Amphetamine enantiomer excretion profile following administration of Adderall.
Amphetamine remains a widely abused drug throughout the world. It is also used therapeutically for weight loss, narcolepsy, and attention deficit disorder with hyperactivity (ADHD). ADHD has grown dramatically recently both in terms of diagnosis and treatment. Increasingly, older individuals are diagnosed and treated for ADHD, and treatment often continues into adulthood. Of the available treatments for ADHD, Adderall is widely prescribed. Despite its widespread use, there are no published data regarding the expected amphetamine excretion profile following its use. This is problematic because, in this case, medical review officers (MRO) and forensic toxicologists are asked to assess results in terms of use pursuant to valid medical prescription without specific data on which to base a sound decision. To address this situation, a study to determine the concentration and enantiomer composition of amphetamine excretion following administration of Adderall was undertaken. Adderall (20 mg) was administered to five healthy subjects with all subsequent ad lib urine samples (total urine void) collected for seven days. Adderall is a 3:1 mixture of d- and l-enantiomers of amphetamine salts. Peak amphetamine concentrations ranged from 2645 to 5948 ng/mL. Samples containing > or = 500 ng/mL of amphetamine (the administrative cutoff for a positive result by gas chromatography-mass spectrometry) were seen up to 47:30 h post dose. The number of samples that contained amphetamine concentrations of > or = 500 ng/mL ranged among individuals from 7 to 13. As anticipated, analysis showed the d-enantiomer to be in excess of the l-enantiomer, with the proportion of l-enantiomer increasing over time. Because of the mixture of enantiomers, not all samples that contained > or = 500 ng/mL of amphetamine were positive when tested by immunoassay. The drug concentration profiles were quite variable within and between subjects because of dilution and fluctuations in pH of the samples. These results are the first to describe the excretion of amphetamine following administration of Adderall. The presence of the l-enantiomer separates this drug from other preparations of the drug that are composed of only the d-enantiomer (i.e., dexedrine and much illicit amphetamine), thus readily differentiating them from Adderall use. Some illicit and medicinal amphetamine is, however, a mixture of amphetamine enantiomers. Because the enantiomers are metabolized at different rates, their proportion offers the opportunity to describe excretion versus time. Coupling this data with drug concentration makes it possible for forensic toxicologists and MROs to come to an informed decision about the involvement of this drug in a positive drug test result. Using the combination of enantiomer composition and quantitative data will allow MROs and forensic toxicologists to better assess the use of this drug from abuse of amphetamine.


Pharmacology and therapeutic effects of dehydroepiandrosterone in older subjects.
Man and higher primates have adrenals that secrete large amounts of dehydroepiandrosterone (DHEA) [prasterone] and its sulphate (DHEAS) [PB 008]. A remarkable feature of plasma DHEAS levels in humans is their great decrease with aging. Researchers have postulated that this age-related decline of DHEAS levels may explain some of the degenerative changes associated with aging. Moreover, administration of DHEA to laboratory animals has demonstrable beneficial effects such as prevention of diabetes mellitus, obesity, cancer, heart disease and positive immunomodulator effects. However, in rodents DHEA(S) circulating levels are so low that it is impossible to detect any significant age-related decrease. Therefore results from rodent experiments are not relevant to human beings. Three mechanisms of action of DHEA(S) have been identified. DHEA and DHEAS are precursors of testosterone and estradiol, DHEAS is a neurosteroid which modulates neuronal excitability via specific interactions with neurotransmitter receptors and DHEA is an activator of calcium-gated potassium channels. Randomised, placebo-controlled clinical trials which included healthy individuals aged 60 years and over treated with (near) physiological doses of DHEA (50-100 mg/day) have yielded very few positive results. Impact of DHEA replacement treatment was assessed on mood, well being, cognitive and sexual functions, bone mass, body composition, vascular risk factors, immune functions and skin. The major limitations of these trials were their short duration (maximum 1 year) and the low number of study participants involved (maximum 280). Many elderly people in western countries take DHEA without medical supervision. In the US, DHEA is even classified as food supplement. At present there is no scientific evidence to recommend DHEA replacement in the elderly. Further studies are needed to form conclusions about the efficacy and the safety of DHEA replacement in elderly, and to better understand the mechanisms of action of DHEA at the molecular and cellular levels.


Performing label-fusion-based segmentation using multiple automatically generated templates.
Classically, model-based segmentation procedures match magnetic resonance imaging (MRI) volumes to an expertly labeled atlas using nonlinear registration. The accuracy of these techniques are limited due to atlas biases, misregistration, and resampling error. Multi-atlas-based approaches are used as a remedy and involve matching each subject to a number of manually labeled templates. This approach yields numerous independent segmentations that are fused using a voxel-by-voxel label-voting procedure. In this article, we demonstrate how the multi-atlas approach can be extended to work with input atlases that are unique and extremely time consuming to construct by generating a library of multiple automatically generated templates of different brains (MAGeT Brain). We demonstrate the efficacy of our method for the mouse and human using two different nonlinear registration algorithms (ANIMAL and ANTs). The input atlases consist a high-resolution mouse brain atlas and an atlas of the human basal ganglia and thalamus derived from serial histological data. MAGeT Brain segmentation improves the identification of the mouse anterior commissure (mean Dice Kappa values (κ = 0.801), but may be encountering a ceiling effect for hippocampal segmentations. Applying MAGeT Brain to human subcortical structures improves segmentation accuracy for all structures compared to regular model-based techniques (κ = 0.845, 0.752, and 0.861 for the striatum, globus pallidus, and thalamus, respectively). Experiments performed with three manually derived input templates suggest that MAGeT Brain can approach or exceed the accuracy of multi-atlas label-fusion segmentation (κ = 0.894, 0.815, and 0.895 for the striatum, globus pallidus, and thalamus, respectively).


Suppression of spontaneous melanoma metastasis in scid mice with an antibody to the epidermal growth factor receptor.
The human melanoma cell line M24met metastasizes spontaneously from s.c. tumors to multiple distant sites in mice with severe combined immunodeficiency. Metastasis to lymph nodes and lungs is found in 100% of the animals. M24met has an undifferentiated phenotype and extra copies of the short arm of chromosome 7. This cell line expresses the epidermal growth factor receptor, and 425.3, a monoclonal antibody to the epidermal growth factor receptor, binds to 291,000 receptor molecules per M24met cell with a KD of 2.3 x 10(-10) M. This antibody has no effect on the proliferation of M24met cells under tissue culture conditions and does not mediate effector cell or complement-dependent cytotoxicity of these cells in vitro. However, treatment of established s.c. M24met tumors in mice with severe combined immunodeficiency with monoclonal antibody 425.3 specifically suppresses spontaneous metastasis of these tumors. Total doses of 4, 2, and 1 mg antibody per mouse decrease the number and size of melanoma metastases and prolong the life span of treated animals. Treatment with 4 mg of the F(ab')2 fragment of monoclonal antibody 425.3 does not influence M24met melanoma metastasis, implying a significant contribution of the Fc portion to the antimetastatic effect of this antibody.


