[Raynaud's syndrome in children. Study of 23 cases].
To analyze the epidemiological characteristics of Raynaud's syndrome in childhood. We conducted a nine-year-retrospective survey of children up to 17 y seen with Raynaud's syndrome. Charts were retrieved from pediatrics and dermatology outpatient units, and from the registry of capillaroscopy. A specific questionnaire was designed and missing data were completed after a phone interview of the parents. A definite diagnosis of Raynaud's syndrome was ascertained in 23 patients with marked female predominance (SR = 0.27). Triggering factors were essentially a cold environment and emotions. The mean age at the diagnosis was 11 y (5 to 16 y) with an onset after ten years in 65% of cases. Eleven of these Raynaud's syndromes were secondary with ten connectivitis, eight remained essential and four were suspected to be secondary. This series of pediatric Raynaud's syndromes was important according to scarcity of literature on this topic. The diagnosis is made upon exclusive clinical basis and we underline the high frequency of serious underlying conditions. Further etiologic investigations are mandatory for any pediatric patient with Raynaud's syndrome. The sensitivity (78%) and specificity (80%) of capillaroscopy were of interest in our patients; its prognosis value needs to be evaluated in a larger group of patients.


Optimization of sulphur production in a biotechnological sulphide-removing reactor.
A new biotechnological process for sulphide removal is proposed. The principle of this process is that sulphide is converted into elemental sulphur, which can be removed by sedimentation. In this article, investigations on the optimization of the sulphur production are reported. It seems that less than 10% sulphate is produced at low oxygen concentration, when the sulphide concentration in the reactor exceeds 10 mg/L. At sulphide concentrations higher than 20 mg/L only 5% of the incoming sulphide is converted to sulphate even at high oxygen concentrations. An immobilized biomass on recticulated polyurethane produced more sulphate than a free cell suspension at the same oxygen and sulphide concentration.


The relationship between bullying and self-worth in children with movement coordination problems.
Past research has indicated that there is a negative relationship between victimization and self-worth. Furthermore, children with movement problems such as developmental coordination disorder (DCD) are considered at risk of both victimization and low self-worth. This study investigated the relationship between peer-victimization and self-worth in a group of children with DCD and control children. Forty-three children aged 7-11 years were identified as at risk of DCD, and were matched on age and gender with 43 control children. Children were individually assessed using the Multi-dimensional peer victimization scale (MPVS; Mynard & Joseph, 2000) to assess the degree and type of bullying, and the self perception profile for children (SPPC; Harter, 1985) to determine self-worth. The two groups did not differ significantly on mean reported self-worth or mean peer-victimization. The relationship between these two measures, however, differed across group and gender. Peer victimization and self-worth were negatively correlated only for the children at risk of DCD. Furthermore, peer victimization accounted for a greater and statistically significant proportion of the variance in the self-worth of girls at risk of DCD compared with boys. This effect of peer-victimization on self-worth in girls with DCD was uniquely attributed to the effects of verbal victimization. Although children with and without motor coordination problems reported equivalent amounts of victimization, there were differences in the impact of that bullying. Specifically, self-worth was negatively affected by bullying for the girls with DCD. Teachers and parents should not only focus on the amount of bullying a child receives, but should also be aware of how bullying impacts differently on self-worth across groups.


Three-dimensional quantitative structure: activity relationship studies on diverse structural classes of HIV-1 integrase inhibitors using CoMFA and CoMSIA.
Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques, were applied to a set of 89 HIV-1 integrase (IN) inhibitors (training set=61, test set=28), belonging to 11 structurally different classes. The biological data for 3' processing mechanism were used. For CoMFA calculations, three different fitting methods for alignment process were investigated. The best CoMFA model yielded the cross-validated r(2) r(2)(cv) =0.698 and the non-cross-validated r(2) (r(2))=0.947. The derived model indicated the importance of steric (60.8%) as well as electrostatic (39.2%) contributions. For CoMSIA calculations, different combinations of the fields were tested. The best CoMSIA model gave r(2)(cv) =0.724 and r(2)=0.864. This model showed that steric (30.3%), hydrogen bond donor (43.4%) and hydrogen bond acceptor (26.3%) properties played major roles in HIV-1 IN inhibition. The mapping of hydrogen bond interaction fields with the HIV-1 IN active site gave details on hydrogen bond forming between ligands and enzyme. These obtained results agree well with the experimental observations that there should be hydrogen bond interactions between ligands and Glu152, Lys156 and Lys159 residues. The results not only lead to a better understanding of structural requirements of HIV-1 IN inhibitors but also can help in the design of new IN inhibitors.


Rapid expansion of Neisseria gonorrhoeae ST7827 clone in Australia, with variable ceftriaxone phenotype unexplained by genotype.
Neisseria gonorrhoeae is identified as a priority pathogen due to its capacity to rapidly develop antimicrobial resistance (AMR). Following the easing of SARS-CoV-2 pandemic travel restrictions across international borders in the state of New South Wales (NSW), Australia, a surge of gonococcal isolates with raised ceftriaxone MIC values were detected. All N. gonorrhoeae isolates (n = 150) with increased ceftriaxone MIC values in NSW between 1 January 2021 and July 2022 from males and females from all sites were sequenced. A new emergence and rapid expansion of an N. gonorrhoeae ST7827 clone was documented within NSW, Australia and provides further evidence of the ability of N. gonorrhoeae to undergo sufficient genomic changes and re-emerge as a geographically restricted subclone. Mapping AMR determinants to MIC results did not reveal any genomic pattern that correlated with MIC values. The rapid dissemination and establishment of this clone at the population level is a new and concerning demonstration of the agility of this pathogen, and underscores concerns about similar incursions and establishment of MDR clones. Moreover, it is notable that in this context the AMR genotype-phenotype correlates remain unclear, which requires further investigation to enable better understanding of genomic aspects of AMR in N. gonorrhoeae.


Combined comparative and chemical proteomics on the mechanisms of levo-tetrahydropalmatine-induced antinociception in the formalin test.
This study investigated the mechanisms involved in the antinociceptive action induced by levo-tetrahydropalmatine (l-THP) in the formalin test by combined comparative and chemical proteomics. Rats were pretreated with l-THP by the oral route (40 mg/kg) 1 h before formalin injection. The antinociceptive effect of l-THP was shown in the first and second phases of the formalin test. To address the mechanisms by which l-THP inhibits formalin-induced nociception in rats, the combined comparative and chemical proteomics were applied. A novel high-throughput comparative proteomic approach based on 2D-nano-LC-MS/MS was applied to simultaneously evaluate the deregulated proteins involved in the response of l-THP treatment in formalin-induced pain rats. Thousands of proteins were identified, among which 17 proteins survived the stringent filter criteria and were further included for functional discussion. Two proteins (Neurabin-1 and Calcium-dependent secretion activator 1) were randomly selected, and their expression levels were further confirmed by Western Blots. The results matched well with those of proteomics. In the present study, we also described the development and application of l-THP immobilized beads to bind the targets. Following incubation with cellular lysates, the proteome interacting with the fixed l-THP was identified. The results of comparative and chemical proteomics were quite complementary. Although the precise roles of these identified moleculars in l-THP-induced antinociception need further study, the combined results indicated that proteins associated with signal transduction, vesicular trafficking and neurotransmitter release, energy metabolism, and ion transport play important roles in l-THP-induced antinociception in the formalin test.


RNAI-FRID: novel feature representation method with information enhancement and dimension reduction for RNA-RNA interaction.
Different ribonucleic acids (RNAs) can interact to form regulatory networks that play important role in many life activities. Molecular biology experiments can confirm RNA-RNA interactions to facilitate the exploration of their biological functions, but they are expensive and time-consuming. Machine learning models can predict potential RNA-RNA interactions, which provide candidates for molecular biology experiments to save a lot of time and cost. Using a set of suitable features to represent the sample is crucial for training powerful models, but there is a lack of effective feature representation for RNA-RNA interaction. This study proposes a novel feature representation method with information enhancement and dimension reduction for RNA-RNA interaction (named RNAI-FRID). Diverse base features are first extracted from RNA data to contain more sample information. Then, the extracted base features are used to construct the complex features through an arithmetic-level method. It greatly reduces the feature dimension while keeping the relationship between molecule features. Since the dimension reduction may cause information loss, in the process of complex feature construction, the arithmetic mean strategy is adopted to enhance the sample information further. Finally, three feature ranking methods are integrated for feature selection on constructed complex features. It can adaptively retain important features and remove redundant ones. Extensive experiment results show that RNAI-FRID can provide reliable feature representation for RNA-RNA interaction with higher efficiency and the model trained with generated features obtain better performance than other deep neural network predictors.


Management of Osteoarthritic Axial Neck Pain With Cervical Neuromodulation.
Chronic refractory facetogenic axial neck pain is a challenging diagnosis to manage long-term. With limited options available for patients who have failed cervical medial branch blocks, patients often have to endure a poor quality of life. Although neuromodulation devices such as peripheral nerve stimulators are currently available for the management of various chronic conditions, their role in the treatment of axial neck pain has not been studied. We present a case of successful management of facetogenic axial neck pain with cervical medial branch peripheral nerve stimulation.


[Direct Observation on the Temporal and Spatial Patterns of the CO2 Concentration in the Atmospheric of Nanjing Urban Canyon in Summer].
Direct observation of urban atmospheric CO2 concentration is vital for the research in the contribution of anthropogenic activity to the atmospheric abundance since cities are important CO2 sources. The observations of the atmospheric CO2 concentration at multiple sites/heights can help us learn more about the temporal and spatial patterns and influencing mechanisms. In this study, the CO2 concentration was observed at 5 sites (east, west, south, north and middle) in the main city area of Nanjing from July 18 to 25, 2014, and the vertical profile of atmospheric CO2 concentration was measured in the middle site at 3 heights (30 m, 65 m and 110 m). The results indicated that: (1) An obvious vertical CO2 gradient was found, with higher CO2 concentration [molar fraction of 427. 3 x 10(-6) (±18. 2 x 10(-6))] in the lower layer due to the strong influences of anthropogenic emissions, and lower CO2 concentration in the upper layers [411. 8 x 10(-6) (±15. 0 x 10(-6)) and 410. 9 x 10(-6) (±14. 6 x 10(-6)) at 65 and 110 m respectively] for the well-mixed condition. The CO2 concentration was higher and the vertical gradient was larger when the atmosphere was stable. (2) The spatial distribution pattern of CO2 concentration was dominated by wind and atmospheric stability. During the observation, the CO2 concentration in the southwest was higher than that in the northeast region with the CO2 concentration difference of 7. 8 x 10(-6), because the northwest wind was prevalent. And the CO2 concentration difference reduced with increasing wind speed since stronger wind diluted CO2 more efficiently. The more stable the atmosphere was, the higher the CO2 concentration was. (3) An obvious diurnal variation of CO2 concentration was shown in the 5 sites. A peak value occurred during the morning rush hours, the valley value occurred around 17:00 (Local time) and another high value occurred around 19:00 because of evening rush hour sometimes.


