxicity was infection (47%), which caused four treatment-related mortalities. Grade 3-4 neutropenia occurred in five patients, but other toxicities were mild and manageable. In the population with majority of refractory disease of SCCHN, the response rate to TE was lower than expected. Such dose schedule is not recommended unless in chemotherapy naïve patients or in combination with newer agents.


Interparental Relationship Quality During Pregnancy: Implications for Early Parent-Infant Bonding and Infant Socioemotional Development.
Research demonstrates the central role of mother-child relationships in child socioemotional development; however, families are complex systems and the unique roles of multiple family subsystems in early infant development have received less attention. In the present study, we investigated the role of multiple family relationships (interparental, mother-infant, father-infant), during pregnancy and the first month after childbirth, in infant socioemotional functioning at 6 months. We administered semi-structured interviews during pregnancy to assess multiple qualities of the interparental relationship. At 1 month postpartum, parents completed reports about their feelings and attitudes toward their infant to assess impaired bonding. At 6 months, parents provided reports of child socioemotional functioning. Both mother-infant and father-infant impaired bonding were uniquely associated with infant socioemotional impairment, controlling for prenatal interparental relationship quality. Additionally, multiple dimensions of the interparental relationship (i.e., poor-quality conflict management, inadequate support for fathers, and low levels of respect toward mothers) were associated with infant socioemotional impairment controlling for parent-infant bonding. Results also demonstrated an indirect pathway, such that poor sexual quality during pregnancy was associated with fathers (but not mothers) reporting more impaired bonding with their infants, which was linked to greater infant socioemotional impairment. Results highlight the importance of understanding the broad family environment, prior to and immediately following the birth of the child, to identify at-risk children at the earliest possible stages of intervention.


Performance indicators to measure dementia risk reduction activities in primary care.
The increasing burden of chronic diseases including cardiovascular and cerebrovascular disease, diabetes and dementia has led to greater emphasis on health promotion, prevention and early intervention (PPEI) activities within primary care. At the same time, there is growing recognition of the importance of measuring and benchmarking health-care system performance. This includes the measurement of PPEI activities. This paper considers the issue of measuring PPEI activities that are relevant to reducing the risk of dementia within the Australian primary care system. Although Australia does not currently have a comprehensive data collection regarding primary health-care services, there are a number of national, state and other data sources. These sources could be utilised, either in their current format or modified to provide data regarding PPEI activities in primary care that may reduce the risk of dementia and we have made recommendations regarding the development of such indicators.


The venous drainage of the cervical vertebrae of the ox (Bos taurus L.).
The venous drainage of the cervical vertebrae of the ox was studied in 16 animals (Friesland, Jersey and Guernsey cross-breeds), ranging from near full-term foetuses to adults. The extra- and intraosseous veins of the cervical vertebrae are described and illustrated. The nutrient vessels are derived from the vertebral, deep cervical, occipital and internal jugular veins. In addition to the dorsal and ventral external venous plexuses, a lateral external venous plexus is described. The intraosseous veins correspond in the main to the arteries. They are described and illustrated with reference to the available literature. In both young and adult animals anastomoses between epi- and metaphysial vessels are reported. The role of the internal ventral vertebral venous system as a collateral pathway is stressed and comments are made on its possible functional role.


Dynamical adaptation in photoreceptors.
Adaptation is at the heart of sensation and nowhere is it more salient than in early visual processing. Light adaptation in photoreceptors is doubly dynamical: it depends upon the temporal structure of the input and it affects the temporal structure of the response. We introduce a non-linear dynamical adaptation model of photoreceptors. It is simple enough that it can be solved exactly and simulated with ease; analytical and numerical approaches combined provide both intuition on the behavior of dynamical adaptation and quantitative results to be compared with data. Yet the model is rich enough to capture intricate phenomenology. First, we show that it reproduces the known phenomenology of light response and short-term adaptation. Second, we present new recordings and demonstrate that the model reproduces cone response with great precision. Third, we derive a number of predictions on the response of photoreceptors to sophisticated stimuli such as periodic inputs, various forms of flickering inputs, and natural inputs. In particular, we demonstrate that photoreceptors undergo rapid adaptation of response gain and time scale, over ∼ 300[Formula: see text] ms-i. e., over the time scale of the response itself-and we confirm this prediction with data. For natural inputs, this fast adaptation can modulate the response gain more than tenfold and is hence physiologically relevant.


Ethnic comparisons of antipsychotic use in schizophrenia.
The aim of the present study was to compare ethnic groups for antipsychotic prescribing in schizophrenia over 4.5 years. All clinical files in three mental health services caring for outpatients in Auckland, New Zealand were reviewed at two time points (T1 =31 March 2000, T2 =31 October 2004). Data were collected (patient characteristics, diagnosis, antipsychotic treatment) and analysed at each time point. Adjustments were made for age and sex in the comparisons. After the first audit, feedback was provided to all three services. Differences in baseline prescribing were found between ethnic groups; rates of antipsychotic polypharmacy, second-generation antipsychotic (SGA) use, depot antipsychotic use, clozapine use and total antipsychotic dose. Overall five of the six prescribing outcome variables changed over the 4.5 years; only mean antipsychotic daily dose remained the same. Monotherapy rates increased in all ethnic groups with no difference found between them at T2 (85-86%). Similarly the prescribing variables of oral SGA use increased (83-87%), depots decreased (T2 =14-19%) and oral first-generation antipsychotics (FGAs) decreased (T2 =5-8%), all with no difference found between ethnic groups at T2. While clozapine use increased in all ethnic groups, a significant difference remained at T2; European, NZ Maori and Pacific all increased to 33-39%, but rates for Asian subjects increased only to 20%. The difference in mean daily antipsychotic dose between ethnic groups (122 mg day(-1) chlorpromazine equivalent (CPZe) at T1; 86 mg day(-1) CPZe at T2) reached statistical significance at both time points but overall the average dose (total mg day(-1)) for each group was within the usual clinical range. Adjustment for age and sex did not change the significance of any of the comparisons between ethnic groups. Most baseline differences in antipsychotic prescribing between ethnic groups resolved over time, with equal access for patients to recommended best practice with antipsychotic treatment in schizophrenia. Further work is required to look at differences in access to clozapine for Asian people.


A role for AQP5 in activation of TRPV4 by hypotonicity: concerted involvement of AQP5 and TRPV4 in regulation of cell volume recovery.
Regulation of cell volume in response to changes in osmolarity is critical for cell function and survival. However, the molecular basis of osmosensation and regulation of cell volume are not clearly understood. We have examined the mechanism of regulatory volume decrease (RVD) in salivary gland cells and report a novel association between osmosensing TRPV4 (transient receptor potential vanalloid 4) and AQP5 (aquaporin 5), which is required for regulating water permeability and cell volume. Exposure of salivary gland cells and acini to hypotonicity elicited an increase in cell volume and activation of RVD. Hypotonicity also activated Ca2+ entry, which was required for subsequent RVD. Ca2+ entry was associated with a distinct nonselective cation current that was activated by 4alphaPDD and inhibited by ruthenium red, suggesting involvement of TRPV4. Consistent with this, endogenous TRPV4 was detected in cells and in the apical region of acini along AQP5. Importantly, acinar cells from mice lacking either TRPV4 or AQP5 displayed greatly reduced Ca2+ entry and loss of RVD in response to hypotonicity, although the extent of cell swelling was similar. Expression of N terminus-deleted AQP5 suppressed TRPV4 activation and RVD but not cell swelling. Furthermore, hypotonicity increased the association and surface expression of AQP5 and TRPV4. Both these effects and RVD were reduced by actin depolymerization. These data demonstrate that (i) activation of TRPV4 by hypotonicity depends on AQP5, not on cell swelling per se, and (ii) TRPV4 and AQP5 concertedly control regulatory volume decrease. These data suggest a potentially important role for TRPV4 in salivary gland function.