NFL, the tobacco homolog of FLORICAULA and LEAFY, is transcriptionally expressed in both vegetative and floral meristems.
The homologous genes FLORICAULA (FLO) of Antirrhinum and LEAFY (LFY) of Arabidopsis regulate the formation of determinate floral meristems. Transcripts of these single-copy genes are confined to floral meristems and some floral organs as well as to the leaflike bracts that subtend Antirrhinum flowers. Based on these observations, we hypothesized that the transcription of genes homologous to FLO and LFY in tobacco, a determinate plant in which the primary shoot apex is consumed in the production of a terminal flower, would serve as a molecular marker for floral commitment. Surprisingly, transcripts of the tobacco homologs NFL1 and NFL2 (Nicotiana FLO/LFY) were found not only in floral meristems, but also in indeterminate vegetative meristems. This implies that the transcriptional expression of the FLO/LFY homologous genes in the apical meristem is not sufficient for the initiation of floral meristem development. In addition, the transcript patterns of the NFL genes identified a previously undescribed subset of cells within the shoot apical meristem that may indicate unique functional compartmentalization. This suggests that, unlike FLO and LFY, which specify determinacy only during floral development, the NFL genes act to specify determinacy in the progenitor cells for both flowers and leaves.


Modulation of plant-mediated interactions between herbivores of different feeding guilds: Effects of parasitism and belowground interactions.
Herbivory affects subsequent herbivores, mainly regulated by the phytohormones jasmonic (JA) and salicylic acid (SA). Additionally, organisms such as soil microbes belowground or parasitoids that develop inside their herbivorous hosts aboveground, can change plant responses to herbivory. However, it is not yet well known how organisms of trophic levels other than herbivores, below- and above-ground, alter the interactions between insect species sharing a host plant. Here, we investigated whether the parasitoid Aphidius colemani and different soil microbial communities (created through plant-soil feedbacks) affect the JA and SA signalling pathways in response to the aphid Myzus persicae and the thrips Frankliniella occidentalis, as well as subsequent thrips performance. Our results show that the expression of the JA-responsive gene CaPINII in sweet pepper was more suppressed by aphids than by parasitised aphids. However, parasitism did not affect the expression of CaPAL1, a biosynthetic gene of SA. Furthermore, aphid feeding enhanced thrips performance compared with uninfested plants, but this was not observed when aphids were parasitised. Soils where different plant species were previously grown, did not affect plant responses or the interaction between herbivores. Our study shows that members of the third trophic level can modify herbivore interactions by altering plant physiology.


Evaluation of Rasna panchaka (indigenous drug) as oxidative stress down-regulator using serum-free explant culture system.
The importance of phytochemicals/natural products as potential therapeutic agents in the present context is gaining a lot of importance. India with a rich heritage of such preparations needs evaluation as potent drugs. Explant culture system is a method, which is sensitive, reliable, reproducible and is capable of mimicking the in situ conditions maintaining the tissue in sufficiently high level of integration. The current study aimed to test the antioxidant activity of test compounds, namely, traditional aqueous (4212) and aqueous-methanolic (4308) extracts of Rasna panchaka using liver explant cultures. Dose-response optima of extracts (0.2-10 μg/mL) were determined using mouse liver explant culture system up to 48 h. The antioxidant property of extracts was assessed by primary oxidative defense parameters, namely, superoxide-dismutase (SOD), catalase, reduced glutathione (GSH), and malondialdehyde (MDA). The results indicated that the cellular architecture of the cultured tissue was well conserved in the first 6 h with a gradual display of specific changes in the next 24 h. There was a significant increase in MDA levels in experimental groups indicating the oxidative stress induction in explants. A dose of 2.0 μg/mL extracts have shown statistically significant (P < 0.05) protection against oxidative stress. MDA levels, a measure of lipid peroxidation, were significantly (P < 0.01) reduced by 50% in extract treated explants compared to control. This effect was accompanied by the increase in the first defense enzymes SOD (50%) and catalase (18%) with no change in reduced GSH levels. The study enforces the importance of "explant culture system," as it not only reduces the use of nonclinical/animal model but also is rapid and sensitive. Further, results of the current study also suggest that aqueous-methanolic extract of Rasna panchaka is having superior antioxidant activity compared to traditional water extract.


Bio-psychosocial factors of children and adolescents with internet gaming disorder: a systematic review.
Previous large-scale studies suggest that internet gaming disorder (IGD) among children and adolescents has become an important public concern. Minors are known to be particularly susceptible to problematic internet gaming use owing to age-related underdevelopment of cognitive control. It has been shown that precursors of addictions appear during adolescence; therefore, prevention efforts must be established targeting minors who have their first experience with addictive substances and behaviors during pubescence. Since the DSM-5 classification of IGD in 2013, studies on IGD have drastically increased in number. Thus, we performed an updated review of studies of IGD in children and adolescents to assess the clinical implications of IGD. The search included all publication years, using PubMed, MEDLINE, and PsycINFO. Across studies, the presence of IGD had a negative effect on sleep and schoolwork in minors. Additionally, family factors, including the quality of parent-child relationships, were important social factors in minors with IGD. Brain imaging studies indicate that impaired cognitive control in minors with IGD is associated with abnormal function in the prefrontal cortex and striatum. Persistent pathological online game use from childhood may aggravate abnormal brain function; therefore, preventive care and early intervention are increasingly important. Although extant research supports the effectiveness of cognitive behavioral therapy for minors with IGD, effective psychological intervention for minors with IGD is an urgent issue that requires further research. This review, which presents updated findings of IGD in minors, is expected to contribute to the development of future research and be useful in clinical practice in the field of child and adolescent psychiatry.


Dynamic properties of water in silicalite-1 powder.
Self-diffusion of D(2)O in partially filled silicalite-1 crystals was studied at 25°C by (2)H nuclear magnetic resonance (NMR) with bipolar field gradient pulses and longitudinal Eddy-current-delay. For the first time, reliable experimental diffusion data for this system were obtained. Analysis of NMR diffusion decays revealed the presence of a continuous distribution of apparent self-diffusion coefficients (SDCs) of water, ranging from 10(-7) to ∼10(-10) m(2)/s, which include values much higher and lower than that of bulk water (∼10(-9) m(2)/s) in liquid phase. The observed distribution of SDC changes with variation of the diffusion time in the range of 10-200 ms. A two-site Kärger exchange model was successfully fitted to the data. Finally, the water distribution and exchange in silicalite-1 pores were described by taking into account (a) a gas-like phase in the zeolite pores, a gas-like phase in mesopores and an intercrystalline gas-like phase and (b) intercrystalline liquid droplets with intermediate exchange rate with the other phases. The other phases experience fast exchange on the NMR diffusion time scale. Diffusion coefficients and mean residence times of water in some of these states were estimated.


Mechanism of action of blocking immunoglobulin G for Neisseria gonorrhoeae.
Blocking immunoglobulin G (IgG) inhibits complement-mediated killing of serum-resistant Neisseria gonorrhoeae (GC) in immune human serum. We examined the mechanism of action of blocking IgG. Presensitization of GC with increasing concentrations of blocking IgG or F(ab')2 before incubation with bactericidal antibody and absorbed pooled normal human serum increased consumption and deposition of the third component of human complement (C3) and the ninth component of human complement (C9) but inhibited killing in dose-related fashion. We next showed that blocking IgG or F(ab')2 partially inhibited binding of bactericidal IgG to GC. Also, binding of a monoclonal antibody recognizing GC outer membrane protein PIII was almost completely inhibited by blocking F(ab')2, confirming other work (Rice, P. A., M. R. Tam, and M. S. Blake, manuscript submitted for publication) showing that PIII is a target for blocking antibody. Studies of the C3 deposition site showed that one quarter of the C3 deposited on GC in the presence of blocking IgG bound covalently to the antibody molecule. Finally, 125I-GC constituents with covalently bound C3 were affinity purified on Sepharose bearing antibodies to C3 and identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis. C3 deposition on a 40,000-mol wt surface protein was enhanced six- to ninefold by blocking IgG, which indicates that the site of complement deposition was altered by blocking antibody. These studies show that blocking IgG competes with bactericidal antibody for binding to GC, but enhances rather than blocks complement activation, and leads to complement deposition at new sites that do not result in serum killing.