Photophysical properties of Ru(II) bipyridyl complexes containing hemilabile phosphine-ether ligands.
Emission and absorbance spectra, along with low-temperature excited-state lifetimes, were obtained for the hemilabile complexes, [Ru(bpy)2L](PF6)2 [L = (2-methoxyphenyl)diphenylphosphine (RuPOMe) (1) and (2-ethoxyphenyl)diphenylphosphine (RuPOEt) (2)] in solid 4:1 ethanol/methanol solution. Spectral data were evaluated with ground-state reduction potentials using Lever parameters. Lifetime data for these complexes were collected from 77 to 160 K, and the rate constant for the combined radiative and nonradiative decay process, k, the thermally activated process prefactor, k'(0), the rate constant for the MLCT --> d-d transition, k', and the activation energy, DeltaE', were calculated from a plot of ln(1/tau) versus 1/T for both (1) and (2). The low-temperature luminescence lifetimes of (1) were observed to decrease with increases in water concentration. The photophysical and kinetic data of (1) and (2) are compared to literature data for [Ru(bpy)3](PF6)2. The emission maxima of (1) and (2) are blue-shifted relative to [Ru(bpy)3](PF6)2 due to the presence of the strong-field phosphine ligand, which enhances pi back-bonding to the bipyridyl ligands. The thermal activation energy, DeltaE', is significantly larger for [Ru(bpy)3](PF6)2 than for (1) and (2) resulting in a faster MLCT --> d-d transition for (1) and (2). These results are discussed in the context of radiationless decay through thermally activated ligand-field states on the metal complex.


Determinants of social behavior deficits and recovery after pediatric traumatic brain injury.
Traumatic brain injury (TBI) during early childhood is associated with a particularly high risk of developing social behavior impairments, including deficits in social cognition that manifest as reduced social interactions, with profound consequences for the individuals' quality of life. A number of pre-injury, post-injury, and injury-related factors have been identified or hypothesized to determine the extent of social behavior problems after childhood TBI. These include variables associated with the individual themselves (e.g. age, genetics, the injury severity, and extent of white matter damage), proximal environmental factors (e.g. family functioning, parental mental health), and more distal environmental factors (e.g. socioeconomic status, access to resources). In this review, we synthesize the available evidence demonstrating which of these determinants influence risk versus resilience to social behavior deficits after pediatric TBI, drawing upon the available clinical and preclinical literature. Injury-related pathology in neuroanatomical regions associated with social cognition and behaviors will also be described, with a focus on findings from magnetic resonance imaging and diffusion tensor imaging. Finally, study limitations and suggested future directions are highlighted. In summary, while no single variable can alone accurately predict the manifestation of social behavior problems after TBI during early childhood, an increased understanding of how both injury and environmental factors can influence social outcomes provides a useful framework for the development of more effective rehabilitation strategies aiming to optimize recovery for young brain-injured patients.


[MicroRNA and left ventricular hypertrophy].
MicroRNAs (miRNA) plays an important role in biological development and disease occurrence and development, and acts as a "main switch" in biology. Among patients of essential hypertension, around 1/3 would suffer left ventricular hypertrophy (LVH). Hence, essential hypertension becomes an independent risk factor for cardiovascular diseases. And miRNAs plays an important role in the occurrence and development of LVH. This paper reviewed the role of miRNA in regulating the stress signaling pathway, defined its impact on the occurrence of LVH, and further emphasized the opportunities and challenges of miRNA as a biomarker and therapeutic target.


Separation of Semiconducting Carbon Nanotubes for Flexible and Stretchable Electronics Using Polymer Removable Method.
Electronics that are soft, conformal, and stretchable are highly desirable for wearable electronics, prosthetics, and robotics. Among the various available electronic materials, single walled carbon nanotubes (SWNTs) and their network have exhibited high mechanical flexibility and stretchability, along with comparable electrical performance to traditional rigid materials, e.g. polysilicon and metal oxides. Unfortunately, SWNTs produced en masse contain a mixture of semiconducting (s-) and metallic (m-) SWNTs, rendering them unsuitable for electronic applications. Moreover, the poor solubility of SWNTs requires the introduction of insulating surfactants to properly disperse them into individual tubes for device fabrication. Compared to other SWNT dispersion and separation methods, e.g., DNA wrapping, density gradient ultracentrifugation, and gel chromatography, polymer wrapping can selectively disperse s-SWNTs with high selectivity (>99.7%), high concentration (>0.1 mg/mL), and high yield (>20%). In addition, this method only requires simple sonication and centrifuge equipment with short processing time down to 1 h. Despite these advantages, the polymer wrapping method still faces two major issues: (i) The purified s-SWNTs usually retain a substantial amount of polymers on their surface even after thorough rinsing. The low conductivity of the residual polymers impedes the charge transport in SWNT networks. (ii) Conjugated polymers used for SWNT wrapping are expensive. Their prices ($100-1000/g) are comparable or even higher than those of SWNTs ($10-300/g). These utilized conjugated polymers represent a large portion of the overall separation cost. In this Account, we summarize recent progresses in polymer design for selective dispersion and separation of SWNTs. We focus particularly on removable and/or recyclable polymers that enable low-cost and scalable separation methods. First, different separation methods are compared to show the advantages of the polymer wrapping methods. In specific, we compare different characterization methods used for purity evaluation. For s-SWNTs with high purity, i.e., >99%, short-channel (smaller than SWNT length) electrical measurement is more reliable than optical methods. Second, possible sorting mechanism and molecular design strategies are discussed. Polymer parameters such as backbone design and side chain engineering affect the polymer-SWNT interactions, leading to different dispersion concentration and selectivity. To address the above-mentioned limiting factors in both polymer contamination and cost issues, we describe two important polymer removal and cycling approaches: (i) changing polymer wrapping conformation to release SWNTs; (ii) depolymerization of conjugated polymer into small molecular units that have less affinity toward SWNTs. These methods allow the removal and recycling of the wrapping polymers, thus providing low-cost and clean s-SWNTs. Third, we discuss various applications of polymer-sorted s-SWNTs, including flexible/stretchable thin-film transistors, thermoelectric devices, and solar cells. In these applications, polymer-sorted s-SWNTs and their networks have exhibited good processability, attractive mechanical properties, and high electrical performance. An increasing number of studies have shown that the removable polymer approaches can completely remove polymer residues in SWNT networks and lead to enhanced charge carrier mobility, higher conductivity, and better heterojunction interface.


Modeling of peptaibol analogues incorporating nonpolar α,α-dialkyl glycines shows improved α-helical preorganization and spontaneous membrane permeation.
In this study, we investigate the effect of nine noncanonical α,α-dialkyl glycines on the structure, dynamics, and membrane permeation properties of a small peptaibol, peptaibolin. The noncanonical amino acids under study are Aib (α-amino isobutyric acid), Deg (α,α-diethyl glycine), Dpg (α,α-dipropyl glycine), Dibg (α,α-di-isobutyl glycine), Dhg (α,α-dihexyl glycine), DΦg (α,α-diphenyl glycine), Db(z)g (α,α-dibenzyl glycine), Ac6c (α,α-cyclohexyl glycine), and Dmg (α,α-dihydroxymethyl glycine). It is hypothesized that these amino acids are able to induce well-defined secondary structures in peptidomimetics. To investigate this hypothesis, we designed new peptaibolin peptidomimetics by replacing the native Aib positions with a new α,α-dialkyl glycine. We show that Dhg and Ac6c noncanonical amino acids are able to induce α-helix secondary structures of peptaibolin in water, which are not present in the native structure. We also demonstrate that the α,α-dialkyl glycines increase the membrane permeability of peptaibolin in 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) membranes. However, there is no apparent correlation between increased helicity and membrane permeability. In summary, we show that some α,α-dialkyl glycines under study induce the formation of α-helix secondary structures in peptaibolin and promote spontaneous membrane permeation. Our findings increase the knowledge of the membrane permeability and folding of peptides incorporating α,α-dialkyl glycines.


Fosfomycin therapeutic drug monitoring in real-life: development and validation of a LC-MS/MS method on plasma samples.
Individualization of fosfomycin dosing based on therapeutic drug monitoring (TDM) of plasma concentrations could reduce drug-related adverse events and improve clinical outcome in complex clinical conditions. Quantification of fosfomycin in plasma samples was performed by a rapid ultraperformance liquid chromatography mass spectrometry method. Sample preparation involved protein precipitation with [13C3]-fosfomycin benzylamine salt as internal standard. The calibration curve ranged from 2 to 800 mg/L. Within- and between-day precision and accuracy, sensitivity, selectivity, dilution integrity, recovery were investigated and the results met the acceptance criteria. In patients, multiple drug dosing (every 6 or 8 hours) or in continuous administration were adopted, resulting in a large interpatient variability in drug concentrations (from 7.4 mg/L and 644.6 mg/L; CV: 91.1%). In critical care patient setting TDM can represent an important tool to identify the best fosfomycin dosing in single patients, taking into consideration clinical characteristics, infection sites and susceptibility of the treated pathogens.