Effect of mouse intestinal bacteria on incidence of colorectal tumors induced by 1,2-dimethylhydrazine injection in gnotobiotic transgenic mice harboring human prototype c-Ha-ras genes.
We produced transgenic (Tg) gnotobiotic (GB) mice carrying human prototype c-Ha-ras genes and compared the incidence of colorectal tumors induced by 1,2-dimethylhydrazine (DMH) injection. At 7 to 11 weeks of age, germfree (GF) CB6F1-Tg Hras2 mice were inoculated with various mouse fecal suspensions or mixtures of bacteria isolated from mouse feces. Three weeks after bacterial inoculation, DMH was administered by subcutaneous injection at 20 mg per kg body weight for 20 weeks. Mice were euthanized 5 weeks after the last injection to investigate the number of colorectal tumors. The incidence of colorectal tumors was high in both Tg- and non-Tg-GF mice (100%). In Tg-specific pathogen-free (SPF) mice and Tg-GB-4 mice associated with basic mouse flora consisting of Escherichia coli, lactobacilli, Bacteroides and clostridia, the incidence of colorectal tumors was as high as that in GF mice. In Tg-SPF mice, the tumor score was higher than in Tg-GF mice (p < 0.01), but no colorectal tumors were detected in non-Tg groups of SPF, and the tumor incidence was remarkably low in non-Tg-GB-4 mice. The tumor incidence and score in Tg- and non-Tg-GB mice varied depending on the bacterial combination in their intestine. These results indicate that the presence of human c-Ha-ras genes and intestinal bacteria substantially modify colorectal tumorigenesis induced by DMH.


Self-regulatory cognition and immune reactivity: idiographic success and failure feedback effects on the natural killer cell.
Inducing depressed and anxious individuals to write about their personal goals decreases natural killer (NK) cell activity, revealing a psychobiological pathway whereby experiences of failure can influence health (Strauman et al., 1993). However, it is unclear whether similar effects also occur in non-distressed individuals. This study used the same writing task to examine the acute physiological effects of presenting idiographic success and failure feedback by priming self-congruencies or self-discrepancies on three occasions (including a control condition). Blood samples were collected after each writing session to determine NK activity, and the number and type of lymphocytes in circulation were enumerated to help explain the cytolytic changes. The two self-relevant priming conditions were associated with significant alterations in immunity, and the high self-discrepant participants were more responsive. Both self-congruent (success) and self-discrepant (failure) priming induced significant shifts in mood, which partially mediated immune alterations but did not account for them completely. If repeated and sustained over time, incidental activation of self-discrepancies and self-congruencies could account for individual variation in immune responses.


Machine Learning Algorithms for Intelligent Decision Recognition and Quantification of Cr(III) in Chromium Speciation.
Cr(III) is a common oxidation state of chromium, and its presence in the environment can occur naturally or as a result of human activities, such as industrial processes, mining, and waste disposal. This article explores the application of machine learning algorithms for the intelligent decision recognition and quantification of Cr(III) in chromium speciation. Three different machine learning models, namely, the Decision Tree (DT) model, the PCA-SVM (Principal Component Analysis-Support Vector Machine) model, and the LDA (Linear Discriminant Analysis) model, were employed and evaluated for accurate and efficient classification of chromium concentrations based on their fluorescence responses. Furthermore, stepwise multiple linear regression analysis was utilized to achieve a more precise quantification of trivalent chromium concentrations through fluorescence visualization. The results demonstrate the potential of machine learning algorithms in accurately detecting and quantifying Cr(III) in chromium speciation with implications for environmental and industrial applications in chromium detection and quantification. The findings from this research pave the way for further exploration and implementation of these models in real-world scenarios, offering valuable insights into various environmental and industrial contexts.


Providing health care to human beings trapped in the poverty culture.
The culture of poverty impacts everything patients in this socioeconomic group think and do. If what poor patients say does not sit well with the way we think, that doesn't mean they are wrong. Physicians have to adjust their mental model and think in different cultural terms. The author recently completed his thirtieth year of a career dedicated to providing health care to people living in poverty. He shares seven concepts important in building a mental model that will enable physicians to successfully provide health care to this patient population: (1) Poverty is the number one health problem; (2) we see same diseases as everyone else; (3) patients are trapped in the poverty culture; (4) patients' behavior is often manipulative; (5) compliance is a unique challenge; (6) patients have limited resources; and (7) the ultimate contributors to poverty are unwanted adolescent pregnancy and substance abuse. These concepts can help physicians to be more effective in providing health care to patients living in poverty. They can help them understand what is happening, so that their experience might be fulfilling rather than demoralizing.


Cell kinetics of urethane induced murine pulmonary adenomata: I. The growth rate.
A single injection of urethane into adult male A2G mice produced an increase in the proliferative rate of alveolar wall cells, reaching a peak at 2 weeks post urethan (PU) and declining to control levels by 2 months PU. During this urethane induced proliferative response the single and double labelling indices and the native metaphase index were all elevated although there was no corresponding alteration in the arrested metaphase index. This proliferative response may not be restricted to hyperplasia of potentially neoplastic cells, such as type II epithelium, but may also include type I epithelial cells and alveolar macrophage precursors. However, it was impossible to identify individual cell populations by methods used. The growth rate of adenomata decrease with time and cell kinetic techniques showed that the rates of entry of adenoma cells into DNA synthesis and into metaphase were decreasing concurrently with the growth rate. Thus the rate of cell production falls as adenomata age but how much cell loss contributes to the decrease in growth rate is not yet known. Decreasing cell production could be due to an increased cell cycle time and/or a decreased growth fraction. The duration of DNA synthesis in adenomata increased markedly as the mice survived, suggesting that the cell cycle time might be increased, but further experiments are required to determine whether the growth fraction changes. Attention is drawn to a complication that Colcemid introduces into kinetic studies on alveolar wall cells.


Low ecological disparity in Early Cretaceous birds.
Ecological divergence is thought to be coupled with evolutionary radiations, yet the strength of this coupling is unclear. When birds diversified ecologically has received much less attention than their hotly debated crown divergence time. Here, we quantify how accurately skeletal morphology can predict ecology in living and extinct birds, and show that the earliest known assemblage of birds (=pygostylians) from the Jehol Biota (≈125 Ma) was substantially impoverished ecologically. The Jehol avifauna has few representatives of highly preservable ecomorphs (e.g. aquatic forms) and a notable lack of ecomorphological overlap with the pterosaur assemblage (e.g. no large or aerially foraging pygostylians). Comparisons of the Jehol functional diversity with modern and subfossil avian assemblages show that taphonomic bias alone cannot explain the ecomorphological impoverishment. However, evolutionary simulations suggest that the constrained ecological diversity of the Early Cretaceous pygostylians is consistent with what is expected from a relatively young radiation. Regardless of the proximate biological explanation, the anomalously low functional diversity of the Jehol birds is evidence both for ecological vacancies in Cretaceous ecosystems, which were subsequently filled by the radiation of crown Aves, and for discordance between taxonomic richness and ecological diversity in the best-known Mesozoic ecosystem.