Enhanced processivity of RNA polymerase II triggered by Tat-induced phosphorylation of its carboxy-terminal domain.
The protein Tat is encoded by the HIV-1 genome and is essential for viral replication because of its activation of viral transcription. Tat enhances the ability of RNA polymerase II (Pol II) to move long distances down the DNA through a poorly understood mechanism that involves its binding the to the 5' end of the nascent HIV-1 transcript. It has been suggested that the stimulation of transcript elongation by conventional DNA-binding activators may involve phosphorylation of the carboxy-terminal domain (CTD) of Pol II by the transcription factor TFIIH through the associated CAK kinase. Here we show that Tat-enhanced HIV-1 transcription in vitro requires both TFIIH and the CTD of Pol II. In addition, Tat, through its activation domain, both interacts with a functional TFIIH-containing complex and stimulates phosphorylation of a CTD-containing substrate by the TFIIH kinase. Under conditions that jointly restrict transcriptional elongation and TFIIH-mediated CTD phosphorylation, Tat stimulates both these activities. Furthermore, RNA synthesis is required for Tat to stimulate phosphorylation of the CTD when it is part of an initiation complex, as expected from Tat's interaction with viral transcripts. Thus, stimulation of Pol II elongation by Tat may involve direct effects on TFIIH-mediated CTD phosphorylation.


Poly(ADP-ribose): a co-regulator of DNA methylation?
The formation of multiprotein complexes is l'ordre du jour in regulatory pathways. In this issue of Oncogene, Reale et al. report the formation of a particularly sophisticated complex of two important regulatory enzymes, DNMT1 (DNA methyltransferase-1) and PARP-1 (poly(ADP-ribose)polymerase-1). The former evolved with a specific sequence motif binding the enzymatic product of the latter. The product, poly(ADP-ribose), bonds the two partners into a heterodimeric complex and, as a consequence, the catalytic function of DNMT1 is silenced. Thus, PARP-1 becomes a conditional negative regulator of DNMT1. In a larger perspective, Reale et al. highlight the potential role of PARP-1 as a co-regulator of DNA methylation leading to epigenetic reprogramming of cancer cells.


Subcellular localization of seven VirB proteins of Agrobacterium tumefaciens: implications for the formation of a T-DNA transport structure.
Plant cell transformation by Agrobacterium tumefaciens involves the transfer of a single-stranded DNA-protein complex (T-complex) from the bacterium to the plant cell. One of the least understood and important aspects of this process is how the T-complex exits the bacterium. The eleven virB gene products have been proposed to specify the DNA export channel on the basis of their predicted hydrophobicity. To determine the cellular localization of the VirB proteins, two different cell fractionation methods were employed to separate inner and outer membranes. Seven VirB-specific antibodies were used on Western blots (immunoblots) to detect the proteins in the inner and outer membranes and soluble (containing cytoplasm and periplasm) fractions. VirB5 was in both the inner membrane and cytoplasm. Six of the VirB proteins were detected in the membrane fractions only. Three of these, VirB8, VirB9, and VirB10, were present in both inner and outer membrane fractions regardless of the fractionation method used. Three additional VirB proteins, VirB1, VirB4, and VirB11, were found mainly in the inner membrane fraction by one method and were found in both inner and outer membrane fractions by a second method. These results confirm the membrane localization of seven VirB proteins and strengthen the hypothesis that VirB proteins are involved in the formation of a T-DNA export channel or gate. That most of the VirB proteins analyzed are found in both inner and outer membrane fractions suggest that they form a complex pore structure that spans both membranes, and their relative amounts in the two membrane fractions reflect their differential sensitivity to the experimental conditions.


DNA repair gene polymorphisms and susceptibility to familial breast cancer in a group of patients from Campinas, Brazil.
Several studies have reported that the genes involved in DNA repair and in the maintenance of genome integrity play a crucial role in protecting against mutations that lead to cancer. Epidemiologic evidence has shown that the inheritance of genetic variants at one or more loci results in a reduced DNA repair capacity and in an increased risk of cancer. Polymorphisms have been identified in several DNA repair genes, such as XRCC1, XPD, XRCC3, and RAD51, but the influence of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. This was a case-control study design with three case groups: 53 women with breast cancer and family history; 33 women with sporadic breast cancer; 175 women with no breast cancer but with family history. The control group included 120 women with no breast cancer and no family history. The PCR-RFLP method was used to analyze the XRCC1-Arg399Gln, XPD-Lys751Gln, XRCC3-Thr241Met, and RAD51-G135C polymorphisms. No statistically significant differences were found between the case groups and the control group for any of the polymorphisms analyzed, and also between the breast cancer and family history group and the sporadic breast cancer group. Sample sizes of women with breast cancer, whether familial or sporadic, were insufficient to show any small true differences between the groups, but we have to consider that currently there is no clear consensus with respect to the association of these polymorphisms with breast cancer risk. Considering the data available, it can be conjectured that if there is any risk association between these single-nucleotide polymorphisms and breast cancer, this risk will probably be minimal. The greater the risk associated with cancer, the smaller the sample size required to demonstrate this association, and the data of different studies are usually, therefore, more concordant.


Giving office-based physicians electronic access to patients' prior imaging and lab results did not deter ordering of tests.
Policy-based incentives for health care providers to adopt health information technology are predicated on the assumption that, among other things, electronic access to patient test results and medical records will reduce diagnostic testing and save money. To test the generalizability of findings that support this assumption, we analyzed the records of 28,741 patient visits to a nationally representative sample of 1,187 office-based physicians in 2008. Physicians' access to computerized imaging results (sometimes, but not necessarily, through an electronic health record) was associated with a 40-70 percent greater likelihood of an imaging test being ordered. The electronic availability of lab test results was also associated with ordering of additional blood tests. The availability of an electronic health record in itself had no apparent impact on ordering; the electronic access to test results appears to have been the key. These findings raise the possibility that, as currently implemented, electronic access does not decrease test ordering in the office setting and may even increase it, possibly because of system features that are enticements to ordering. We conclude that use of these health information technologies, whatever their other benefits, remains unproven as an effective cost-control strategy with respect to reducing the ordering of unnecessary tests.