Prune extract (Prunus domestica L.) suppresses the proliferation and induces the apoptosis of human colon carcinoma Caco-2.
Prunes are the dried fruits of certain cultivars of Prunus domestica L., and are recognized as a health food. The separated ethanol fraction from concentrated prune juice by DIAION HP-20 (PE) was investigated for cytotoxic effects on two different cancer cell lines in vitro. PE dose-dependently reduced the viable cell number of Caco-2, KATO III, but does not reduce the viable cell number of human normal colon fibroblast cells (CCD-18Co) used as a normal cell model. PE treatment for 24 h led to apoptotic changes in Caco-2 such as cell shrinkage and blebbed surfaces due to the convolutions of nuclear and plasma membranes and chromatin condensation, but this was not observed in CCD-18Co. PE induced nucleosomal DNA fragmentation typical of apoptosis in Caco-2 after 24 h of treatment. These results show that PE induced apoptosis in Caco-2. Furthermore, by Caco-2 treatment with H2O2 chelator catalase and Ca2+-chelator BAPTA/AM, the PE-induced cytotoxic pathway was completely blocked, and the viable cell number of Caco-2 was not affected.


Inhibition of the plastidic ATP/ADP transporter protein primes potato tubers for augmented elicitation of defense responses and enhances their resistance against Erwinia carotovora.
Tubers of transgenic potato (Solanum tuberosum) plants with decreased activity of the plastidic ATP/ADP transporter AATP1 display reduced levels of starch, modified tuber morphology, and altered concentrations of primary metabolites. Here, we demonstrate that the spontaneous production of hydrogen peroxide, the endogenous content of salicylic acid, and the levels of mRNAs of various defense-related genes are similar in tuber discs of wild-type and AATP1(St) antisense plants. However, upon challenging the tissue with fungal elicitors or culture supernatants of the soft rot-causing pathogen Erwinia carotovora subsp. atroseptica, the AATP1(St) antisense tubers exhibit highly potentiated activation of defense responses when compared with wild-type tissue. The augmented defense responses comprise enhanced accumulation of transcripts of five defense-related genes (beta-1,3-GLUCANASE B2 and A1, CHITINASE B3 and A2, and Phe AMMONIA-LYASE) and enhanced elicitation (up to 21-fold) of the early hydrogen peroxide burst. The potentiated activation of cellular defense responses in AATP1(St) antisense tubers is not accompanied by a precedent increase in endogenous salicylic acid levels, but is associated with a strongly enhanced resistance of the tissue to E. carotovora. From these results, we conclude that inhibition of primary metabolic reactions induces a primed state that sensitizes the potato tubers for improved elicitation of various cellular defense responses, which likely contribute to enhanced E. carotovora resistance.


Statistical-mechanical liquid theories reproduce anomalous thermodynamic properties of explicit two-dimensional water models.
We have developed an analytical theory for a simple model of liquid water. We apply Wertheim's thermodynamic perturbation theory (TPT) and integral equation theory (IET) for associative liquids to the rose model, which is among the simplest models of water. The particles interact through rose potentials for orientation dependent pairwise interactions. Modifying both the shape and range of a three-petal rose function, we construct an efficient and dynamical mimic of the two-dimensional (2D) Mercedes-Benz (MB) water model. The particles in 2D MB are 2D Lennard-Jones disks with three hydrogen bonding arms arranged symmetrically, resembling the Mercedes-Benz logo. Both models qualitatively predict both the anomalous properties of pure water and the anomalous solvation thermodynamics of nonpolar molecules. The IET is based on the orientationally averaged version of the Ornstein-Zernike equation. This is one of the main approximations in the present work. IET correctly predicts the pair correlation functions at high temperatures. Both TPT and IET are in semi-quantitative agreement with the Monte Carlo values of the molar volume, isothermal compressibility, thermal expansion coefficient, and heat capacity. A major advantage of these theories is that they require orders of magnitude less computer time than the Monte Carlo simulations.


Molecular profiles of mitogen activated protein kinase signaling pathways in orofacial development.
Formation of the mammalian orofacial region involves multiple signaling pathways regulating sequential expression of and interaction between molecular signals during embryogenesis. The present study examined the expression patterns of members of the MAPK family in developing murine orofacial tissue. Total RNA was extracted from developing embryonic orofacial tissue during gestational days (GDs) 12-14 and used to prepare biotinylated cDNA probes, which were then denatured and hybridized to murine MAPK signaling pathways gene arrays. Expression of a number of genes involved in the (ERK1/2) cascade transiently increased in the embryonic orofacial tissue over the developmental period examined. Numerous members of the SAPK/JNK cascade were constitutively expressed in the tissue. Genes known to play a role in p38 MAPK signaling exhibited constitutive expression during orofacial development. Western blot analysis demonstrated that ERK2/1, p38, and SAPK/JNK kinases are present in embryonic orofacial tissue on each of GD 12, 13, and 14. By using phospho-specific antibodies, active ERK was shown to be temporally regulated during orofacial development. Minimal amounts of active p38 and active SAPK/JNK were detected in orofacial tissue during GDs 12-14. Our study documents specific expression patterns of genes coding for proteins belonging to the ERK1/2, p38, and SAPK/JNK MAPK families in embryonic orofacial tissue. We also demonstrate that active, phosphorylated forms of ERK1/2 only were detected in the embryonic tissue investigated, suggesting a more central role for members of this family in embryonic orofacial development.


That's me in the spotlight: neural basis of individual differences in self-consciousness.
A long-standing literature implicates activity within the default mode network (DMN) to processes linked to the self. However, contemporary work suggests that other large-scale networks networks might also be involved. For instance, goal-directed autobiographical planning requires positive functional connectivity (FC) between DMN and frontoparietal control (FPCN) networks. The present study examined the inter-relationship between trait self-focus (measured via a self-consciousness scale; SCS), incidental memory in a self-reference paradigm, and resting state FC of large-scale networks. Behaviourally, we found that private SCS was linked to stronger incidental memory for self-relevant information. We also examined how patterns of FC differed according to levels of self-consciousness by using the SCS data to drive multiple regression analyses with seeds from the DMN, the FPCN and the limbic network. High levels of SCS was not linked to differences in the functional behaviour of the DMN, however, it was linked to stronger FC between FPCN and a cluster extending into the hippocampus, which meta analytic decoding using Neurosynth linked to episodic memory retrieval. Subsequent analysis demonstrated that trait variance in this pattern of FC was a moderator for the observed relationship between private SCS and enhanced memory for self-items. Together these findings suggest that interactions between the FPCN and hippocampus may support the memory advantage of self-relevant information associated with SCS and confirm theoretical positions that argue that that self-related processing does not simply depend upon the DMN, but instead relies on complex patterns of interactions between multiple large-scale networks.


[Finite element analysis of different load mode on tooth movement for space closure in patient with bimaxillary protrusion].
To investigate the stress distribution on the maxillary anterior teeth retracted with sliding mechanics and micro-implant anchorage using different retraction hook heights and positions. DICOM image data including maxilla and upper teeth were obtained with cone-beam CT. The three-dimensional finite element model was constructed using Mimics software. Brackets and archwire model were constructed using Creo software. The models were instantiated using Pro/Engineer software. Abaqus software was used to simulate the sliding mechanics by loading 2 N force on 0, 2, 4, 6, 8, 10 mm retraction hooks and three different positions, repectively. Rotation of the occlusal plane, the initial displacement and stress distribution of teeth were analyzed. Lingual rotation of maxillary central incisor(0.021°), gingival movement of the maxillary first molar(0.005 mm), and clockwise rotation of the maxillary occlusal plane(0.012°) were observed when the force application point located at the archwire level (0 mm). In contrast, 0.235° labial rotation of the maxillary central incisor, 0.015 mm occlusal movement of the maxillary first molar, and 0.075° anti-clockwise rotation of the maxillary occlusal plane were observed when the force application point located at the higher level(10 mm retraction hook). The more the force application point was located posteriorly at the archwire level, the less lingual rotation of the maxillary central incisor and the more buccal displacement of maxillary first molar was observed. Maxillary anterior tooth rotation and retraction, vertical displacement of posterior segment, and rotation of the occlusal plane could be controlled by adjusting the height and position of the retraction hook in space closure using miniscrew and sliding mechanics.


Reactive arthritis associated with Shigella sonnei infection.
Several studies have failed to show an association between Shigella sonnei dysentery and reactive arthritis. We describe 3 patients who had reactive arthritis and a recent or concurrent S sonnei infection. To our knowledge, this is only the second study to suggest this association. We propose that S sonnei should be considered as a triggering agent for reactive arthritis.


Detection of St. Louis encephalitis virus antigen in mosquitoes by capture enzyme immunoassay.
Surveillance methods that measure St. Louis encephalitis (SLE) virus activity in nature may provide forewarning of its epidemic occurrence in humans. An antigen capture enzyme immunoassay was developed to detect SLE virus in infected mosquitoes. The assay detected purified SLE viral antigen at a concentration of 62 pg/0.1 ml when antigen was incubated overnight; 250 pg/0.1 ml was detected in a single-day assay (antigen incubated for 3 h). The assay detected 67.9 and 70.8% of laboratory-prepared pools of infected mosquitoes after 3 h and overnight incubation, respectively. The sensitivity of the procedure was 90.5% in identifying pools with infectious titers greater than dex 3.0. The specificity of the assay was controlled by retesting positive pools preincubated with SLE virus and normal antibodies, which led to a diminution of signal in the pools containing viral antigen. The procedure was suitably specific in discriminating between SLE and related flaviviruses, detecting only high infectious doses of heterologous antigens.


Role of interaction of CD2 molecules with lymphocyte function-associated antigen 3 in T-cell recognition of nominal antigen.
The role of the interaction of CD2 molecules with lymphocyte function-associated antigen 3 (LFA-3) in facilitating nominal antigen recognition by T lymphocytes was studied by utilizing an HLA-DR4-restricted CD4+ cytotoxic human T-cell clone specific for human immunodeficiency virus envelope glycoprotein gp120 as a responder and murine fibroblasts transfected with human class II major histocompatibility complex (MHC) and/or human LFA-3 molecules as antigen-presenting cells (APC). Although expression of the DR4 restriction element in fibroblasts is sufficient for T-cell recognition of a gp120 peptide as judged by induction of proliferation coexpression of human LFA-3 on DR4+ APC decreases the molar requirement of nominal antigen by greater than one order of magnitude. Both LFA-3 and the relevant class II MHC molecules are necessary for antigen-independent conjugate formation, but the binding is further enhanced by specific nominal antigen. CD2-LFA-3 interaction is independent of T-cell receptor-MHC interaction and contributes directly to the stabilized conjugate between the T cell and LFA-3-bearing APC; soluble CD2 and monoclonal antibodies to LFA-3 and CD2 reduce T-cell-APC binding to the level mediated by nominal antigen and MHC. During conjugate formation, CD2 but not CD3 molecules are reorganized into the cell-cell interaction site in an antigen-independent manner. Thus, reorganization and/or coassociation of CD2 with CD3 molecules is not essential for T-cell activation.