A modified amino acid network model contains similar and dissimilar weight.
For a more detailed description of the interaction between residues, this paper proposes an amino acid network model, which contains two types of weight--similar weight and dissimilar weight. The weight of the link is based on a self-consistent statistical contact potential between different types of amino acids. In this model, we can get a more reasonable representation of the distance between residues. Furthermore, with the network parameter, average shortest path length, we can get a more accurate reflection of the molecular size. This amino acid network is a "small-world" network, and the network parameter is sensitive to the conformation change of protein. For some disease-related proteins, the highly central residues of the amino acid network are highly correlated with the hot spots. In the compound with the related drug, these residues either interacted directly with the drug or with the residue which is in contact with the drug.


Analysis of the Borrelia burgdorferi GeHo fla gene and antigenic characterization of its gene product.
The fla gene of Borrelia burgdorferi GeHo was analyzed and expressed in Escherichia coli. The structural gene encodes a flagellar protein of 336 amino acids. Comparative sequence analysis of the amino acid sequence revealed a high degree of sequence conservation with flagellins from both phylogenetically related and unrelated bacteria. The antigenic properties of the B. burgdorferi Fla protein were studied by synthesizing overlapping octapeptides, which were screened by using a battery of different monoclonal and polyclonal antibodies from various species directed against native and denatured flagellar proteins. No single species-independent immunodominant epitope could be located. However, immunoreactive oligopeptides clustered within the variable middle region (N-180 to I-260). This region could constitute a candidate antigen for more specific and sensitive serodiagnosis of Lyme borreliosis.


Control of oligomeric enzyme thermostability by protein engineering.
The ability to control the resistance of an enzyme to inactivation due to exposure to elevated temperatures is essential for the understanding of thermophilic behavior and for developing rational approaches to enzyme stabilization. By means of site-directed mutagenesis, point mutations have been engineered in the dimeric enzyme yeast triosephosphate isomerase that improve its thermostability. Cumulative replacement of asparagine residues at the subunit interface by residues resistant to heat-induced deterioration and approximating the geometry of asparagine (Asn-14----Thr-14 and Asn-78----Ile-78) nearly doubled the half-life of the enzyme at 100 degrees C, pH 6. Moreover, in an attempt to model the deleterious effects of deamidation, we show that replacement of interfacial Asn-78 by an aspartic acid residue increases the rate constant of irreversible thermal inactivation, drastically decreases the reversible transition temperature, and reduces the stability against dilution-induced dissociation.


1994-1996 U.S. singleton birth weight percentiles for gestational age by race, Hispanic origin, and gender.
Establishing and comparing race, ethnic, and gender-specific birth weight percentiles for gestational age is requisite for investigating the determinants of variations in fetal growth. In this study, we calculate percentiles of birth weight for gestational age for the total 1994-1996 U.S. population and contrast these percentiles by racial/ethnic and gender groups. Single live births to U.S. resident mothers were selected from the 1994-1996 U.S. Natality Files. After exclusions, 5,973,440 non-Hispanic Whites, 1,393,908 non-Hispanic African Americans, 1,683,333 Hispanics, 80,187 Native Americans, and 510,021 other racial/ethnic groups were used to calculate distribution percentiles of birth weight for each gestational age for which there were at least 50 cases to calculate the 50th percentile and 100 cases to calculate the 10th percentile. Fetal growth patterns among the four U.S. racial/ethnic groups varied markedly and, across the gestational age range, there was considerable oscillation in the relative ranking of any one group's birth weight percentile value in comparison to the others. Males had relatively higher birth weight percentile values than females. The proportion of infants with a birth weight value less than 1994-1996 U.S. population's 10th percentile value of birth weight for their corresponding gestational age was 7.87 for non-Hispanic Whites, 15.43 for non-Hispanic African Americans, 9.30 for Hispanics, and 8.81 for Native Americans. While the factors underlying trends and population subgroup differences in fetal growth are unclear, nutrition, smoking habits, health status, and maternal morbidity are possible precursors for part of the variations in patterns of fetal growth. As prenatal care has been touted as a means to reduce the risk of fetal growth restriction at term, assuring the availability and accessibility of comprehensive prenatal care services is viewed as an essential corollary in the effort to improve fetal growth patterns in the United States.


Thoracic outlet syndrome mimicking angina pectoris with elevated creatine phosphokinase values.
Four patients with elevated creatine phosphokinase (CPK) values and recurrent chest pain were found to have thoracic outlet syndrome. This association of abnormal CPK levels and chest pain due to thoracic outlet syndrome has not been previously reported. Symptoms and CPK values improved with anti-inflammatory medications and/or proper posture instruction. It is proposed that CPK values become elevated by ischemic or neurologic compromise of muscles supplied by the subclavian artery or brachial plexus respectively. Accordingly, chest pain in the same dermatomal distribution as that of angina pectoris may be simulated by ischemic skeletal muscle. Thoracic outlet syndrome therefore should be suspected in any patient with chronically abnormal CPK values and chest pain in whom no other etiology can be determined.


MicroRNA miR-124 controls the choice between neuronal and astrocyte differentiation by fine-tuning Ezh2 expression.
Polycomb group protein Ezh2 is a histone H3 Lys-27 histone methyltransferase orchestrating an extensive epigenetic regulatory program. Several nervous system-specific genes are known to be repressed by Ezh2 in stem cells and derepressed during neuronal differentiation. However, the molecular mechanisms underlying this regulation remain poorly understood. Here we show that Ezh2 levels are dampened during neuronal differentiation by brain-enriched microRNA miR-124. Expression of miR-124 in a neuroblastoma cells line was sufficient to up-regulate a significant fraction of nervous system-specific Ezh2 target genes. On the other hand, naturally elevated expression of miR-124 in embryonic carcinoma cells undergoing neuronal differentiation correlated with down-regulation of Ezh2 levels. Importantly, overexpression of Ezh2 mRNA with a 3'-untranslated region (3'-UTR) lacking a functional miR-124 binding site, but not with the wild-type Ezh2 3'-UTR, hampered neuronal and promoted astrocyte-specific differentiation in P19 and embryonic mouse neural stem cells. Overall, our results uncover a molecular mechanism that allows miR-124 to balance the choice between alternative differentiation possibilities through fine-tuning the expression of a critical epigenetic regulator.