Aortic Stiffness, Increased White Matter Free Water, and Altered Microstructural Integrity: A Continuum of Injury.
Previous reports from the Framingham Heart Study have identified cross-sectional associations of arterial stiffness, as reflected by carotid-femoral pulse wave velocity (CFPWV) and systolic blood pressure with vascular brain injury. The purpose of this study is to examine free water (FW), fractional anisotropy (FA), and white matter hyperintensities (WMH) in relation to arterial stiffness among subjects of the Framingham Offspring and Third-Generation cohorts. In 2422 participants aged 51.3±11.6 years, FA, FW, and WMH were related to CFPWV using voxel-based linear and generalized linear regressions, adjusting for relevant covariables. Mean FW, mean FA, and WMH burden (log transformed) were computed within white matter (WM) region and related to systolic blood pressure and CFPWV using multiple mediation analyses. CFPWV was found to be associated with higher FW, lower FA, and higher WMH incidence in WM areas covering, respectively, 356.1, 211.8, and 10.9 mL of the WM mask. Mediation analyses revealed that the effect of systolic blood pressure on FW was mediated by CFPWV (direct and indirect effects: a=0.040; P<0.001, and a'=0.020; P>0.05). Moreover, the effect of CFPWV on FA was mediated by FW (direct and indirect effects: b=-0.092; P<0.001, and b'=0.012; P>0.05), whose effect on WMH was, in turn, mediated by FA (direct and indirect effects: c=0.246; P<0.001, and c'=0.116; P>0.05). From these data, we propose a biomechanical hypothesis designed for future research experiments to explain how hemodynamic alteration may lead to WM injury by impacting cerebral water content and more subtly WM integrity, to finally lead to WMH development.


Long Term Recidivism Rates Among Individuals at High Risk to Sexually Reoffend.
Preventive detention provisions in the US and Canada assume we can identify, in advance, individuals at high risk for sexual recidivism. To test this assumption, 377 adult males with a history of sexual offending were followed for 20 years using Canadian national criminal history records and Internet searches. Using previously collected information, a high risk/high need (HRHN) subgroup was identified based on an unusually high levels of criminogenic needs (n = 190, average age of 38 years; 83% White, 13% Indigenous, 4% other). A well above average subgroup of 99 individuals was then identified based on high Static-99R (6+) and Static-2002R (7+) scores. In the HRHN group, 40% reoffended sexually. STATIC HRHN norms overestimated sexual recidivism at 5 years (Static-99R, E/O = 1.44; Static-2002R, E/O = 1.72) but were well calibrated for longer follow-up periods (20 years: Static-99R, E/0 = 1.00; Static-2002R, E/O = 1.16). The overall sexual recidivism rate for the well above average subgroup was 52.1% after 20 years, and 74.3% for any violent recidivism. The highest risk individuals (top 1%) had rates in the 60%-70% range. We conclude that some individuals present a high risk for sexual recidivism, and can be identified using currently available methods.


Oral health risk assessment timing and establishment of the dental home.
Early childhood dental caries has been reported by the Centers for Disease Control and Prevention to be perhaps the most prevalent infectious disease of our nation's children. Early childhood dental caries occurs in all racial and socioeconomic groups; however, it tends to be more prevalent in low-income children, in whom it occurs in epidemic proportions. Dental caries results from an overgrowth of specific organisms that are a part of normally occurring human flora. Human dental flora is site specific, and an infant is not colonized until the eruption of the primary dentition at approximately 6 to 30 months of age. The most likely source of inoculation of an infant's dental flora is the mother or another intimate care provider, through shared utensils, etc. Decreasing the level of cariogenic organisms in the mother's dental flora at the time of colonization can significantly impact the child's predisposition to caries. To prevent caries in children, high-risk individuals must be identified at an early age (preferably high-risk mothers during prenatal care), and aggressive strategies should be adopted, including anticipatory guidance, behavior modifications (oral hygiene and feeding practices), and establishment of a dental home by 1 year of age for children deemed at risk.


Correlation between Left Ventricular Mass Index and Calcium Metabolism in Patients with Essential Hypertension.
To determine the correlation between left ventricular mass index and calcium metabolism in patients with essential hypertension. Cross sectional case-control study. Twenty-seven patients with essential hypertension and 20 healthy individuals were compared with respect to calciotropic hormones, left ventricular mass index (LVMI), and urinary and serum biochemical parameters. The correlations between parathormone, vitamin D, and calcitonin levels and LVMI and blood pressure elevation were determined. The parathormone level was significantly higher (p=0.006) and vitamin D level was significantly lower (p=0.01) in the patient group compared with the control group. However, the two groups were similar in terms of albumin-corrected calcium levels, which were within the normal range (p=0.988). The serum sodium (p=0.014) and urinary calcium (p=0.003) levels and LVMI (p<0.01) were also significantly higher in the patient group. No significant correlations were determined between ambulatory blood pressure and parathormone and vitamin D levels, but a significant correlation was found between LVMI and parathormone level (p=0.06) in hypertensive patients. Essential hypertension alters calcium metabolism, causing calciuresis by hypernatremia. Parathormone release increases to compensate for this, and leads to protein synthesis, which in turn provokes the development of myocardial hypertrophy.


The pathology of human diabetic neuropathy.
Quantitative morphological data are presented from a series of studies assessing both nerve fiber and capillary pathology in 30 diabetic patients with varying stages and symptoms of neuropathy. There is a significant relationship between clinical measures of neuropathic severity and myelinated fiber loss. However, unmyelinated fibers continue to regenerate even in patients with established neuropathy. Microvascular abnormalities, particularly basement membrane thickening and endothelial cell hyperplasia, are an early feature of diabetic microangiopathy and relate to neuropathic severity. There are no neurophysiological or morphological differences between patients with type 1 and type 2 diabetes nor between diabetic patients with and without painful neuropathy.


Formation of N-nitrosamines from chlorination and chloramination of molecular weight fractions of natural organic matter.
N-Nitrosamines are a class of disinfection by-products (DBPs) that have been reported to be more toxic than the most commonly detected and regulated DBPs. Only a few studies investigating the formation of N-nitrosamines from disinfection of natural waters have been reported, and little is known about the role of natural organic matter (NOM) and the effects of its nature and reactivity on the formation of N-nitrosamines. This study investigated the influence of the molecular weight (MW) characteristics of NOM on the formation of eight species of N-nitrosamines from chlorination and chloramination, and is the first to report on the formation of eight N-nitrosamines from chlorination and chloramination of MW fractions of NOM. Isolated NOM from three different source waters in Western Australia was fractionated into several apparent MW (AMW) fractions using preparative-scale high performance size exclusion chromatography. These AMW fractions of NOM were then treated with chlorine or chloramine, and analysed for eight species of N-nitrosamines. Among these N-nitrosamines, N-nitrosodimethylamine (NDMA) was the most frequently detected. All AMW fractions of NOM produced N-nitrosamines upon chlorination and chloramination. Regardless of AMW characteristics, chloramination demonstrated a higher potential to form N-nitrosamines than chlorination, and a higher frequency of detection of the N-nitrosamines species was also observed in chloramination. The results showed that inorganic nitrogen may play an important role in the formation of N-nitrosamines, while organic nitrogen is not necessarily a good indicator for their formation. Since chlorination has less potential to form N-nitrosamines, chloramination in pre-chlorination mode was recommended to minimise the formation of N-nitrosamines. There was no clear trend in the formation of N-nitrosamines from chlorination of AMW fractions of NOM. However, during chloramination, NOM fractions with AMW <2.5 kDa were found to produce higher concentrations of NDMA and total N-nitrosamines. The precursor materials of N-nitrosamines appeared to be more abundant in the low to medium MW fractions of NOM, which correspond to the fractions that are most difficult to remove using conventional drinking water treatment processes. Alternative or advanced treatment processes that target the removal of low to medium MW NOM including activated carbon adsorption, biofiltration, reverse osmosis, and nanofiltration, can be employed to minimise the formation of N-nitrosamines.