Kaposi Sarcoma in an Human Immunodeficiency Virus (HIV)-Seronegative Mediterranean Female: Report of a Rare Case.
BACKGROUND Kaposi sarcoma is a malignancy commonly linked to HIV infection or immunosuppression. An association with human herpes virus 8 (HHV-8) infection has also been reported. We present a case of classic Kaposi sarcoma in a female Mediterranean patient. CASE REPORT A 57-year-old white female of Greek ethnicity, with no history of HIV infection or immunosuppression, presented to the Surgical Out-patient Department of our Center, with complaints of extensive discolored skin lesion on both legs, initially considered as chronic vein insufficiency. Histopathological findings from skin biopsies revealed Kaposi sarcoma. CONCLUSIONS Non-HIV-related Kaposi sarcoma is an HHV-8-related, angioproliferating skin cancer that can cause pain, disfigurement, and limb dysfunction. High suspicion of this condition can lead to early treatment and delay progression.


HNetGO: protein function prediction via heterogeneous network transformer.
Protein function annotation is one of the most important research topics for revealing the essence of life at molecular level in the post-genome era. Current research shows that integrating multisource data can effectively improve the performance of protein function prediction models. However, the heavy reliance on complex feature engineering and model integration methods limits the development of existing methods. Besides, models based on deep learning only use labeled data in a certain dataset to extract sequence features, thus ignoring a large amount of existing unlabeled sequence data. Here, we propose an end-to-end protein function annotation model named HNetGO, which innovatively uses heterogeneous network to integrate protein sequence similarity and protein-protein interaction network information and combines the pretraining model to extract the semantic features of the protein sequence. In addition, we design an attention-based graph neural network model, which can effectively extract node-level features from heterogeneous networks and predict protein function by measuring the similarity between protein nodes and gene ontology term nodes. Comparative experiments on the human dataset show that HNetGO achieves state-of-the-art performance on cellular component and molecular function branches.


Growth and substrate consumption of Nitrobacter agilis cells immobilized in carrageenan: part 1. Dynamic modeling.
The modeling of the growth of Nitrobacter agilis cell immobilized in kappa-carrageenan is presented. A detailed description is given of the modeling of internal diffusion and growth of cells in the support matrix in addition to external mass transfer resistance. The model predicts the substrate and biomass profiles in the support as well as the macroscopic oxygen consumption rate of the immobilized biocatalyst in time. The model is tested by experiments with continuously operated airlift loop reactors containing cells immobilized in kappa-carrageenan. The model describes experimental data very well. It is clearly shown that external mass transfer may not be neglected. Furthermore, a sensitivity analysis of the parameters at their values during the experiments revealed that apart from the radius of the spheres and the substrate bulk concentration, the external mass transfer resistance coefficient is the most sensitive parameter for our case.


Fine needle aspiration cytology diagnosis of metastatic malignant diffuse type tenosynovial giant cell tumor.
Tenosynovial giant cell tumors (TGCTs) arise from the synovium of joint, bursa, and tendon sheath, and are classified into localized and diffuse types. Diffused type often affects the large joint, and has more recurrence, metastasis, and malignant transformation potential compared to the localized type. Malignant diffused TGCT (D-TGCT) usually occurs as a large tumor (>5 cm), in older patients, and its histopathologic features include necrosis, cellular anaplasia, prominent nucleoli, high nuclear cytoplasmic ratio, brisk mitosis, discohesion of tumor cells, paucity of giant cells, and a diffuse growth pattern. At least five of these criteria are required for the histopathologic diagnosis of malignant TGCT because the benign TGCT also shares many of these morphological features. We describe the cytomorphologic features of a malignant D-TGCT from an unusual case of pulmonary metastasis in an adult patient. Fine needle aspiration cytologic features of malignant D-TGCT have not been described earlier in the English literature.


Using evaluation to adapt health information outreach to the complex environments of community-based organizations.
After arguing that most community-based organizations (CBOs) function as complex adaptive systems, this white paper describes the evaluation goals, questions, indicators, and methods most important at different stages of community-based health information outreach. This paper presents the basic characteristics of complex adaptive systems and argues that the typical CBO can be considered this type of system. It then presents evaluation as a tool for helping outreach teams adapt their outreach efforts to the CBO environment and thus maximize success. Finally, it describes the goals, questions, indicators, and methods most important or helpful at each stage of evaluation (community assessment, needs assessment and planning, process evaluation, and outcomes assessment). Literature from complex adaptive systems as applied to health care, business, and evaluation settings is presented. Evaluation models and applications, particularly those based on participatory approaches, are presented as methods for maximizing the effectiveness of evaluation in dynamic CBO environments. If one accepts that CBOs function as complex adaptive systems-characterized by dynamic relationships among many agents, influences, and forces-then effective evaluation at the stages of community assessment, needs assessment and planning, process evaluation, and outcomes assessment is critical to outreach success.


Component separation of the index finger to reconstruct the thumb: case report with review of literature.
Treatment options for severely damaged finger joints include amputation, arthroplasty, arthrodesis, and reconstruction using nonvascularized or vascularized joint transfers. The thumb contributes significantly to global hand function, and functioning metacarpophalangeal and interphalangeal joints are crucial. When 2 adjacent joints are damaged by trauma, vascularized joint transfer from an injured index finger to the thumb is an option to maximize remaining thumb function. Complex composite injuries involving joints, soft tissues, and tendons require customized reconstructive solutions to retain and optimize hand function. We present a case of component separation of an injured index finger as the donor area for 2 flaps to reconstruct a complex bone, joint, and soft tissue thumb defect, which resulted in a high level of patient satisfaction and a return to heavy manual work.


Development of a Facebook Addiction Scale.
The Bergen Facebook Addiction Scale (BFAS), initially a pool of 18 items, three reflecting each of the six core elements of addiction (salience, mood modification, tolerance, withdrawal, conflict, and relapse), was constructed and administered to 423 students together with several other standardized self-report scales (Addictive Tendencies Scale, Online Sociability Scale, Facebook Attitude Scale, NEO-FFI, BIS/BAS scales, and Sleep questions). That item within each of the six addiction elements with the highest corrected item-total correlation was retained in the final scale. The factor structure of the scale was good (RMSEA = .046, CFI = .99) and coefficient alpha was .83. The 3-week test-retest reliability coefficient was .82. The scores converged with scores for other scales of Facebook activity. Also, they were positively related to Neuroticism and Extraversion, and negatively related to Conscientiousness. High scores on the new scale were associated with delayed bedtimes and rising times.


Preparing children and families psychologically for day surgery: an evaluation.
The increasing use of ambulatory care settings for children's surgery places more responsibility on parents for psychological preparation of children for surgery and for their post-operative care. This paper describes the evaluation of a pre-admission programme to prepare children between the ages of 3 and 15 years and their families psychologically for day surgery. Seventy-five families comprised the study sample, 23 in the programme group and 53 in the non-intervention group. The programme focused on familiarizing families with the physical and procedural components of day surgery through a videotape of a family in a naturally occurring day surgery situation, a tour, and hospital play. Fewer children and parents in the programme group reported high anxiety levels awaiting surgery. Children and parents with previous surgical experience reported higher levels of pre-surgical anxiety than inexperienced families. Families reported the physicians and day surgery nurse as their primary sources of information and rated the day surgery nurse highest in their satisfaction with information received. Implications for practice, particularly for meeting the needs of young children and out-of-town families, are discussed.


Bictegravir/emtricitabine/tenofovir alafenamide plus doravirine in highly treatment-experienced men with multidrug-resistant HIV.
To evaluate the safety and efficacy of switching highly treatment-experienced people with HIV (HTE PWH) from rilpivirine/emtricitabine/tenofovir alafenamide (RPV/FTC/TAF) plus dolutegravir (DTG) to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus doravirine (DOR). A pharmacokinetic (PK) analysis was conducted to assess the potential interaction between BIC and DOR. This open-label switch trial enrolled HTE PWH from a primary care private practice in the United States. Eligible participants were male, aged ≥45 years, with documented viral resistance to protease inhibitors, nucleoside reverse transcriptase inhibitors, and/or nonnucleoside reverse transcriptase inhibitors but no resistance to RPV or DOR, and no K65R or T69 insertion mutations. Virologic suppression (≤50 copies/ml) while on RPV/FTC/TAF plus DTG for ≥6 months was required prior to enrollment. The primary endpoint of the study was virologic suppression (<50 and <200 copies/ml) at 48 weeks. Secondary endpoints included safety, tolerability, changes in body mass index (BMI), and identification of PK parameters of BIC and DOR. Twenty males [median age: 65 years (range, 46-74), median time since HIV diagnosis: 37 years (range, 12-42)] completed the study. BIC/FTC/TAF plus DOR was well tolerated with no serious or treatment-related adverse events reported and no appreciable changes in BMI from baseline to Week 48. At Week 48, 100% of participants had <50 viral copies/ml. PK parameters for BIC and DOR ( n = 10) were consistent with published data. Switching from RPV/FTC/TAF plus DTG to BIC/FTC/TAF plus DOR was well tolerated and efficacious in HTE men aged ≥45 years with HIV.