Characterization of dietary protein in Brassica carinata meal when used as a protein supplement for beef cattle consuming a forage-based diet.
As a novel oilseed crop in Florida, Brassica carinata has the capacity of producing high-quality jet biofuel, with a protein-dense meal (~40% crude protein; CP) obtained as a by-product of oil extraction. Characterization of the meal protein is limited, yet necessary for formulation of beef cattle diets; therefore, the objective of this experiment was to determine ruminal and postruminal digestibility of protein from B. carinata. Eight ruminally cannulated Angus crossbred steers (473 ± 119 kg) were used in a duplicated 4 × 4 Latin square design, in which in situ ruminal and postruminal degradability of nutrients were evaluated. The three-step in vitro procedure was used to compare CP and amino acid (AA) degradation in B. carinata meal pellets (BCM) with that of cottonseed meal (CSM), dry distillers grains with solubles (DDGS), and soybean meal (SBM). In situ bags were incubated in the rumen for 0 to 96 hr, with the undegraded supplement remaining after 16 hr subjected to serial in vitro enzymatic solutions. Data were analyzed using the MIXED procedure of SAS. Ruminal rate of degradation of dry matter, organic matter, and CP was greatest (P ˂ 0.01; 10.9, 11.3, and 11.5 %/h, respectively) for SBM. Rumen degradable protein (RDP) content did not differ (P = 0.20; 47.8% and 55.1%, respectively) between CSM and DDGS, but was decreased (P ˂ 0.01) compared with SBM and BCM, which did not differ (P = 0.99; 72.3% and 71.8% RDP, respectively). Compared with DDGS, SBM had greater (P < 0.01) intestinal digestibility of rumen undegradable protein (RUP). Intestinally absorbable digestible protein (IADP) was greatest (P < 0.01) for CSM, with SBM and BCM having the least IADP. Total tract digestibility of CP (TTDP) was greater (P < 0.01) for SBM compared with CSM and DDGS. The contribution of RUP to intestinally absorbable AA was 7.2 and 3.1 g of lysine and methionine per kilogram of CP in BCM, respectively. The evaluation of B. carinata meal as protein supplemented for cattle consuming a forage-based diet resulted in 71.8% RDP and 97.1% TTDP, thus indicating its viability as a high-quality protein supplement for beef cattle.


Perception is key? Does perceptual sensitivity and parenting behavior predict children's reactivity to others' emotions?
When interacting with other people, both children's biological predispositions and past experiences play a role in how they will process and respond to social-emotional cues. Children may partly differ in their reactions to such cues because they differ in the threshold for perceiving such cues in general. Theoretically, perceptual sensitivity (i.e., the amount of detection of slight, low-intensity stimuli from the external environment independent of visual and auditory ability) might, therefore, provide us with specific information on individual differences in susceptibility to the environment. However, the temperament trait of perceptual sensitivity is highly understudied. In an experiment, we tested whether school-aged children's (N=521, 52.5% boys, Mage=9.72years, SD=1.51) motor (facial electromyography) and affective (self-report) reactivities to dynamic facial expressions and vocalizations is predicted by their (parent-reported) perceptual sensitivity. Our results indicate that children's perceptual sensitivity predicts their motor reactivity to both happy and angry expressions and vocalizations. In addition, perceptual sensitivity interacted with positive (but not negative) parenting behavior in predicting children's motor reactivity to these emotions. Our findings suggest that perceptual sensitivity might indeed provide us with information on individual differences in reactivity to social-emotional cues, both alone and in interaction with parenting behavior. Because perceptual sensitivity focuses specifically on whether children perceive cues from their environment, and not on whether these cues cause arousal and/or whether children are able to regulate this arousal, it should be considered that perceptual sensitivity lies at the root of such individual differences.


Ensuring optimal insulin utilization in the hospital setting: role of the pharmacist.
To summarize essential information for the hospital pharmacist to support the safe and effective use of insulin for the treatment of inpatient hyperglycemia. Ensuring optimal insulin utilization in the hospital setting requires collaboration of a multidisciplinary team, including physicians (and endocrinologists specifically), nurses, pharmacists, dieticians, diabetes educators, laboratory staff, quality management staff, and others. The role of pharmacists in this multidisciplinary team is to assist in the standardization of insulin therapy via selection of appropriate insulin treatment protocols, participate in formulary management of insulin products, and contribute to the development of order sets and policies and procedures to minimize the risk of medication errors and misadventures. In addition, pharmacists can provide guidelines or treatment recommendations in special situations, such as those involving patients receiving enteral or parenteral nutrition or high-dose corticosteroids and the transition from i.v. to subcutaneous insulin therapy. Education of patients and providers is another key role for pharmacists. Nurses are important allies in the effort to ensure safe insulin use, as they are at the bedside of patients administering and adjusting insulin therapy. Recommendations are provided for the safe and effective use of insulin for the treatment of inpatient hyperglycemia. Pharmacists are an integral part of the multidisciplinary team ensuring the safe and effective implementation of inpatient hyperglycemic control and insulin usage.


Decrease in plasma levels of vasoactive intestinal polypeptide in short bowel syndrome: experimental study.
To investigate the behaviour of the vasoactive intestinal polypeptide (VIP) in short bowel syndrome (SBS), an experimental model of massive intestinal resection (MIR) was developed. For this purpose, 20 'minipigs' were divided into two experimental groups: A (control) and B (MIR). The parameters determined were the mean plasma levels of VIP and the degree of steatorrhea at four different times: T1 (basal), T2 (one week after surgery), T3 (two weeks after surgery), and T4 (24 weeks after surgery). The results indicated that, after MIR, a progressive decrease in the mean plasma levels of VIP takes place, with statistical significance in T3 (p < 0.05) and T4 (p < 0.01). This situation seems to be a direct result of the massive loss of intestinal tissue, and could lead to the use of this peptide to mark the evolution of the intestinal adaptation process.


Least median of squares filtering of locally optimal point matches for compressible flow image registration.
Compressible flow based image registration operates under the assumption that the mass of the imaged material is conserved from one image to the next. Depending on how the mass conservation assumption is modeled, the performance of existing compressible flow methods is limited by factors such as image quality, noise, large magnitude voxel displacements, and computational requirements. The Least Median of Squares Filtered Compressible Flow (LFC) method introduced here is based on a localized, nonlinear least squares, compressible flow model that describes the displacement of a single voxel that lends itself to a simple grid search (block matching) optimization strategy. Spatially inaccurate grid search point matches, corresponding to erroneous local minimizers of the nonlinear compressible flow model, are removed by a novel filtering approach based on least median of squares fitting and the forward search outlier detection method. The spatial accuracy of the method is measured using ten thoracic CT image sets and large samples of expert determined landmarks (available at www.dir-lab.com). The LFC method produces an average error within the intra-observer error on eight of the ten cases, indicating that the method is capable of achieving a high spatial accuracy for thoracic CT registration.


Diminazene Is a Slow Pore Blocker of Acid-Sensing Ion Channel 1a (ASIC1a).
Acid-sensing ion channels (ASICs) are neuronal receptors for extracellular protons. They contribute to the excitatory postsynaptic current and to the detection of painful acidosis. Moreover, they are activated during peripheral inflammation and acidosis associated with various neuronal disorders, such as stroke and neuroinflammation, rendering them interesting drug targets. Diminazene aceturate is a small-molecule inhibitor of ASICs with a reported apparent affinity in the low micromolar range, making it an interesting lead compound. It was reported that diminazene accelerates desensitization of ASICs, which was, however, not explained mechanistically. Furthermore, a binding site in a groove of the extracellular domain was proposed but not experimentally verified. In this study, we revisited the mechanism of inhibition by diminazene and its binding site on ASIC1a, the ASIC subunit with the greatest importance in the central nervous system. We show that diminazene slowly blocks ASIC1a, leading to the apparent acceleration of desensitization and underestimating its potency; we show that diminazene indeed has a submicromolar potency at ASIC1a (IC50 0.3 μM). Moreover, we show that the inhibition is voltage-dependent and competes with that by amiloride, a pore blocker of ASICs. Finally, we identify by molecular docking a binding site in the ion pore that we confirm by site-directed mutagenesis. In summary, our results show that diminazene blocks ASIC1a by a slow open-channel block and suggest that diminazene is an interesting lead compound for high-affinity blockers of ASICs.