Female meiotic sex chromosome inactivation in chicken.
During meiotic prophase in male mammals, the heterologous X and Y chromosomes remain largely unsynapsed, and meiotic sex chromosome inactivation (MSCI) leads to formation of the transcriptionally silenced XY body. In birds, the heterogametic sex is female, carrying Z and W chromosomes (ZW), whereas males have the homogametic ZZ constitution. During chicken oogenesis, the heterologous ZW pair reaches a state of complete heterologous synapsis, and this might enable maintenance of transcription of Z- and W chromosomal genes during meiotic prophase. Herein, we show that the ZW pair is transiently silenced, from early pachytene to early diplotene using immunocytochemistry and gene expression analyses. We propose that ZW inactivation is most likely achieved via spreading of heterochromatin from the W on the Z chromosome. Also, persistent meiotic DNA double-strand breaks (DSBs) may contribute to silencing of Z. Surprisingly, gammaH2AX, a marker of DSBs, and also the earliest histone modification that is associated with XY body formation in mammalian and marsupial spermatocytes, does not cover the ZW during the synapsed stage. However, when the ZW pair starts to desynapse, a second wave of gammaH2AX accumulates on the unsynapsed regions of Z, which also show a reappearance of the DSB repair protein RAD51. This indicates that repair of meiotic DSBs on the heterologous part of Z is postponed until late pachytene/diplotene, possibly to avoid recombination with regions on the heterologously synapsed W chromosome. Two days after entering diplotene, the Z looses gammaH2AX and shows reactivation. This is the first report of meiotic sex chromosome inactivation in a species with female heterogamety, providing evidence that this mechanism is not specific to spermatogenesis. It also indicates the presence of an evolutionary force that drives meiotic sex chromosome inactivation independent of the final achievement of synapsis.


A randomised, double-masked comparison study of diquafosol versus sodium hyaluronate ophthalmic solutions in dry eye patients.
To compare the efficacy and safety of 3% diquafosol ophthalmic solution with those of 0.1% sodium hyaluronate ophthalmic solution in dry eye patients, using mean changes in fluorescein and rose bengal staining scores as endpoints. TRIAL DESIGN AND METHODS: In this multicenter, randomised, double-masked, parallel study of 286 dry eye patients with fluorescein and rose bengal staining scores of ≥3 were randomised to the treatment groups in a 1 : 1 ratio. Efficacy and safety were evaluated after drop-wise instillation of the study drug, six times daily for 4 weeks. After 4 weeks, the intergroup difference in the mean change from baseline in fluorescein staining score was -0.03; this verified the non-inferiority of diquafosol. The mean change from baseline in rose bengal staining score was significantly lower in the diquafosol group (p=0.010), thus verifying its superiority. The incidence of adverse events was 26.4% and 18.9% in the diquafosol and sodium hyaluronate groups, respectively, with no significant difference. Diquafosol (3%) and sodium hyaluronate (0.1%) exhibit similar efficacy in improving fluorescein staining scores of dry eye patients, whereas, diquafosol exhibits superior efficacy in improving rose bengal staining scores. Diquafosol has high clinical efficacy and is well tolerated with a good safety profile.


DNA polymerase structure-based insight on the mutagenic properties of 8-oxoguanine.
An aerobic environment burdens DNA polymerase substrates with oxidized substrates (DNA and nucleotide pools). A major promutagenic lesion resulting from oxidative stress is 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG). Guanine oxidation alters the hydrogen bonding properties of the base and glycosidic-preference of the nucleotide. The favored glycosidic syn-conformation exposes the Hoogsteen edge of the base for hydrogen bonding with adenine during DNA synthesis. The cell has recognized the threat of this lesion and has evolved an intricate surveillance system to provide DNA polymerases with unmodified substrates. Failure to do so leads to transversion mutations. Since the mutagenic properties of the base are dictated by the anti-syn-conformation of the nucleotide, the molecular interactions of 8-oxoG in the confines of the DNA polymerase active site are expected to influence its coding potential. Recent structural characterization of DNA polymerases from several families with this lesion in the nascent base pair binding pocket has provided insight to the mutagenic properties of this modified nucleotide. These structures reveal that flexibility around the template-binding pocket can permit 8-oxoG to assume an anti- or syn-conformation and code for cytosine or adenine incorporation, respectively. In contrast, the binding pocket for the incoming nucleotide does not have this flexibility so that 8-oxodGTP insertion opposite cytosine is strongly discouraged.


Symmetrically reduced stiffness and increased extensibility in compression and tension at the mineralized fibrillar level in rachitic bone.
In metabolic bone diseases, the alterations in fibrillar level bone-material quality affecting macroscopic mechanical competence are not well-understood quantitatively. Here, we quantify the fibrillar level deformation in cantilever bending in a mouse model for hereditary rickets (Hpr). Microfocus in-situ synchrotron small-angle X-ray scattering (SAXS) combined with cantilever bending was used to resolve nanoscale fibril strain in tensile- and compressive tissue regions separately, with quantitative backscattered scanning electron microscopy used to measure microscale mineralization. Tissue-level flexural moduli for Hpr mice were significantly (p<0.01) smaller compared to wild-type (~5 to 10-fold reduction). At the fibrillar level, the fibril moduli within the tensile and compressive zones were significantly (p<0.05) lower by ~3- to 5-fold in Hpr mice compared to wild-type mice. Hpr mice have a lower mineral content (24.2±2.1Cawt.% versus 27.4±3.3Ca wt.%) and its distribution was more heterogeneous compared to wild-type animals. However, the average effective fibril modulus did not differ significantly (p>0.05) over ages (4, 7 and 10weeks) between tensile and compressive zones. Our results indicate that incompletely mineralized fibrils in Hpr mice have greater deformability and lower moduli in both compression and tension, and those compressive and tensile zones have similar moduli at the fibrillar level.


Effects of clozapine and haloperidol treatment on plasma concentrations of androgen hormones and androgendependent organ changes in rats.
Metabolic and endocrine adverse effects are among the most concerning unfavorable consequences of commonly used psychotropic drugs. The present research was planned to assess and determine the effects of haloperidol and clozapine on testosterone, cortisol, and corticosterone levels and also their influence on androgen-dependent organs in adult male Wistar rats. Animals were casually distributed into three groups (n = 10 in each group). Drugs were administered intraperitoneally for 28 days. The control group received 2 mL of physiological saline, the second group received haloperidol (0.5 mg/kg), and the third group received clozapine (0.5 mg/kg). The subsequent testosterone, cortisol, and corticosterone plasma concentration levels were analyzed with chemiluminescent immunoassay. Clozapine and haloperidol treatments altered testosterone hormone levels. Testosterone mean values in both the clozapine (1.00-0.58) and haloperidol (0.65-0.62) groups were found to be lower than compared to controls (P = 0.003, P < 0.001). Histomorphometric analysis results also showed reduced testes size and reduced weight of androgen-dependent organs in drug-treated rats. It can be suggested that clozapine and haloperidol are effective in reducing the testosterone plasma concentration level and androgen-dependent organ sizes; therefore, clinicians should be aware of these effects when considering the use of antipsychotic drugs.