The influence of single monkey cortico-motoneuronal cells at different levels of activity in target muscles.
1. This study assessed the facilitation by cortico-motoneuronal (CM) cells of hand and forearm muscles at different levels of EMG activity. 2. Twenty-three CM cells were recorded in six hemispheres of four trained monkeys. CM cells were identified by the presence of post-spike facilitation (PSF) in spike-triggered averages (STAs) of their target muscles. Cell and muscle activity was recorded during performance of a low force (0.2-1.5 N) precision grip task between the index finger and thumb. The hold periods of this task lasted 1-1.5 s and provided segments of steady EMG activity. 3. The discharge activity of each CM cell, and the amplitude of the PSF produced in one or two target muscles, were compared across two to six different levels of EMG activity during the hold periods. 4. Of the forty-two CM cell-muscle combinations tested, twenty (48%) showed a significant increase in CM cell discharge rate with increased target muscle EMG activity (P < 0.001); three (7%) showed significant negative correlation; and no correlation was found for nineteen combinations (45%). 5. From a low to a high level of EMG activity (0.3-8.65% of the maximum EMG activity recorded), the absolute amount of facilitation produced by each CM cell increased by a factor of 1.2-32 (median value 3.7). This increase in facilitation occurred irrespective of the presence or absence of correlation between CM cell discharge rate and target muscle activity. 6. For thirty cell-muscle combinations in which a significant PSF could be measured at more than one level of EMG activity, the relative degree of facilitation remained constant in nine, increased in thirteen and decreased in seven combinations. In some cases saturation effects were evident. For ten combinations PSF was observed at high but not at low levels of EMG activity. 7. The changes in PSF amplitude with level of EMG activity were also present in STAs compiled from only those spikes with long interspike intervals (20-25 ms or greater). The results suggested that spikes with short interspike intervals did not make a significant contribution to the increase in PSF amplitude observed at the higher levels of EMG activity. 8. The changes in PSF amplitude with target muscle activity are probably explained best by changes at the spinal motoneuronal level, which set the response to the CM input. These changes may also reflect differences in the strength of synaptic connectivity made by a CM cell within the motoneurone pool of the target muscle.


Research uncovers 'unacceptable risks'.
Dr Melvyn Langford C.Eng, MIMechE, MCIBSE, who worked in the NHS for nearly 40 years, including as an estates and facilities manager at several NHS Trusts, has written several previous HEJ articles on 'systematic failures' in the way maintenance of NHS healthcare buildings has been managed, and on what he claims is a 'fundamental flaw' within the national guidance for backlog maintenance (see HEJ - November 2009, September 2010, and September 2011). Here he outlines the conclusions of a recent three-year research project, which he says strongly suggest that that the service's continuing use of fixed yearly budgets, and a lack of sufficient monitoring, may be resulting in what he dubs 'a catalogue of systematic failures within most organisations that are generating risk profiles that expose patients, visitors, and staff, to unacceptable levels of risk'.


High response reliability of neurons in primary visual cortex (V1) of alert, trained monkeys.
The reliability of neuronal responses determines the resources needed to represent the external world and constrains the nature of the neural code. Studies of anesthetized animals have indicated that neuronal responses become progressively more variable as information travels from the retina to the cortex. These results have been interpreted to indicate that perception must be based on pooling across relatively large numbers of cells. However, we find that in alert monkeys, responses in primary visual cortex (V1) are as reliable as the inputs from the retina and the thalamus. Moreover, when the effects of fixational eye movements were minimized, response variability (variance/mean - Fano factor, FF) in all V1 layers was low. When presenting optimal stimuli, the median FF was 0.3. High variability, FF approximately 1, was found only near threshold. Our results suggest that in natural vision, suprathreshold perception can be based on small numbers of optimally stimulated cells.


Microstructure Evolution and Deformation Behavior of Extruded Mg-5Al-0.6Sc Alloy during Room and Elevated Temperature Tension Revealed by Ex-Situ EBSD and VPSC.
In this study, the microstructure evolution and deformation behavior of the extruded Mg-5Al-0.6Sc (AS51) alloy during tensile testing at room temperature (RT) and 250 °C were investigated by electron backscattered diffraction (EBSD) characterization and Visco Plastic Self Consistent (VPSC) simulation. The results showed that a continuous hardening behavior of the alloy occurred during the deformation at RT, and a certain softening was caused by the occurrence of dynamic recovery (DRV) and dynamic recrystallization (DRX) in the late stage of deformation at 250 °C. The primary deformation mechanism at both RT and 250 °C was dislocation slip, with prismatic <a> slip being the dominant deformation mode, and no significant changes in grain size or texture type occurred. By identifying the activated twin variants, the results indicated that the selection of twin variants was closely related to the local stress concentration. The relatively low activation frequency of extension twinning at 250 °C is partly attributed to the fact that the consumption of dislocations by DRV and DRX can effectively relax the local stress concentration. Meanwhile, the DRX mechanism during the deformation of the alloy at 250 °C was mainly discontinuous dynamic recrystallization (DDRX), with a low recrystallization fraction.


Epidemiology and bacterial colonization of burn injuries in Blantyre.
Forty-nine patients from the Burns Unit at the QECH had swabs taken from various sites in order to determine the bacterial profile and antibiotic susceptibilities in burn wounds colonized by bacteria. The mean age was 16 years (range 1-70 years); 27 (55 %) of the study population were female and 22 (45%) were male. Twenty-four (49%) patients were epileptic. Open fire (41%) was the most common cause of burn injuries among epileptics while hot water burns (29%) were commonest among non-epileptics. Burn injury and percentage total burn surface area (% TBSA) injuries decreased with age, and the upper and lower limbs, trunk, head and neck were the most commonly affected sites. Staphylococcus aureus was the commonest isolate (23%), followed by Proteus mirabilis (22.7%), Streptococci spp (15.9%), Pseudomonas aeruginosa (4.5%) and 3.4% for Escherichia coli, Salmonella and Klebsiella spp. There was a significant trend of bacterial growth with increasing % TBSA (p<0.001). Bacterial growth was significantly more common in more recent burns of less than 20 days compared to burns of longer duration (OR 4.1 [95% CI 1.58-10.99]). Broad-spectrum antibiotics are required as first-line therapy for burns-related sepsis but there is need for surveillance of antibiotic susceptibility to help determine appropriate therapy.


Derivation and dispersal of Acacia (Leguminosae), with particular reference to Australia, and the recognition of Senegalia and Racosperma.
The morphology of seedlings, leaves, flowers and inflorescences, anatomy of the pod, the occurrence of extra-floral nectaries, free amino acids of the seeds, flavonoid compounds in heartwoods, cyanogenic compounds and porate, colporate and extraporate pollen, and susceptibility to rusts, all indicate that three genera, Acacia Miller, Senegalia Raf. and Racosperma Martius, should be recognized. These correspond to currently accepted subgenera of Acacia. The size of these more narrowly circumscribed genera is in keeping with the size of genera of other tribes of low diversity in Leguminosae. Acacia and Senegalia arose independently from the Ingeae, with Racosperma being derived from Senegalia. Section Filicinae is more advanced than section Senegalia of Senegalia, and sections Racosperma and Pukhella, both with at least some species with bipinnate foliage, are the most advanced of Racosperma, while the other sections Pleurinervia and Lycopodiifolia have only phyllodinous species. Long-range dispersal of Racosperma from the Australian region has occurred, but the broad pattern of distribution is interpreted in terms of plate tectonics. Racosperma was present in Australia in the late Cretaceous but did not become widespread until the general drying of the continent in the Miocene. The flora of SW Australia has been isolated from the rest of the continent by climatic barriers since the late Tertiary and has a high proportion of endemic species. Barriers to plant migration in the east have operated only intermittently and there is no area comparable in endemism to the southwest.


Enantioselective Formal [3 + 1 + 1] Cycloaddition Reaction by Ru(II)/Iminium Cocatalysis for Construction of Multisubstituted Pyrrolidines.
A Ru(II)/iminium cocatalyzed asymmetric formal [3 + 1 + 1] cycloaddition reaction of diazoacetophenones, anilines, and enals is disclosed to construct multisubstituted pyrrolidines in one step with excellent diastereoselectivity and enantioselectivity. The reaction mechanism was postulated as a successful trapping of Ru(II)-associated ammonium ylides via a selective 1,4-addition to chiral amine activated enals followed by a tandem aza-aldol process. The control experiments and theoretical density functional theory investigation revealed that the reversible NaOAc-facilitated aza-aldol process led to the diastereomeric conversion to provide a stable product.


[Treatment of duodenal ulcer with herbazol].
A total of 61 patients were treated - 30 with Herbazol , 16 with placebo and 15 with Biomet . Pain and dyspeptic complaints disappeared in a high percentage of the patients after 25-day treatment with the phytopreparation Herbazol , with no statistical significance of the differences with placebo and Biomet . The preparation Herbazol has the tendency to reduce the basal salt-acid production of the stomach and reduces the stimulated one with a statistical significance. Cicatrization of the ulcer nich é was obtained in 56.67 per cent, after the 25-day treatment with Herbazol , the results being higher, with statistical significance, that those obtained with placebo, and as compared with Biomet - there was no statistical significance of the difference. No adverse and toxic effects were observed during the treatment.


Forms and functions of p53.
There is evidence that wild-type p53 can both promote and suppress cell proliferation and these opposing functions correlate with alternative conformations of the p53 protein. In the light of more recent evidence I now propose that wild-type p53 can adopt at least three different forms, each of which correlates with a defined function in cell growth control. The three forms are most simply defined by reactivity with two monoclonal antibodies, PAb421 and PAb1620. One form (421 degrees/1620+) suppresses cell growth and maintains quiescence, and a second form (421+/1620 degrees) activates and promotes cell proliferation. The third form (421+/1620+) acts as a differential sensor for incoming positive and negative growth regulatory signals and can be converted either to the suppressor or to the promoter form for cell growth. Regulation of p53 tertiary structure involves redox modulation and phosphorylation, and offers a novel rationale for anti-cancer therapy.


Spinal ultrasound in infants.
This paper discusses the indications for spinal ultrasound, including its advantages and disadvantages compared with spinal MRI. The features and ultrasound findings both in normal infants and in those with spinal dysraphism are reviewed.


Factors influencing prehospital delay in patients experiencing chest pain.
Patients experiencing chest pain (or other cardiac symptoms) in the community delay hours, even days, in seeking medical care. Given the potential effectiveness of thrombolytic therapy, it is important to determine patterns of patient delay. A descriptive study was conducted to determine the amount of time patients delayed in seeking medical care when experiencing chest pain and the characteristics of patients delaying longer than 3 hours. Adult patients (N = 77) admitted to an emergency department with chest pain participated. Data were obtained using the Response to Symptoms Questionnaire and chart review. The mean prehospital delay times (ie, symptom onset to hospital arrival) was 25.4 hours (+/- 46.5), and the median was 5 hours. Delay groups were divided into those arriving less than 3 hours (n = 31 or 40%) and those arriving more than 3 hours (n = 46 or 60%) after symptom onset. Three hours was chosen based on a mean time, taken from the literature, of 84 minutes spent in the emergency department so that patients in the first group would be able to receive thrombolysis within 4 hours. Univariate statistical analyses revealed that advanced age, symptom onset with a family member present, and self-determination of symptoms as not being serious in nature all contributed to a delay of longer than 3 hours. Critical care nurses and physicians should focus on patients at high risk for prolonged delay and educate the public about action to take if a family member experiences cardiac symptoms.