Approximate Bayesian computation and ecological niche models elucidate the demographic history and current fragmented population distribution of a Korean endemic shrub.
Climatic fluctuations and geological events since the LGM are believed to have significantly impacted the population size, distribution, and mobility of many species that we observe today. In this paper, we determined the processes driving the phylogeographic structure of the Korean endemic white forsythia by combining the use of genome-wide SNPs and predicting paleoclimatic habitats during the LGM (21 kya), Early Holocene (10 kya), Mid-Holocene (6 kya), and Late Holocene (3 kya). Using a maximum of 1897 SNPs retrieved from 124 samples across nine wild populations, five environmental predictors, and the species' natural occurrence records, we aimed to infer the species' demographic history and reconstruct its possible paleodistributions with the use of approximate Bayesian computation and ecological niche models, respectively. Under this integrated framework, we found strong evidence for patterns of range shift and expansion, and population divergence events from the onset of the Holocene, resulting in the formation of its five distinct genetic units. The most highly supported model inferred that after the split of an ancestral population into the southern group and a larger central metapopulation lineage, the latter gave rise to the eastern and northern clusters, before finally dividing into two sub-central groups. While the use of molecular data allowed us to identify and refine the (phylo)genetic relationships of the species' lineages and populations, the use of ecological data helped us infer a past LGM refugium and the directions of post-glacial range dynamics. The time frames of these demographic events were shown to be congruent with climatic and geological events that affected the central Korean Peninsula during these periods. These findings gave us a better understanding of the consequences of past spatiotemporal factors that may have resulted in the current fragmented population distribution of this endangered plant.


Mechanisms of resistance to systemic therapy in metastatic castration-resistant prostate cancer.
Patients with metastatic castration-resistant prostate cancer (mCPRC) now have an unprecedented number of approved treatment options, including chemotherapies (docetaxel, cabazitaxel), androgen receptor (AR)-targeted therapies (enzalutamide, abiraterone), a radioisotope (radium-223) and a cancer vaccine (sipuleucel-T). However, the optimal treatment sequencing pathway is unknown, and this problem is exacerbated by the issues of primary and acquired resistance. This review focuses on mechanisms of resistance to AR-targeted therapies and taxane-based chemotherapy. Patients treated with abiraterone, enzalutamide, docetaxel or cabazitaxel may present with primary resistance, or eventually acquire resistance when on treatment. Multiple resistance mechanisms to AR-targeted agents have been proposed, including: intratumoral androgen production, amplification, mutation, or expression of AR splice variants, increased steroidogenesis, upregulation of signals downstream of the AR, and development of androgen-independent tumor cells. Known mechanisms of resistance to chemotherapy are distinct, and include: tubulin alterations, increased expression of multidrug resistance genes, TMPRSS2-ERG fusion genes, kinesins, cytokines, and components of other signaling pathways, and epithelial-mesenchymal transition. Utilizing this information, biomarkers of resistance/response have the potential to direct treatment decisions. Expression of the AR splice variant AR-V7 may predict resistance to AR-targeted agents, but available biomarker assays are yet to be prospectively validated in the clinic. Ongoing prospective trials are evaluating the sequential use of different drugs, or combination regimens, and the results of these studies, combined with a deeper understanding of mechanisms of primary and acquired resistance to treatment, have the potential to drive future treatment decisions in mCRPC.


Depressed cardiac performance after mitral valve replacement. A problem of myocardial preservation during operation.
Our experimental studies since 1972 show that the heart is preserved best during cardiopulmonary bypass when it is in the beating, nonworking state. Results after mitral valve replacement (MVR) from 1968 to 1974 using various techniques of cardiac preservation were compared. In group I were 47 patients (1968 to 1972) in which either profound, topical hypothermia with prolonged ischemic arrest (19) or ventricular fibrillation with continuous coronary perfusion (28) was used. In group II there were 22 patients (1972 to 1974) in whom the heart was in a beating, nonworking state between brief periods of ischemic arrest. In group I 55% (25/47) required inotropic support postoperatively, and 17% (8/47) died. In group II 5% (1/22) required inotropic support postoperatively, and this patient died (5% mortality). Extended periods of ischemic arrest were necessary because of intraoperative complications in this patient. These data show that depressed postoperative myocardial performance occurs rarely when the heart is preserved in the beating, nonworking state during MVR and ventricular fibrillation and prolonged topical hypothermic anoxic arrest are avoided.


Bridging atomistic simulations and thermodynamic hydration models of aqueous electrolyte solutions.
Chemical thermodynamic models of solvent and solute activities predict the equilibrium behavior of aqueous solutions. However, these models are semi-empirical. They represent micro-scale ion and solvent behaviors controlling the macroscopic properties using small numbers of parameters whose values are obtained by fitting to activities and other partial derivatives of the Gibbs energy measured for the bulk solutions. We have conducted atomistic simulations of aqueous electrolyte solutions (MgCl2 and CaCl2) to determine the parameters of thermodynamic hydration models. We have implemented a cooperative hydration model to categorize the water molecules in electrolyte solutions into different subpopulations. The value of the electrolyte-specific parameter, k, was determined from the ion-affected subpopulation with the lowest absolute value of the free energy of removing the water molecule. The other equilibrium constant parameter, K1, associated with the first degree of hydration, was computed from the free energy of hydration of hydrated clusters. The hydration number, h, was determined from a reorientation dynamic analysis of the water subpopulations compared to bulk-like behavior. The reparameterized models [R. H. Stokes and R. H. Robinson, J. Solution Chem. 2, 173 (1973) and Balomenos et al., Fluid Phase Equilib. 243, 29 (2006)] using the computed values of the parameters lead to the osmotic coefficients of MgCl2 solutions that are consistent with measurements. Such an approach removes the dependence on the availability of experimental data and could lead to aqueous thermodynamic models capable of estimating the values of solute and solvent activities as well as thermal and volumetric properties for a wide range of compositions and concentrations.


Social support and high resilient coping in carers of people with dementia.
High resilience is associated with improved carer outcomes. Both individual factors and the availability of social support have been linked with resilience. This study was conducted to compare socio-demographic characteristics and the availability of social support for carers with low and high resilient coping, and identify if any domain of social support predicted high resilient coping in informal carers of people with dementia. The participants in this cross sectional survey included 108 informal carers of people with dementia. Findings showed the availability of emotional/informational support was most likely to predict resilient coping and tangible support the least likely. However, when controlling for all covariates, only gender predicted high resilient coping, individual social support domains were no longer significant. Therefore, as no single domain of social support has a significantly greater influence on resilient coping, service providers should enable carers to build a wide, multi-function support network.


Ethics and total parenteral nutrition: issues for intravenous nurse professionals.
Healthcare ethics is a hot topic these days. Decisions to withhold or withdraw various forms of medical therapy are daily events in most hospitals and long-term care facilities. Intravenous nurse professionals do not need to be bioethicists; however, they do need to be able to identify problems quickly and know how to address them. Some of the ethical issues that could be encountered by i.v. nurse professionals involved in the provision of total parenteral nutritional support in various clinical settings are examined and explored.