Evidence that the negative BOLD response is neuronal in origin: a simultaneous EEG-BOLD-CBF study in humans.
Unambiguous interpretation of changes in the BOLD signal is challenging because of the complex neurovascular coupling that translates changes in neuronal activity into the subsequent haemodynamic response. In particular, the neurophysiological origin of the negative BOLD response (NBR) remains incompletely understood. Here, we simultaneously recorded BOLD, EEG and cerebral blood flow (CBF) responses to 10 s blocks of unilateral median nerve stimulation (MNS) in order to interrogate the NBR. Both negative BOLD and negative CBF responses to MNS were observed in the same region of the ipsilateral primary sensorimotor cortex (S1/M1) and calculations showed that MNS induced a decrease in the cerebral metabolic rate of oxygen consumption (CMRO2) in this NBR region. The ∆CMRO2/∆CBF coupling ratio (n) was found to be significantly larger in this ipsilateral S1/M1 region (n=0.91±0.04, M=10.45%) than in the contralateral S1/M1 (n=0.65±0.03, M=10.45%) region that exhibited a positive BOLD response (PBR) and positive CBF response, and a consequent increase in CMRO2 during MNS. The fMRI response amplitude in ipsilateral S1/M1 was negatively correlated with both the power of the 8-13 Hz EEG mu oscillation and somatosensory evoked potential amplitude. Blocks in which the largest magnitude of negative BOLD and CBF responses occurred therefore showed greatest mu power, an electrophysiological index of cortical inhibition, and largest somatosensory evoked potentials. Taken together, our results suggest that a neuronal mechanism underlies the NBR, but that the NBR may originate from a different neurovascular coupling mechanism to the PBR, suggesting that caution should be taken in assuming the NBR simply represents the neurophysiological inverse of the PBR.


Evaluation of Parenting Interventions to Prevent Violence Against Children in Colombia: A Randomized Controlled Trial.
The effects of the International Child Development Programme (ICDP) and the specific addition of a violence prevention module were observed in a preidentified population in Colombia where children are experiencing high levels of violence. Participants were 176 parents of 3- to 4-year-olds attending child centers who were randomly allocated to one of three conditions: organized Community Activities at child centers and ICDP (CA + ICDP), CA, ICDP, and a preventive Violence Curriculum (CA + ICDP + VC), or a comparison group with only CA. The parents completed questionnaires about corporal punishment, intimate partner violence, community violence, and mental health at baseline and at 6 months follow-up. Univariate logistic regressions were used to examine uses of child violence, predictors of intimate partner violence, and prevalence of mental health problems. McNemar tests were used to assess differences between intervention groups and comparison group at two different time points. Participants were mostly female (78.5%) and had an average age of 32 years. Among these, 58.5% had been exposed to community violence and 98.3% reported using physical assault to discipline their children. Reported prevalence of child violence decreased in all groups whereas the reduction of severe forms of violence was larger for the intervention groups, and especially for the CA + ICDP + VC group. There was a significant reduction of victimization of intimate partner violence in both intervention groups as well as a decrease in mental health problems, especially for the CA + ICDP group (from 22.4% to 5.1%). The general ICDP seems effective in reducing violence. The addition of a specific violence intervention component seemed to reduce intimate partner violence, but not violence related to children. The comparison group attending the child center and other social activities also reported reduced violence but to a lesser extent than the groups who attended specific interventions.


α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors' Gating Modules.
The ionotropic glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) is responsible for most excitatory transmission in the brain. AMPA receptor function is altered in numerous neurological illnesses, making AMPA receptors appealing therapeutic targets for clinical intervention. Alpha-Lipoic acid (α-LA) is a naturally occurring compound, which functions as a co-factor in metabolism and energy production. α-LA is an antioxidant with various benefits in treating diabetes, including managing symptomatic diabetic neuropathy. This study will test a novel and innovative strategy to synthesize a new isomer of lipoic acid (R-LA) derivatives (bifunctional NO-donor/antioxidant) in one chemical on homomeric and heteromeric AMPA receptor subunits. We used patch-clamp electrophysiology to examine LA derivatives expressed in human embryonic kidney 293 cells (HEK293) for inhibition and changes in desensitization or deactivation rates. LA derivatives were shown to be potent antagonists of AMPA receptors, with an 8-11-fold reduction in AMPA receptor currents seen following the delivery of the compounds. Furthermore, the LA derivatives influenced the rates of desensitization and deactivation of AMPA receptors. Based on our results, especially given that α-LA is closely connected to the nervous system, we may better understand using AMPA receptors and innovative drugs to treat neurological diseases associated with excessive activation of AMPA receptors.


Placebo response in studies of major depression: variable, substantial, and growing.
Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials. To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time. We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion. Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author. The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P =.02). The association between year of publication and response rate was more statistically robust for placebo than medication. The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.


Residential noise exposure and the longitudinal risk of hospitalization for depression after pregnancy: Postpartum and beyond.
Depression is a major public health concern, but the link with the built environment is unclear. We sought to determine the relationship between residential noise during pregnancy and later risk of severe depression in women. We analyzed a population-based cohort of 140,456 women with no documented history of mental illness who were pregnant in Montreal between 2000 and 2016. We obtained residential noise estimates (LAeq. 24 h, Lden, Lnight) from land use regression models, and followed the women over time for up to 18 years after pregnancy to identify subsequent hospitalizations for depression or other mental disorders. We used Cox regression to compute hazard ratios and 95% confidence intervals (CI) adjusted for maternal characteristics. There were 8.0 incident hospitalizations for depression and 16.4 for other mental disorders per 10,000 person-years in women exposed to an LAeq. 24 h of 60-64.9 dB(A). The incidence was lower for noise at < 55 dB(A), with 7.4 hospitalizations for depression and 13.8 for other mental disorders per 10,000 person-years. Compared with 50 dB(A), an LAeq. 24 h of 60 dB(A) was associated with 1.16 times (95% CI 0.84-1.62) the risk of depression hospitalization, and 1.34 times (95% CI 1.04-1.74) the risk of other mental disorders. Associations were more prominent for Lnight, with 1.32 times (95% CI 1.08-1.63) the risk of depression hospitalization at 60 dB(A) and 1.68 times the risk (95% CI 1.05-2.67) at 70 dB(A). Pregnant women exposed to noise, especially nighttime noise, have a greater risk of hospitalization for depression and other mental disorders later in life. Residential noise may be a risk factor for depression after pregnancy.


Association of plasma cardiotrophin-1 with stage C heart failure in hypertensive patients: potential diagnostic implications.
Cardiotrophin-1 is a cytokine that induces hypertrophy and dysfunction in cardiomyocytes and has been shown to be increased in hypertensive patients. The objective of this study was to evaluate the association of cardiotrophin-1 with heart failure (HF) in hypertensive patients and its usefulness as a biomarker of stage C heart failure. Hypertensive patients without cardiac abnormalities (stage A, n = 64), with left ventricular hypertrophy (LVH) (stage B, n = 58), and with left ventricular hypertrophy and clinical manifestations of chronic heart failure (stage C, n = 39) were studied. Plasma cardiotrophin-1 was measured by an enzyme-linked inmunosorbent assay. Plasma cardiotrophin-1 progressively increased (P < 0.001), along with progression of heart failure stages, in hypertensive patients. Plasma cardiotrophin-1 was directly (r = 0.416, P < 0.001) and inversely (r = 0.263, P < 0.01) correlated with left ventricular (LV) mass index and ejection fraction, respectively, in all hypertensive patients. These associations were independent of a number of potential confounding factors. Receiver operating characteristic curves showed that a cut-off of 48.72 fmol/ml for cardiotrophin-1 provided higher sensitivity for diagnosing stage C heart failure than a cut-off of 375.54 pg/ml for amino-terminal probrain natriuretic peptide (NT-proBNP) (80% vs. 72%). Sixty-four percent of stage C hypertensive patients with NT-proBNP values below 375.54 pg/ml value exhibited cardiotrophin-1 values above 49.16 fmol/ml. These findings indicate that plasma cardiotrophin-1 is associated with progression of heart failure in hypertensive patients. Cardiotrophin-1 measurement may provide additional information to that afforded by NT-proBNP to diagnose stage C heart failure in these patients.