Fabrication of GaN doped ZnO nanocrystallines by laser ablation.
Here, we present the fabrication of pure and GaN doped ZnO nanocrystallines on Si(111) substrates by KrF excimer laser. The targets for the ablation have been prepared by conventional ceramic method. The fabricated nanocrystallines have been investigated by X-ray diffraction, photoluminescence and atomic force microscopy. The X-ray diffraction analysis shows that the crystalline size of pure ZnO is 36 nm and it is 41 nm while doped with 0.8 mol% of GaN due to best stoichiometry between Zn and O. Photoluminescence studies reveal that intense deep level emissions have been observed for pure ZnO and it has been suppressed for the GaN doped ZnO structures. The images of atomic force microscope show that the rms surface roughness is 27 nm for pure ZnO and the morphology is improved with decrease in rms roughness, 18 nm with fine crystallines while doped with 1 mol% GaN. The improved structural, optical and morphological properties of ZnO nanocrystalline due to GaN dopant have been discussed in detail.


[Secondary Dementia Due to Leptomeningeal Metastasis of Breast Cancer Improved by Whole Brain Radiation].
A 62-year-old woman received chemotherapy for breast cancer with bone metastasis and malignant pleural and pericardial effusion. She was examined by imaging for progressive cognitive impairment and headache. Enhanced MRI findings showed multiple solid tumors on brain surface, and brain perfusion scintigraphy showed blood flow decrease in both parietal lobes. She was diagnosed with secondary dementia due to leptomeningeal metastases of breast cancer, and whole brain external irradiation was performed(30 Gy/15 Fr). After treatment, multiple tumors were decreased in size and her cognitive impair- ment was improved.


Indomethacin blocks enhanced paracellular backflux in proximal tubules.
Renal interstitial hydrostatic pressure (RIHP) is a link between increased arterial BP and natriuresis. The mechanism whereby increases in RIHP inhibits sodium and water transport across the mammalian proximal tubule epithelium may involve changes in flux across the tight junction of the proximal tubule. The purpose of this study was to determine the effects of increases in RIHP and inhibition of cyclooxygenase on paracellular backflux of an extracellular marker from the renal interstitium into the proximal tubule of the rat. During in vivo microperfusion of proximal tubules, the extracellular tracer of paracellular flux, lanthanum (La), was infused directly into the renal interstitium via a chronically implanted matrix. The net paracellular interstitium-to-lumen lanthanum backflux was measured before and after direct renal interstitial volume expansion (DRIVE) in the absence and presence of indomethacin. DRIVE significantly increased RIHP by 37% (Delta1.8 +/- 0.2 mmHg) and interstitium-to-lumen La backflux by 32% (Delta40.2 +/- 16.6 pg/min per mm), and it significantly decreased proximal reabsorption by 27% (Delta-7.7 +/- 3.8 nl/min; n = 6). In indomethacin-treated rats (n = 6), DRIVE again significantly increased RIHP by 40% (Delta1.9 +/- 0.2 mmHg), but it did not increase La backflux (Delta-39.0 +/- 24.4 pg/min per mm) or significantly decrease proximal reabsorption (Delta1.2 +/- 2.3 nl/min). These results demonstrate that increased RIHP increases paracellular backflux of lanthanum from the renal interstitium to the proximal tubule lumen in association with decreases in proximal reabsorption. Furthermore, indomethacin blocks the effects of increased RIHP on proximal reabsorption and paracellular backflux of lanthanum through the intercellular tight junctions of the proximal tubule epithelium.


Automating the extraction of information from a historical text and building a linked data model for the domain of ecology and conservation science.
Data heterogeneity is a pressing issue and is further compounded if we have to deal with data from textual documents. The unstructured nature of such documents implies that collating, comparing and analysing the information contained therein can be a challenging task. Automating these processes can help to unleash insightful knowledge that otherwise remains buried in them. Moreover, integrating the extracted information from the documents with other related information can help to make more information-rich queries. In this context, the paper presents a comprehensive review of text extraction and data integration techniques to enable this automation process in an ecological context. The paper investigates into extracting valuable floristic information from a historical Botany journal. The purpose behind this extraction is to bring to light relevant pieces of information contained within the document. In addition, the paper also explores the need to integrate the extracted information together with other related information from disparate sources. All the information is then rendered into a query-able form in order to make unified queries. Hence, the paper makes use of a combination of Machine Learning, Natural Language Processing and Semantic Web techniques to achieve this. The proposed approach is demonstrated through the information extracted from the journal and the information-rich queries made through the integration process. The paper shows that the approach has a merit in extracting relevant information from the journal, discusses how the machine learning models have been designed to classify complex information and also gives a measure of their performance. The paper also shows that the approach has a merit in query time in regard to querying floristic information from a multi-source linked data model.


Value of routine angiography before traumatic lower-limb reconstruction with microvascular free tissue transplantation.
From November 1993 to June 1997, long-bone defects in 40 trauma patients were reconstructed with free osteoseptocutaneous fibula flaps. To determine the necessity of routine angiography in traumatized lower limbs before free flap transplantation, a prospective study was carried out. The study subjects were 34 patients, 25 males and 9 females, with an average age of 40.6 years. Reconstruction was performed primarily for bone defects after Gustillo type III b open fractures in 17 patients and secondarily for malunion and osteomyelitis in 17 patients. Reconstructed bone defects included 25 tibias and 9 femurs. Normal pedal pulses were palpable in 31 patients. Angiographic findings were abnormal in seven patients. In the three patients with abnormal pedal pulses, the particular nonpalpable pulses correlated with the vascular lesions shown in the angiograms (one in the tibial anterior artery and two in the tibial posterior artery). Four patients with either injury of the peroneal artery (three cases) or pseudoaneurysm of the tibial anterior artery (one case) had normal pedal pulses. In all patients, microvascular transplantations were performed successfully. Our study demonstrates the importance of thorough clinical evaluation. Preoperative angiography of the injured lower limbs did not provide relevant additional informations in this series. Familiarity with all available techniques makes it possible to cope with almost any difficult posttraumatic vascular condition. Routine recipient-site angiography before microsurgical reconstruction, therefore, seems unjustified.


Effects of a new antiallergic drug, VUF-K-8788, on infiltration of lung parenchyma by eosinophils in guinea pigs and eosinophil-adhesion to human umbilical vein endothelial cells (HUVEC).
Airway inflammation and reversible airway obstruction are hallmarks of bronchial asthma. In this study, we investigated the effects of a new antiallergic drug, 7-[3-[4-(2-quinolinylmethyl)-1-piperazinyl]-propoxy]-2,3-dihydro-4H-1,4-benzothiazin-3-one (VUF-K-8788), on histopathological changes in lung parenchyma of guinea pigs during late-phase asthmatic reaction (LAR), and on eosinophil-adhesion to human umbilical vein endothelial cells (HUVEC). Repeated exposure to ovalbumin of sensitized guinea pigs induced inflammatory phenomena such as hyperplasia of airway epithelial cells, perivascular edema and infiltration of lung parenchyma by eosinophils. VUF-K-8788 inhibited these histopathological phenomena at 10 mg/kg p.o. Moreover, the eosinophil-adherence to HUVEC was inhibited by VUF-K-8788 at the concentration of 10-30 microM. In conclusion, this inhibitory effect of VUF-K-8788 on eosinophil-adherence might contribute to the prevention of LAR and infiltration by eosinophils in the experimental asthmatic model in guinea pigs.


Integration of a medication management model into outcome-based quality improvement: a pilot program in a rural propriety home healthcare agency.
This article describes a rural proprietary home health agency's successful initiative to adapt a previously tested medication management model and integrate it into existing processes of care. The rationale to improve medication management in response to current national fiscal, clinical and external quality measures and evolution of this process in the agency is detailed. The agency refined the model's screening procedures, incorporating them into the mandated OASIS assessment and then computerizing the medication risk analysis, in keeping with the original intent of the model. In a four-month pilot test of the computerized risk assessment procedure 1006 OASIS assessments were screened; risk factors for medication-related problems in 201 (19.9%) resulted in pharmacist review. Of these, 30 (17%) were ruled out as potential medication errors, 143 (82.6%) were found with potential MRP and 58 (33.5%) had evidence of problems warranting follow-up. With this computer-assisted process, the agency created a more comprehensive assessment that was in line with the new regulatory emphasis on patient outcomes. Consultant pharmacist services also transitioned from drug regimen review to more comprehensive medication therapy management. By enhancing efficiencies in its medication management program, an agency not only stands to improve quality of care, but also to maximize resources, making the intervention affordable to implement and decreasing burden on staff.


Black soldier fly and yellow mealworm live larvae for broiler chickens: Effects on bird performance and health status.
The commercial broiler chicken strains are the result of successful selection programmes. Most of the problems related to welfare arise from the high growth rate and body weight. The use of environmental enrichments in intensive farming could have a positive effect on birds by increasing animal welfare. The aim of the study was to evaluate the effects of Hermetia illucens (HI) and Tenebrio molitor (TM) live larvae in the diets of broiler chickens on growth performance, carcass yield and health status. A total of 180 four-day-old male broiler chickens (Ross 308) were randomly allotted to 18 pens. Each pen was assigned to one of the three dietary treatments (6 replicates/treatment, 10 birds/replicate) as follows: (i) control diet (C): commercial feed (two feeding phases: starter [4-11 days] and grower [12-38 days]), (ii) HI: C + 5% of the expected daily feed intake (DFI) HI live larvae (calculated on dry matter [DM]) and (iii) TM: C + 5% of DFI TM live larvae (DM). At 39 days of age, birds were slaughtered. Growth performance parameters were overall not affected by dietary treatments, except for the grower phase feed conversion ratio (FCR) and the overall FCR being better in the TM broilers than the others (p < 0.01). No differences were observed for slaughtering performance and haematological and serum parameters, except for the spleen relative weight being higher (p < 0.01) in the birds administered with larvae when compared to the C group. Gut morphometric indexes and histopathological alterations were not influenced by insect larvae administration. In conclusion, the administration in limited quantities of HI and TM live larvae as environmental enrichment has no negative effects on broiler chicken growth performance and health status. A behavioural study could confirm that live insect larvae represent a novel natural environmental enrichment in broiler farming.