T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10.
Signaling to the mechanistic target of rapamycin (mTOR) regulates diverse cellular processes, including protein translation, cellular proliferation, metabolism, and autophagy. Most models place Akt upstream of the mTOR complex, mTORC1; however, in T cells, Akt may not be necessary for mTORC1 activation. We found that the adaptor protein Carma1 [caspase recruitment domain (CARD)-containing membrane-associated protein 1] and at least one of its associated proteins, the paracaspase MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), were required for optimal activation of mTOR in T cells in response to stimulation of the T cell receptor (TCR) and the co-receptor CD28. However, Bcl10, which binds to Carma1 and MALT1 to form a complex that mediates signals from the TCR to the transcription factor NF-κB (nuclear factor κB), was not required. The catalytic activity of MALT1 was required for the proliferation of stimulated CD4+ T cells, but not for early TCR-dependent activation events. Consistent with an effect on mTOR, MALT1 activity was required for the increased metabolic flux in activated CD4+ T cells. Together, our data suggest that Carma1 and MALT1 play previously unappreciated roles in the activation of mTOR signaling in T cells after engagement of the TCR.


Pharmacokinetic/Pharmacodynamic Optimization of Hospital-Acquired and Ventilator-Associated Pneumonia: Challenges and Strategies.
Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are correlated with high mortality rates worldwide. Thus, the administration of antibiotic therapy with appropriate dosing regimen is critical. An efficient antibiotic is needed to maintain an adequate concentration at the infection site, for a sufficient period of time, to achieve the best therapeutic outcome. It can, however, be challenging for antibiotics to penetrate the pulmonary system due to the complexity of its structure. Crossing the blood alveolar barrier is a difficult process determined by multiple factors that are either drug related or infection related. Thus, the understanding of pharmacokinetics/pharmacodynamics (PK/PD) of antibiotics identifies the optimum dosing regimens to achieve drug penetration into the epithelial lining fluid at adequate therapeutic concentrations. Critically ill patients in the ICU can express augmented renal clearance (ARC), characterized by enhanced renal function, or may have renal dysfunction necessitating supportive care such as continuous renal replacement therapy (CRRT). Both ARC and CRRT can alter drug elimination, thus affecting drug concentrations. PK of critically ill patients is less clear due to the multiple variabilities associated with their condition. Therefore, conventional dosing regimens often lead to therapeutic failure. Another major hurdle faced in optimizing treatment for HAP/VAP is the reduction of the in vitro potency. Therapeutic drug monitoring (TDM), if available, may allow health care providers to personalize treatment to maximize efficacy of the drug exposures while minimizing toxicity. TDM can be of significant importance in populations whom PK are less defined and for resistant infections to achieve the best therapeutic outcome.


Percutaneous trephine biopsy of the vertebral body in the rhesus monkey (Macaca mulatta).
Two methods of percutaneous vertebral body biopsy were performed in the Rhesus monkey, using a 3-mm diameter trephine and a pneumatic driver placed at a 30 degrees angle of approach to the transverse plane of the spine. The freehand method involved placing needle landmarks in the spine, followed by examination of a lateral radiograph of the lumbar region to verify landmark positioning and to estimate placement of the trephine. In the 2nd method, a pneumatic trephine guide was oriented according to a trigonometric calculation based on radiographic data. The pneumatic trephine guide allowed precise placement of the driver and steadied the trephine as it passed through the bone.


Ultrastructure of the synaptic junctional lattice isolated from mammalian brain.
Synaptic membranes can be treated with detergents to yield postsynaptic densities from which the lipid unit membrane has been removed. The ultrastructure of these densities is identical to THAT of the synaptic lattice observed in undigested synaptic membranes; a1000-3000 A diameter planar array of 200 A diameter dense-staining subunits. The persistence of this synaptic lattice in the absence of lipid membrane may reflect a functional role in the maintenance of defined synaptic junctional structures in intact tissue.


Implications for implementation science.
Implementing evidence into healthcare practice is essential to maximize the benefits of research and billions of dollars spent generating new knowledge. Implementation science is the investigation of methods, interventions (strategies), and variables to influence adoption of evidence-based healthcare practices by individuals and organizations to improve clinical and operational decision making, and includes testing the effectiveness of interventions to promote and sustain use of evidence-based healthcare practices. Estabrooks and her research team are to be applauded not only for the excellent contributions to the understanding of research utilization but also for setting forth a series of articles to stimulate thinking and comments across national boundaries and lines of inquiry. Described here are the implications for implementation science with regard to conceptual frameworks, measurement issues, and research designs, stimulated by the papers of the Estabrooks investigative team set forth in this special issue.


English-Chinese and Chinese-English Translations of Literary Texts: The Influence of Stylistic Features on the Translation Process and Eyetracking Technology.
This study is based on an experimental method of eye-tracking to investigate how translators perceive and understand translated literary texts and how different stylistic features influence their perception. This methodology allowed us to observe which parts of the text translators focused on the most, providing valuable data on their reading patterns and cognitive processes. Among English-Chinese translators, 95 out of 120 participants (79%) showed a tendency to prioritize faithfully conveying the source text's meaning over crafting a target text that aligns with Chinese stylistically. In the specific context of Chinese-English translation out of the 120 instances examined, the translators exhibited a reduced fixation duration on words in the source language, accounting for 34 instances (28%). This suggests a greater concern for preserving the source text's meaning rather than adapting it to the target culture. This research can assist translators and linguists in translating the stylistic features of English and Chinese literary texts more effectively. Future studies can explore other language stylistic features that may impact translation and compare translation styles across various literary genres and language pairs.


Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis.
Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's disease. Following reports of lymphocytic colitis and small bowel enteropathy in children with regressive autism, we aimed to see whether similar changes were seen in the stomach. We thus studied gastric antral biopsies in 25 affected children, in comparison to 10 with Crohn's disease, 10 with Helicobacter pylori infection, and 10 histologically normal controls. All autistic, Crohn's, and normal patients were H. pylori negative. Snap-frozen antral biopsies were stained for CD3, CD4, CD8, gammadelta T cells, HLA-DR, IgG, heparan sulphate proteoglycan, IgM, IgA, and C1q. Cell proliferation was assessed with Ki67. Distinct patterns of gastritis were seen in the disease states: diffuse, predominantly CD4+ infiltration in H. pylori, and focal-enhanced gastritis in Crohn's disease and autism, the latter distinguished by striking dominance of CD8+ cells, together with increased intraepithelial lymphocytes in surface, foveolar and glandular epithelium. Proliferation of foveolar epithelium was similarly increased in autism, Crohn's disease and H. pylori compared to controls. A striking finding, seen only in 20/25 autistic children, was colocalized deposition of IgG and C1q on the subepithelial basement membrane and the surface epithelium. These findings demonstrate a focal CD8-dominated gastritis in autistic children, with novel features. The lesion is distinct from the recently recognized focal gastritis of Crohn's disease, which is not CD8-dominated. As in the small intestine, there is epithelial deposition of IgG.


Label-free real-time detection of DNA methylation based on quartz crystal microbalance measurement.
DNA methylation plays an important role in the regulation of gene transcription, chromatin compaction, genome imprinting, and X-chromosome inactivation. DNA methyltransferase is considered a potential target for anticancer drug design. It is important to locate aberrantly methylated sequences on the human genome that are linked to specific diseases and to discover new low-toxic methylation inhibitors for medical treatments. We developed a DNA methylation detection method using a quartz crystal microbalance (QCM). We applied this method to assay genes p16 and GALR2 in two cell lines. Methylation of p16 was detected in both HT29 and HepG2 cell lines, whereas methylation of GALR2 was detected only in the HT29 cell line. We also used this method to evaluate the effect of 5-aza-2'-deoxycytidine (decitabine), a methyltransferase inhibitor used in clinical treatment. We found methylation of genes p16 and GALR2 to be strongly inhibited. The results show that this method is sensitive to DNA methylation and is fit for evaluation of methyltransferase inhibitors.