Plasmonics on the slope of enlightenment: the role of transition metal nitrides.
The key problem currently faced by plasmonics is related to material limitations. After almost two decades of extreme excitement and research largely based on the use of noble metals, scientists have come to a consensus on the importance of exploring alternative plasmonic materials to address application-specific challenges to enable the development of new functional devices. Such a change in motivation will undoubtedly lead to significant advancements in plasmonics technology transfer and could have a revolutionary impact on nanophotonic technologies in general. Here, we report on one of the approaches that, together with other new material platforms, mark an insightful technology-driven era for plasmonics. Our study focuses on transition metal nitrides as refractory plasmonic materials that exhibit appealing optical properties in the visible and near infrared regions, along with high temperature durability. We take heat-assisted magnetic recording as a case study for plasmonic technology and show that a titanium nitride antenna satisfies the requirements for an optically efficient, durable near field transducer paving the way to the next-generation data recording systems.


A single, low dose of a cGMP recombinant BCG vaccine elicits protective T cell immunity against the human respiratory syncytial virus infection and prevents lung pathology in mice.
Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection. Here, we describe that a recombinant Bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of hRSV formulated under current good manufacture practices (cGMP rBCG-N-hRSV) confers protective immunity to the virus in mice. Our results show that a single dose of the GMP rBCG-N-hRSV vaccine retains its capacity to protect mice against a challenge with a disease-causing infection of 1×107 plaque-forming units (PFUs) of the hRSV A2 clinical strain 13018-8. Compared to unimmunized infected controls, vaccinated mice displayed reduced weight loss and less infiltration of neutrophils within the airways, as well as reduced viral loads in bronchoalveolar lavages, parameters that are characteristic of hRSV infection in mice. Also, ex vivo re-stimulation of splenic T cells at 28days post-immunization activated a repertoire of T cells secreting IFN-γ and IL-17, which further suggest that the rBCG-N-hRSV vaccine induced a mixed, CD8+ and CD4+ T cell response capable of both restraining viral spread and preventing damage of the lungs. All these features support the notion that rBCG-N-hRSV is a promising candidate vaccine to be used in humans to prevent the disease caused by hRSV in the susceptible population.


Point-of-Care Testing as an Influenza Surveillance Tool: Methodology and Lessons Learned from Implementation.
Objectives. Disease surveillance combines data collection and analysis with dissemination of findings to decision makers. The timeliness of these activities affects the ability to implement preventive measures. Influenza surveillance has traditionally been hampered by delays in both data collection and dissemination. Methods. We used statistical process control (SPC) to evaluate the daily percentage of outpatient visits with a positive point-of-care (POC) influenza test in the University of Utah Primary Care Research Network. Results. Retrospectively, POC testing generated an alert in each of 4 seasons (2004-2008, median 16 days before epidemic onset), suggesting that email notification of clinicians would be 9 days earlier than surveillance alerts posted to the Utah Department of Health website. In the 2008-09 season, the algorithm generated a real-time alert 19 days before epidemic onset. Clinicians in 4 intervention clinics received email notification of the alert within 4 days. Compared with clinicians in 6 control clinics, intervention clinicians were 40% more likely to perform rapid testing (P = 0.105) and twice as likely to vaccinate for seasonal influenza (P = 0.104) after notification. Conclusions. Email notification of SPC-generated alerts provided significantly earlier notification of the epidemic onset than traditional surveillance. Clinician preventive behavior was not significantly different in intervention clinics.


An enhanced surface passivation effect in InGaN/GaN disk-in-nanowire light emitting diodes for mitigating Shockley-Read-Hall recombination.
We present a detailed study of the effects of dangling bond passivation and the comparison of different sulfide passivation processes on the properties of InGaN/GaN quantum-disk (Qdisk)-in-nanowire based light emitting diodes (NW-LEDs). Our results demonstrated the first organic sulfide passivation process for nitride nanowires (NWs). The results from Raman spectroscopy, photoluminescence (PL) measurements, and X-ray photoelectron spectroscopy (XPS) showed that octadecylthiol (ODT) effectively passivated the surface states, and altered the surface dynamic charge, and thereby recovered the band-edge emission. The effectiveness of the process with passivation duration was also studied. Moreover, we also compared the electro-optical performance of NW-LEDs emitting at green wavelength before and after ODT passivation. We have shown that the Shockley-Read-Hall (SRH) non-radiative recombination of NW-LEDs can be greatly reduced after passivation by ODT, which led to a much faster increasing trend of quantum efficiency and higher peak efficiency. Our results highlighted the possibility of employing this technique to further design and produce high performance NW-LEDs and NW-lasers.


Potential cost-effectiveness of schistosomiasis treatment for reducing HIV transmission in Africa--the case of Zimbabwean women.
Epidemiological data from Zimbabwe suggests that genital infection with Schistosoma haematobium may increase the risk of HIV infection in young women. Therefore, the treatment of Schistosoma haematobium with praziquantel could be a potential strategy for reducing HIV infection. Here we assess the potential cost-effectiveness of praziquantel as a novel intervention strategy against HIV infection. We developed a mathematical model of female genital schistosomiasis (FGS) and HIV infections in Zimbabwe that we fitted to cross-sectional data of FGS and HIV prevalence of 1999. We validated our epidemic projections using antenatal clinic data on HIV prevalence. We simulated annual praziquantel administration to school-age children. We then used these model predictions to perform a cost-effectiveness analysis of annual administration of praziquantel as a potential measure to reduce the burden of HIV in sub-Saharan Africa. We showed that for a variation of efficacy between 30-70% of mass praziquantel administration for reducing the enhanced risk of HIV transmission per sexual act due to FGS, annual administration of praziquantel to school-age children in Zimbabwe could result in net savings of US$16-101 million compared with no mass treatment of schistosomiasis over a ten-year period. For a variation in efficacy between 30-70% of mass praziquantel administration for reducing the acquisition of FGS, annual administration of praziquantel to school-age children could result in net savings of US$36-92 million over a ten-year period. In addition to reducing schistosomiasis burden, mass praziquantel administration may be a highly cost-effective way of reducing HIV infections in sub-Saharan Africa. Program costs per case of HIV averted are similar to, and under some conditions much better than, other interventions that are currently implemented in Africa to reduce HIV transmission. As a cost-saving strategy, mass praziquantel administration should be prioritized over other less cost-effective public health interventions.