Hippocampal atrophy and altered brain responses to pleasant tastes among obese compared with healthy weight children.
The hippocampus is a key structure implicated in food motivation and intake. Research has shown that the hippocampus is vulnerable to the consumption of a western diet (i.e., high saturated fat and simple carbohydrates). Studies of patients with obesity (OB), compared with healthy weight (HW), show changes in hippocampal volume and response to food cues. Moreover, evidence suggests that OB children, relative to HW, have greater hippocampal response to taste. However, no study has examined the association of hippocampal volume with taste functioning in children. We hypothesized that OB children, relative to HW, would show a significant reduction in hippocampal volume and that decreased volume would be significantly associated with greater activation to taste. Finally, we explored whether hippocampal activation would be associated with measures on eating and eating habits. Twenty-five 8-12-year-old children (i.e., 13 HW, 12 OB) completed a magnetic resonance imaging scan while participating in a taste paradigm (i.e., 1 ml of 10% sucrose or ionic water delivered pseudorandomly every 20 s). Children with OB, relative to HW, showed reduced left hippocampal volume (t=1.994, P=0.03, 95% confidence interval (CI)=-40.23, 755.42), and greater response to taste in three clusters within the left hippocampus (z=3.3, P=0.001, 95% CI=-0.241, -0.041; z=3.3, P=0.001, 95% CI=-0.2711, -0.0469; z=2.7, P=0.007, 95% CI=-0.6032, -0.0268). Activation within the hippocampus was associated with eating in the absence of hunger (EAH%; t=2.408, P=0.025, 95% CI= 1.751708, 23.94109) and two subscales on a measure of eating behaviors (Food responsiveness, t=2.572, P=0.017, 95% CI= 0.9565195, 9.043440; Food enjoyment, t=2.298, P=0.032, 95% CI=0.2256749, 4.531298). As hypothesized, OB children, relative to HW, had significantly reduced hippocampal volume, and greater hippocampal activation to taste. Moreover, hippocampal activation was associated with measures of eating. These results contribute to research on the relationship between OB, overeating and cognitive impairment.


Magnetic resonance radiographic features which might lead to misdiagnosis of muscle-invasive bladder cancer based on vesical imaging reporting and data system: the application experience of a single center.
The Vesical Imaging Reporting and Data System (VI-RADS) has been widely used for diagnosing muscle-invasive bladder cancer (MIBC), yet instances of misdiagnosis persist. However, limited research discusses the factors affecting its accuracy. This study aimed to evaluate the diagnostic efficacy of the VI-RADS in our center and to preliminarily identify possible magnetic resonance imaging (MRI) characteristics of misdiagnosis. From January 2018 to February 2023, a consecutive series of 211 participants pathologically diagnosed with bladder cancer (BC) who underwent an MRI exam were retrospectively enrolled. MRI was interpreted by 2 radiologists with different levels of experience, the diagnostic performance was validated using the receiver operating characteristic (ROC) curve, and VI-RADS ≥4 was considered to indicate MIBC-positive status. The clinical and radiographic characteristics of the true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) groups were analyzed using Kruskal-Wallis test or Fisher exact test. With VI-RADS ≥4 as the cutoff value, the area under the ROC curves (AUCs) were 0.951 (0.912-0.976) and 0.847 (0.791-0.893) for the more-experienced reader and less-experienced reader, respectively, with good interobserver agreement (κ=0.74105). The median tumor size in the TP (more experienced: 57 cases; less experienced: 44 cases) and FP (more experienced: 8 cases; less experienced: 9 cases) groups was larger than that in the TN (more experienced: 141 cases; less experienced: 139 cases) group for the more-experienced reader (TP: 28 mm; FP: 31 mm; TN: 19 mm; P<0.001 and P=0.031, respectively) and the less-experienced reader (TP: 31 mm; FP: 28 mm; TN: 19 mm; P<0.001 and P=0.042, respectively). The tumor base in the TP and FP groups was larger than that in the TN group for the more-experienced reader (TP: 37 mm; FP: 48 mm; TN: 15 mm; both P<0.001) and for the less-experienced reader (FP: 42 mm; FP: 36 mm; TN: 15 mm; P<0.001 and P=0.022, respectively). The median tumor base in the TP group was larger than that in the FN group for the less-experienced reader (TP: 42 mm; FN: 17 mm; P=0.004). We observed good to excellent AUCs with good interobserver agreement among radiologists with different levels of expertise using VI-RADS. Large tumor size and wide tumor base affected the accuracy of VI-RADS in MIBC diagnosis.


Control of OXPHOS efficiency by complex I in brain mitochondria.
In the present work we have analysed the efficiency (P/O ratio) of energy production by oxidative phosphorylation (OXPHOS) in rat brain, liver and heart mitochondria. This study has revealed tissue-specific differences in the mean values of P/O ratios and ATP production rates. A marked dependence of the P/O ratio on the respiration rates has been observed with complex I (NADH:ubiquinone oxidoreductase), but not with complex II (succinate dehydrogenase) respiratory substrates. The physiological impact of the P/O variations with complex I substrates has been further confirmed by extending the analysis to brain mitochondria from three independent groups of animals utilized to study the effects of dietary treatments on the age-related changes of OXPHOS. The general site-specificity of the rate-dependent P/O variability indicates that the decoupling, i.e. decreased coupling between electron transfer and proton pumping, is likely to be mostly due to slip of mitochondrial complex I. These findings suggest an additional mechanism for the pivotal role played by the energy-conserving respiratory complex I in the physiological and adaptive plasticity of mitochondrial OXPHOS.


[Qualitative and quantitative analysis of fluoxetine hydrochloride by 19F NMR].
The chemical shift of fluoxetine hydrochloride appears at delta 14.15 in 19F NMR analysis. The delta moved upfield slightly from 14.158 to 14.145 when the concentration of solution became diluted from 2.00 to 0.05 mmol x L(-1). Spiking test was suggested to confirm the existence of the compound for qualitative analysis. 19F NMR detection sensitivity test illustrated that a concentration of 17 mg in 1 L water could be detected while the sample was scanned 500 times with optimum parameters. In quantitative analysis, standard curve of concentration versus fluorine signal intensity was proposed to determine the amount of fluoxetine. Long capillary tube containing trifluoroacetic acid was used as internal standard for the integration measurements and straight line was obtained with good fitting. Direct additions of trifluoroethanol to fluoxetine solutions gave a poorer standard curve.


Signatures of selection and gene conversion associated with human color vision variation.
Trichromatic color vision in humans results from the combination of red, green, and blue photopigment opsins. Although color vision genes have been the targets of active molecular and psychophysical research on color vision abnormalities, little is known about patterns of normal genetic variation in these genes among global human populations. The current study presents nucleotide sequence analyses and tests of neutrality for a 5.5-kb region of the X-linked long-wave "red" opsin gene (OPN1LW) in 236 individuals from ethnically diverse human populations. Our analysis of the recombination landscape across OPN1LW reveals an unusual haplotype structure associated with amino acid replacement variation in exon 3 that is consistent with gene conversion. Compared with the absence of OPN1LW amino acid replacement fixation since divergence from chimpanzee, the human population exhibits a significant excess of high-frequency OPN1LW replacements. Our results suggest that subtle changes in L-cone opsin wavelength absorption may have been adaptive during human evolution.


Characterization of piperine metabolites in rats by ultra-high-performance liquid chromatography with electrospray ionization quadruple time-of-flight tandem mass spectrometry.
Piperine is a major constituent of Piper nigrum L. and is a naturally bioactive alkaloid. Structural changes in piperine have been shown to result in different biological effects. The present study aims to investigate piperine metabolites in rat plasma, bile, urine, and feces after oral administration. The metabolic pathway of piperine in vivo was investigated using ultra-high-performance liquid chromatography (UHLPC) combined with electrospray ionization quadruple time-of-flight tandem mass spectrometry (QTOF-MS). Piperine metabolites were found and identified by fragmentation patterns and accurate mass measurements. The 12 metabolites detected and identified were divided into three groups: methylenedioxycyclic ring-opening metabolites (M01-M08), methylenedioxycyclic ring-oxidizing metabolites (M09-M11), and piperidine ring-cleavage metabolites (M12). Seven piperine metabolites, including M02, M03, M04, M05, M09, M10 and M11, were reported for the first time in the literature. Results showed that the principal metabolism pathways of piperine in rat were reduction and demethylation after ring-opening, and that UHPLC/QTOF-MS can serve as an important analytical platform to gather the piperine metabolism profile. Copyright © 2017 John Wiley & Sons, Ltd.


Liquid crystalline and antinematic behavior of shape-persistent macrocycles from molecular-dynamics simulations.
In this work we present a molecular-dynamics study of a coarse-grained (CG) model for a system of planar shape-persistent macrocycles (SPMs). SPMs are synthetic organic rigid macromolecules typically comprised of meta- and para-aromatics groups connected by acetylene and/or diacetylene units. In the CG model, each SPM is represented as a rigid hexagonal arrangement of 24 soft-repulsive spheres, resembling a large ring or hoop. The supramolecular arrangement of these macrocycles at high pressures is studied using N-P-T molecular-dynamics simulation both by expansion of an initial hexagonal lattice structure and also by compression of an isotropic phase. In both cases, systems under consideration exhibit an isotropic-smectic-A phase transition, which is detected by monitoring relevant order parameters and analyzing snapshots of equilibrium configurations. The smectic-A phase is unique; although the molecules form layers, the system presents antinematic order where the orientation of the molecular axes is perpendicular to the direction of the layers themselves. Due to their planar geometry, the SPM molecules would be expected to form columnar or nematic phases. On the contrary, these phases seem suppressed by a novel smectic-A phase, formed by the mutual interpenetration of the cycles. These results are a unique example of how molecular nonconvexity can, by itself, induce mesomorphism in anisotropic systems.