Mixing and transport during pharmaceutical twin-screw wet granulation: experimental analysis via chemical imaging.
Twin-screw granulation is a promising continuous alternative for traditional batch high shear wet granulation (HSWG). The extent of HSWG in a twin screw granulator (TSG) is greatly governed by the residence time of the granulation materials in the TSG and degree of mixing. In order to determine the residence time distribution (RTD) and mixing in TSG, mostly visual observation and particle tracking methods are used, which are either inaccurate and difficult for short RTD, or provide an RTD only for a finite number of preferential tracer paths. In this study, near infrared chemical imaging, which is more accurate and provides a complete RTD, was used. The impact of changes in material throughput (10-17 kg/h), screw speed (500-900 rpm), number of kneading discs (2-12) and stagger angle (30-90°) on the RTD and axial mixing of the material was characterised. The experimental RTD curves were used to calculate the mean residence time, mean centred variance and the Péclet number to determine the axial mixing and predominance of convective over dispersive transport. The results showed that screw speed is the most influential parameter in terms of RTD and axial mixing in the TSG and established a significant interaction between screw design parameters (number and stagger angle of kneading discs) and the process parameters (material throughput and number of kneading discs). The results of the study will allow the development and validation of a transport model capable of predicting the RTD and macro-mixing in the TSG. These can later be coupled with a population balance model in order to predict granulation yields in a TSG more accurately.


Long-term exposure to low-level air pollution and greenness and mortality in Northern Europe. The Life-GAP project.
Air pollution has been linked to mortality, but there are few studies examining the association with different exposure time windows spanning across several decades. The evidence for the effects of green space and mortality is contradictory. We investigated all-cause mortality in relation to exposure to particulate matter (PM2.5 and PM10), black carbon (BC), nitrogen dioxide (NO2), ozone (O3) and greenness (normalized difference vegetation index - NDVI) across different exposure time windows. The exposure assessment was based on a combination of the Danish Eulerian Hemispheric Model and the Urban Background Model for the years 1990, 2000 and 2010. The analysis included a complete case dataset with 9,135 participants from the third Respiratory Health in Northern Europe study (RHINE III), aged 40-65 years in 2010, with mortality follow-up to 2021. We performed Cox proportional hazard models, adjusting for potential confounders. Altogether, 327 (3.6 %) persons died in the period 2010-2021. Increased exposures in 1990 of PM2.5, PM10, BC and NO2 were associated with increased all-cause mortality hazard ratios of 1.40 (95 % CI1.04-1.87 per 5 μg/m3), 1.33 (95 % CI: 1.02-1.74 per 10 μg/m3), 1.16 (95 % CI: 0.98-1.38 per 0.4 μg/m3) and 1.17 (95 % CI: 0.92-1.50 per 10 μg/m3), respectively. No statistically significant associations were observed between air pollution and mortality in other time windows. O3 showed an inverse association with mortality, while no association was observed between greenness and mortality. Adjusting for NDVI increased the hazard ratios for PM2.5, PM10, BC and NO2 exposures in 1990. We did not find significant interactions between greenness and air pollution metrics. Long term exposure to even low levels of air pollution is associated with mortality. Opening up for a long latency period, our findings indicate that air pollution exposures over time may be even more harmful than anticipated.


[Validation of a new scoring system to predict the risk of postoperative acute renal failure in cardiac surgery].
The aim of this study was to cross validate a new scoring system, based on preoperative risk factors, in predicting the risk of postoperative dialysis after cardiac surgery and recently proposed by Thakar et al. Between January 2003 and March 2006, 1642 consecutive patients underwent cardiac surgery. From our clinical database, using Thakar's method, we calculated the total score for each patient. Univariate analysis was applied to all the risk factors considered for the score to test their statistical power in predicting postoperative acute renal failure. The effectiveness of the scoring system was analyzed with univariate analysis and with the area under the ROC curve. Postoperative dialysis was necessary in 22 patients. The factors that predicted acute renal failure, identified by univariate analysis, were the following: previous cardiac surgery, emergency surgery, coronary artery bypass graft associated with valve procedure, preoperative creatinine (1.2 to 2.1 mg/dl) and preoperative creatinine > or =2.1 mg/dl. The scoring system resulted statistically significant in predicting dialysis risk (p <0.001), the area under the ROC curve was 0.82. The incidence of renal failure in the four scoring groups, identified by Thakar, was similar in the first two groups but higher in the last two groups. Thakar's scoring system was validated in our population and all the major risk factors considered for its calculation were statistically significant in predicting postoperative dialysis after cardiac surgery.


Deferred slanted-edge analysis: a unified approach to spatial frequency response measurement on distorted images and color filter array subsets.
The slanted-edge method of spatial frequency response (SFR) measurement is usually applied to grayscale images under the assumption that any distortion of the expected straight edge is negligible. By decoupling the edge orientation and position estimation step from the edge spread function construction step, it is shown in this paper that the slanted-edge method can be extended to allow it to be applied to images suffering from significant geometric distortion, such as produced by equiangular fisheye lenses. This same decoupling also allows the slanted-edge method to be applied directly to Bayer-mosaicked images so that the SFR of the color filter array subsets can be measured directly without the unwanted influence of demosaicking artifacts. Numerical simulation results are presented to demonstrate the efficacy of the proposed deferred slanted-edge method in relation to existing methods.


Influence of laser enamel and dentine etching on marginal integrity of porcelain laminate veneers.
This investigation evaluated the effect of laser etching and acid etching techniques on the marginal leakage Vitadur N porcelain laminate veneers bonded either entirely on enamel, or with cervical margin located on root dentine of prepared extracted maxillary central incisors. Two different composite resin luting systems (light cured, or light and chemical cured) were used and compared. The bonded specimens were thermocycled and by employing the Standard dye penetration technique the leakage was scored from cervical and incisal margins. The least marginal leakage was observed beneath laminate veneers bonded entirely on enamel. Laser etching improved the sealing qualities of veneers with cervical margins on root dentine below the CEJ. Statistically insignificant differences were observed with the use of the two different composite resin luting systems.


Cryosectioning of Hydrogels as a Reliable Approach to Increase Yield and Further Tune Mechanical Properties.
Decellularized extracellular matrix (dECM) hydrogels have emerged as promising materials in tissue engineering. The steps to produce dECM hydrogels containing the bioactive epitopes found in the native matrix are often laborious, including the initial harvesting and decellularization of the animal organ. Furthermore, resulting hydrogels often exhibit weak mechanical properties that require the use of additional crosslinkers such as genipin to truly simulate the mechanical properties of the desired study tissue. In this work, we have developed a protocol to readily obtain tens of thin dECM hydrogel cryosections attached to a glass slide as support, to serve as scaffolds for two-dimensional (2D) or three-dimensional (3D) cell culture. Following extensive atomic force microscopy (AFM)-based mechanical characterization of dECM hydrogels crosslinked with increasing genipin concentrations (5 mM, 10 mM, and 20 mM), we provide detailed protocol recommendations for achieving dECM hydrogels of any biologically relevant stiffness. Given that our protocol requires hydrogel freezing, we also confirm that the approach taken can be further used to increase the mechanical properties of the scaffold in a controlled manner exhibiting twice the stiffness in highly crosslinked arrays. Finally, we explored the effect of ethanol-based short- and long-term sterilization on dECM hydrogels, showing that in some situations it may give rise to significant changes in hydrogel mechanical properties that need to be taken into account in experimental design. The hydrogel cryosections produced were shown to be biocompatible and support cell attachment and spreading for at least 72 h in culture. In brief, our proposed method may provide several advantages for tissue engineering: (1) easy availability and reduction in preparation time, (2) increase in the total hydrogel volume eventually used for experiments being able to obtain 15-22 slides from a 250 µL hydrogel) with a (3) reduction in scaffold variability (only a 17.5 ± 9.5% intraslide variability provided by the method), and (4) compatibility with live-cell imaging techniques or further cell characterization of cells.


Geographical Variation in Physical Fitness Among Chinese Children and Adolescents From 2005 to 2014.
Introduction: To examine the geographical variation in change in the levels of physical fitness from 2005 to 2014 among Chinese children and adolescents. Methods: A total of 663,813 children 7 to 18 years of age with physical fitness data in 2005, 2010 and 2014, participated in the study. Physical fitness was assessed using six components, and their standardized scores were aggregated to form a summary physical fitness indicator (PFI). Results: Over the study period, there was an increase in the proportion of high PFI (from 15.3% in 2005 to 19.0% in 2014, Ptrend < 0.05) and a decrease in the proportion of low PFI (from 30.6 to 29.8%, Ptrend < 0.05). Children and adolescents in the eastern provinces of China showed a high proportion of high PFI with an increasing trend over time, while those in the western provinces had a high proportion of low PFI with a decreasing trend over time (P < 0.05). Conclusions: The comprehensive physical fitness among Chinese children showed an improved trend from 2005 to 2014. Region-specific interventions with priority policies could be useful to sustainably narrow geographical variation in Chinese children, especially in the western provinces.


Insulin Protects Cortical Neurons Against Glutamate Excitotoxicity.
Glutamate excitotoxicity is implicated in the pathogenesis of numerous diseases, such as stroke, traumatic brain injury, and Alzheimer's disease, for which insulin resistance is a concomitant condition, and intranasal insulin treatment is believed to be a promising therapy. Excitotoxicity is initiated primarily by the sustained stimulation of ionotropic glutamate receptors and leads to a rise in intracellular Ca2+ ([Ca2+] i ), followed by a cascade of intracellular events, such as delayed calcium deregulation (DCD), mitochondrial depolarization, adenosine triphosphate (ATP) depletion that collectively end in cell death. Therefore, cross-talk between insulin and glutamate signaling in excitotoxicity is of particular interest for research. In the present study, we investigated the effects of short-term insulin exposure on the dynamics of [Ca2+] i and mitochondrial potential in cultured rat cortical neurons during glutamate excitotoxicity. We found that insulin ameliorated the glutamate-evoked rise of [Ca2+] i and prevented the onset of DCD, the postulated point-of-no-return in excitotoxicity. Additionally, insulin significantly improved the glutamate-induced drop in mitochondrial potential, ATP depletion, and depletion of brain-derived neurotrophic factor (BDNF), which is a critical neuroprotector in excitotoxicity. Also, insulin improved oxygen consumption rates, maximal respiration, and spare respiratory capacity in neurons exposed to glutamate, as well as the viability of cells in the MTT assay. In conclusion, the short-term insulin exposure in our experiments was evidently a protective treatment against excitotoxicity, in a sharp contrast to chronic insulin exposure causal to neuronal insulin resistance, the adverse factor in excitotoxicity.


A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis.
To investigate the involvement of transient receptor potential ankyrin 1 (TRPA1) in inflammatory hyperalgesia mediated by tumor necrosis factor α(TNFα) and joint inflammation. Mechanical hyperalgesia was assessed in CD1 mice, mice lacking functional TRP vanilloid 1 (TRPV1-/-) or TRPA1 (TRPA1-/-), or respective wildtype (WT) mice. An automated von Frey system was used, following unilateral intraplantar injection of TNFα or intraarticular injection of Freund's complete adjuvant (CFA). Knee swelling and histologic changes were determined in mice treated with intraarticular injections of CFA. TNFα induced cyclooxygenase-independent bilateral mechanical hyperalgesia in CD1 mice. The selective TRPV1 receptor antagonist SB-366791 had no effect on mechanical hyperalgesia when it was coinjected with TNFα, but intrathecally administered SB- 366791 attenuated bilateral hyperalgesia, indicating the central but not peripheral involvement of TRPV1 receptors. A decrease in pain sensitivity was also observed in TRPV1-/- mice. Intraplantar coadministration of the TRPA1 receptor antagonist AP-18 with TNFα inhibited bilateral hyperalgesia. Intrathecal treatment with AP-18 also reduced TNFα-induced hyperalgesia. CFA-induced mechanical hyperalgesia in CD1 mice was attenuated by AP-18 (administered by intraarticular injection 22 hours after the administration of CFA). Furthermore, intraarticular CFA–induced ipsilateral mechanical hyperalgesia was maintained for 3 weeks in TRPA1 WT mice. In contrast, TRPA1-/- mice exhibited mechanical hyperalgesia for only 24 hours after receiving CFA. Evidence suggests that endogenous activation of peripheral TRPA1 receptors plays a critical role in the development of TNFα-induced mechanical hyperalgesia and in sustaining the mechanical hyperalgesia observed after intraaarticular injection of CFA. These results suggest that blockade of TRPA1 receptors may be beneficial in reducing the chronic pain associated with arthritis.


Hippocampal inputs to identified neurons in an in vitro slice preparation of the rat nucleus accumbens: evidence for feed-forward inhibition.
The aim of the present study was to analyze responses of nucleus accumbens neurons to stimulation of the fornix. The recorded neurons were labeled with biocytin and identified as medium spiny neurons. A large majority of cells generated a depolarizing postsynaptic potential in response to stimulation of the fornix. Using intracellular current injection, this depolarizing response was dissociated into an EPSP reversing at -6 +/- 6 mV and an IPSP reversing at -71 +/- 4 mV. Both the EPSP and IPSP were abolished by 6-cyano-7-nitroquinoxaline-2,3-dione. In addition, the IPSP was blocked by bicuculline and picrotoxin. The onset latency of the EPSP was constant in spite of varying stimulus intensities. In contrast, the onset latency of the IPSP increased with decreasing stimulus intensity. Notably, the stimulus threshold for evoking IPSPs was generally lower than for EPSPs. At stimulus intensities well above threshold, the IPSP onset was only slightly delayed with respect to the EPSP onset. These results indicate that the EPSP can be characterized as a monosynaptic and glutamate-mediated synaptic response. The IPSP, however, appears to be mediated by a disynaptic feed-forward pathway involving both glutamate and GABAA receptors. Recurrent and lateral inhibitory interactions have previously been proposed to be predominant organizational principles in the caudate-putamen and nucleus accumbens. This study indicates that feed-forward inhibition is an additional principle governing the activities of striatal neural networks.