Soluble CD8 during T cell activation.
The CD8 Ag has long been used as a surface marker for the identification of cytotoxic and suppressor cells. Recently CD8-positive cells have been shown to release a soluble form of the CD8 Ag. We have devised a sandwich monoclonal enzyme immunoassay for the quantitation of this released CD8. Soluble CD8 was released in response to lymphocyte activation. In vitro, PHA or anti-CD3 mAb-mediated T cell activation led to release of CD8 into the culture supernatant. In vivo, serum from patients with EBV-induced infectious mononucleosis (IM), a disease associated with intense CD8+ T cell activation, demonstrated elevations in soluble CD8 (7939 U/ml, day 0) compared to serum from normal controls (289 U/ml). Levels of soluble CD8 correlated (r = 0.82, p less than 0.001) with the increased percentage of CD8+/HLA-DR+ (activated CD8+ T cells) observed in acute IM. Sequential analysis of serum during the course of IM shows that soluble CD8 levels parallel the decline in CD8+/HLA-DR+ cells that occurs with the resolution of the disease. These data suggest that released CD8 may be of value in monitoring the involvement of CD8+ T cells in response to a pathologic event. The functional role of the released CD8 molecule will require further investigation.


A community development approach to rural recruitment.
Programs designed to empower rural communities for health care provider recruitment have usually focused on the health care sector without aggressively addressing broader community development issues. The Recruitable Community Project (RCP) in West Virginia includes community education on recruiting and also assessments of and recommendations to rural communities on broad-based community development, aiming to enhance communities' recruiting potential. The project provides multidisciplinary university-based planning assistance programs for small communities, involving collaborative community visits. The project also uses a project manager as a "community encourager" who participates in community education and in the formulation of sustained community recruiting efforts. From August 1999 through August 2001, 7 underserved rural communities completed the RCP organizational processes and hosted planning assistance teams. Members of community recruitment boards gave high marks to the RCP process, its planning assistance teams, and its usefulness in establishing community ties to state and academic agencies. Since working with the RCP, the 7 communities have recruited 27 providers, success possibly stimulated by their RCP involvement (data current as of September 2002). This model of community training and development to empower rural communities to better recruit health professionals shows early promise. This model could be broadened to include more collaboration of community development and health science disciplines programs for recruitment and retention efforts.


"You've got a friend in me": can social networks mediate the relationship between mood and MCI?
Social networks can change with age, for reasons that are adaptive or unwanted. Social engagement is beneficial to both mental health and cognition, and represents a potentially modifiable factor. Consequently this study explored this association and assessed whether the relationship between mild cognitive impairment (MCI) and mood problems was mediated by social networks. This study includes an analysis of data from the Cognitive Function and Ageing Study Wales (CFAS Wales). CFAS Wales Phase 1 data were collected from 2010 to 2013 by conducting structured interviews with older people aged over 65 years of age living in urban and rural areas of Wales, and included questions that assessed cognitive functioning, mood, and social networks. Regression analyses were used to investigate the associations between individual variables and the mediating role of social networks. Having richer social networks was beneficial to both mood and cognition. Participants in the MCI category had weaker social networks than participants without cognitive impairment, whereas stronger social networks were associated with a decrease in the odds of experiencing mood problems, suggesting that they may offer a protective effect against anxiety and depression. Regression analyses revealed that social networks are a significant mediator of the relationship between MCI and mood problems. These findings are important, as mood problems are a risk factor for progression from MCI to dementia, so interventions that increase and strengthen social networks may have beneficial effects on slowing the progression of cognitive decline.


Arrhenius analysis of the relationship between hyperthermia and Hsp70 promoter activation: a comparison between ex vivo and in vivo data.
Tight regulation of gene expression in the region where therapy is necessary and for the duration required to achieve a therapeutic effect and to minimise systemic toxicity is very important for clinical applications of gene therapy. Hyperthermia in combination with a temperature sensitive heat shock protein (Hsp70) promoter presents a unique approach allowing non-invasive spatio-temporal control of transgene expression. In this study we investigated the in vivo and ex vivo relationship between temperature and duration of thermal stress with respect to the resulting gene expression using an Arrhenius analysis. A transgenic mouse expressing the luciferase reporter gene under the transcriptional control of a thermosensitive promoter was used to assure identical genotype for in vivo (mouse leg) and ex vivo (bone marrow mononuclear and embryonic fibroblast cells) studies. The mouse leg and cells were heated at different temperatures and different exposure times. Bioluminescence imaging and in vitro enzymatic assay were used to measure the resulting transgene expression. We showed that temperature-induced Hsp70 promoter activation was modulated by both temperature as well as duration of hyperthermia. The relationship between temperature and duration of hyperthermia and the resulting reporter gene expression can be modelled by an Arrhenius analysis for both in vivo as well as ex vivo. However, the increase in reporter gene expression after elevating the temperature of the thermal stress with 1°C is not comparable for in vivo and ex vivo situations. This information may be valuable for optimising clinical gene therapy protocols.


Gesture and speech during shared book reading with preschoolers with specific language impairment.
This study examined (a) the relationship between gesture and speech produced by children with specific language impairment (SLI) and typically developing (TD) children, and their mothers, during shared book-reading, and (b) the potential effectiveness of gestures accompanying maternal speech on the conversational responsiveness of children. Fifteen preschoolers with expressive SLI were compared with fifteen age-matched and fifteen language-matched TD children. Child and maternal utterances were coded for modality, gesture type, gesture-speech informational relationship, and communicative function. Relative to TD peers, children with SLI used more bimodal utterances and gestures adding unique information to co-occurring speech. Some differences were mirrored in maternal communication. Sequential analysis revealed that only in the SLI group maternal reading accompanied by gestures was significantly followed by child's initiatives, and when maternal non-informative repairs were accompanied by gestures, they were more likely to elicit adequate answers from children. These findings support the 'gesture advantage' hypothesis in children with SLI, and have implications for educational and clinical practice.


Inhibition of cholesterol biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic beta-cells.
Insulin secretion from pancreatic beta-cells is mediated by the opening of voltage-gated Ca2+ channels (CaV) and exocytosis of insulin dense core vesicles facilitated by the secretory soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein machinery. We previously observed that beta-cell exocytosis is sensitive to the acute removal of membrane cholesterol. However, less is known about the chronic changes in endogenous cholesterol and its biosynthesis in regulating beta-cell stimulus-secretion coupling. We examined the effects of inhibiting endogenous beta-cell cholesterol biosynthesis by using the squalene epoxidase inhibitor, NB598. The expression of squalene epoxidase in primary and clonal beta-cells was confirmed by RT-PCR. Cholesterol reduction of 36-52% was observed in MIN6 cells, mouse and human pancreatic islets after a 48-h incubation with 10 mum NB598. A similar reduction in cholesterol was observed in the subcellular compartments of MIN6 cells. We found NB598 significantly inhibited both basal and glucose-stimulated insulin secretion from mouse pancreatic islets. CaV channels were markedly inhibited by NB598. Rapid photolytic release of intracellular caged Ca2+ and simultaneous measurements of the changes in membrane capacitance revealed that NB598 also inhibited exocytosis independently from CaV channels. These effects were reversed by cholesterol repletion. Our results indicate that endogenous cholesterol in pancreatic beta-cells plays a critical role in regulating insulin secretion. Moreover, chronic inhibition of cholesterol biosynthesis regulates the functional activity of CaV channels and insulin secretory granule mobilization and membrane fusion. Dysregulation of cellular cholesterol may cause impairment of beta-cell function, a possible pathogenesis leading to the development of type 2 diabetes.


PET Imaging of Pancreatic Dopamine D2 and D3 Receptor Density with 11C-(+)-PHNO in Type 1 Diabetes.
Type 1 diabetes mellitus (T1DM) has traditionally been characterized by a complete destruction of β-cell mass (BCM); however, there is growing evidence of possible residual BCM present in T1DM. Given the absence of in vivo tools to measure BCM, routine clinical measures of β-cell function (e.g., C-peptide release) may not reflect BCM. We previously demonstrated the potential utility of PET imaging with the dopamine D2 and D3 receptor agonist 3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (11C-(+)-PHNO) to differentiate between healthy control (HC) and T1DM individuals. Methods: Sixteen individuals participated (10 men, 6 women; 9 HCs, 7 T1DMs). The average duration of diabetes was 18 ± 6 y (range, 14-30 y). Individuals underwent PET/CT scanning with a 120-min dynamic PET scan centered on the pancreas. One- and 2-tissue-compartment models were used to estimate pancreas and spleen distribution volume. Reference region approaches (spleen as reference) were also investigated. Quantitative PET measures were correlated with clinical outcome measures. Immunohistochemistry was performed to examine colocalization of dopamine receptors with endocrine hormones in HC and T1DM pancreatic tissue. Results: C-peptide release was not detectable in any T1DM individuals, whereas proinsulin was detectable in 3 of 5 T1DM individuals. Pancreas SUV ratio minus 1 (SUVR-1) (20-30 min; spleen as reference region) demonstrated a statistically significant reduction (-36.2%) in radioligand binding (HCs, 5.6; T1DMs, 3.6; P = 0.03). Age at diagnosis correlated significantly with pancreas SUVR-1 (20-30 min) (R2 = 0.67, P = 0.025). Duration of diabetes did not significantly correlate with pancreas SUVR-1 (20-30 min) (R2 = 0.36, P = 0.16). Mean acute C-peptide response to arginine at maximal glycemic potentiation did not significantly correlate with SUVR-1 (20-30 min) (R2 = 0.57, P = 0.05), nor did mean baseline proinsulin (R2 = 0.45, P = 0.10). Immunohistochemistry demonstrated colocalization of dopamine D3 receptor and dopamine D2 receptor in HCs. No colocalization of the dopamine D3 receptor or dopamine D2 receptor was seen with somatostatin, glucagon, or polypeptide Y. In a separate T1DM individual, no immunostaining was seen with dopamine D3 receptor, dopamine D2 receptor, or insulin antibodies, suggesting that loss of endocrine dopamine D3 receptor and dopamine D2 receptor expression accompanies loss of β-cell functional insulin secretory capacity. Conclusion: Thirty-minute scan durations and SUVR-1 provide quantitative outcome measures for 11C-(+)-PHNO, a dopamine D3 receptor-preferring agonist PET radioligand, to differentiate BCM in T1DM and HCs.