Mobility and fractionation of arsenic, chromium and copper in thermally treated soil.
Thermal treatment is used to remediate soil co-contaminated with organic and inorganic contaminants. It destroys organic contaminants, but the remaining inorganic contaminants require further treatment. In this study the effects of thermal treatment on the mobility, speciation and chemical fractionation of As, Cr and Cu in a CCA-polluted soil were evaluated by leaching tests, As speciation assays and a sequential extraction procedure. The soil was sieved into four size fractions (<0.125, 0.125-0.250, 0.250-0.500 and 0.500-1.0 mm), each of which was treated at 800°C and analysed in comparison with the untreated soil. The leaching of As and Cr increased by factors of 18-40 and 2-23, respectively, while the mobility of Cu decreased 12-14-fold after treatment. The concentration of As(V) in pore water of the finest soil fraction increased 19-fold, whereas that of As(III) remained constant. The treatment reduced As, Cr and Cu associated with the reducible soil fraction. In addition, it increased the proportions of As and Cr (slightly) associated with the exchangeable and acid-soluble soil fractions, and the proportions of Cu and Cr (substantially) associated with the residual fraction.


Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder originated by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. The first large series HHT analysis in Spanish population has identified mutations in 17 unrelated families. Ten different mutations in ALK1 and six in ENG genes were found. Six unrelated families had a mutation in ENG gene, four representing new mutations, p.Y258fs, pV323fs, p.F279fs (c.834_837del CTTC), and p.F279fsdupC. Eleven unrelated families harboured mutations in ALK1; ten were new mutations identified as p.H328P, p.R145fs, p.G68C, p.A377T, p.H297R, p.M376T, p.C36Y, p.H328P, p.T82del and p.R47P. Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1), in agreement with data reported for other Mediterranean countries (France, Italy), but at variance with Northern Europe or North America. Endoglin expression in HHT1 or HHT2 activated monocytes and blood outgrowth endothelial cells (BOECs) from older patients was well below the theoretical 50% level expected from the HHT1 haploinsufficiency model, suggesting that the pathogenic endoglin haploinsufficiency leading to the HHT phenotype is age-dependent. Interestingly, ALK1 protein levels of HHT BOECs in some missense ALK1 mutants were similar to controls. In vitro expression of these ALK1 constructs suggests that, in addition to the haploinsufficiency model, certain ALK1 mutants may inhibit the function of the wild type allele.


The clinical application of transcranial direct current stimulation in patients with cerebellar ataxia: a systematic review.
The aim of this review was to investigate the effects of transcranial direct current stimulation (tDCS) on motor function in patients with cerebellar ataxia. Our systematic review has been performed by searching full-text articles on Pubmed and Scopus. Only studies investigating the motor effects of tDCS in patients with cerebellar ataxias were considered. A qualitative analysis of data was performed, as the methodology of the selected studies was highly heterogeneous. Our search yielded a total of twenty-seven hits. Based on the inclusion criteria, 19 of these were excluded and 89 were retained (number of patients = 81).The results reviewed so far suggest that tDCS over cerebellum combined or not with extra-cerebellar areas might be promising approach to improve motor outcomes, with a greater success in patients less impaired. In particular, it is been shown an improvement in both clinical measures assessing cerebellar deficits (i.e. gait, stance and oculomotor disorders) and performance measures (finger dexterity, upper limb coordination and gait speed). Some of the assessed investigations highlighted a restore effect of cerebellar brain inhibition pathway and resting motor threshold after tDCS. tDCS could be considered an effective approach to promote plasticity in patient with cerebellar ataxia with significant motor effects. Future studies, with larger sample sizes are needed in order to evaluate the effective tDCS benefits on motor functionality. Due to the limited number of studies available so far, conclusions on the effectiveness of the reported approaches are premature.


First Report of Seedling Blight of Watermelon Caused by Acidovorax citrulli Transmitted from Rootstock of Pumpkin in China.
Bacterial fruit blotch (BFB) is a devastating disease caused by Acidovorax citrulli, which was first observed in the United States in 1988 (3). A. citrulli can cause severe infection on a wide range of cucurbits, including watermelon, cantaloupe, and pumpkin. Cotyledon symptoms are brown, angular, necrotic spots or large necrotic lesions. The disease is seedborne, so seeds usually serve as the primary inoculum source for BFB outbreaks (2). In July 2012, seedling blight was observed by local farmers from Anhui province in China on watermelon seedlings grafted to pumpkin rootstocks; lesions were morphologically similar to those caused by A. citrulli. Presence of A. citrulli was detected in symptomatic samples by using species-specific primers BX-L1/BX-S-R2 (1). The seed company claimed seeds of watermelon (cv. Changfeng) were certified free of bacterial fruit blotch, but pumpkin seeds (cv. Kangkuxianfeng-1) had not been tested for A. citrulli. For investigating the inoculum source, the remaining seeds of watermelon (cv. Changfeng) and pumpkin (cv. Kangkuxianfeng-1) for seedling production were collected from the farmer and processed for pathogen extraction as described by Walcott and Gitaitis (2). Two microliters of seed wash was used as template for PCR using primers BX-L1/BX-S-R2 (1). The experiment was conducted three times. A 279-bp DNA fragment was consistently amplified by PCR from seed wash of pumpkin seeds, but not from the seed wash of watermelon seeds. Three Acidovorax-like strains (A1, A2, and A3) were isolated from pumpkin seed wash using TWZ semi-selective medium (0.5% peptone, 0.025% CaCl2, 1% Tween-80, 50 mg/liter berberine, 50 mg/liter cycloheximide, 50 mg/liter 2,3,5-triphenyltetrazolium chloride). PCR was performed on the 16S rDNA gene from isolate strain A1, A2, and A3 (1,492 bp; GenBank Accession Nos. JX875533, JX875534, and JX875535) with primers rp1/fd2 (4), and PCR products were sequenced. Results of sequence analysis showed the sequences of strains A1, A2, and A3 were 99% identical to that of the type strain of A. citrulli AAC00-1 (NC_008752). Pathogencity was confirmed by injection of pumpkin cotyledons with bacterial suspensions of each isolate. Collected pumpkin seeds (n = 100 seeds) and watermelon seeds (n = 100 seeds) were planted in plastic pots containing sterilized field soil at room temperature to detect A. citrulli by a wet chamber growing out test. Eight days later, brown, angular, necrotic spots or wilt developed in pumpkin seedlings, but no symptoms were noted on the watermelon seedlings. To our knowledge, this is the first report of A. citrulli causing watermelon seedling blight transmitted from pumpkin seeds by grafting in China. References: (1) O. Bahar et al. Plant Pathol. 57:754, 2008. (2) R. R. Walcott and R. D. Gitaitis. Plant Dis. 84:470, 2000. (3) G. C. Wall et al. Phytopathology 78:1605, 1988. (4) W. G. Weisburg et al. J. Bacteriol. 173:697, 1991.


Use of rotation flap in repair of cleft palate and velopharyngeal insufficiency.
Although cleft palate anomaly is frequent, the criterion standards in surgical treatment have not been determined yet. There are a few techniques described for cleft palate repair owing to the limited tissue in the palatal mucosa, the rigid structure of the palatal mucosa, and the limited vascularity of the hard palate. In this study, a novel cleft palate repair technique based on separating the soft palate from the hard palate as a musculomucosal flap and using it as a rotation flap has been described. The operation is evaluated individually for each anomaly because variations occur in the surgical technique according to the extension of the cleft toward the teeth in the palate. This operation was performed on a total of 28 patients (17 girls and 11 boys) aged between 1.5 and 16 years and presented to our clinic. Patients were assessed for speech analysis outcomes, tympanogram values, hearing functions, magnitude of palatal lengthening during the operation, and rate of fistulae. Statistically significant differences in values of the speech analysis and the audiometric assessment were determined between before and 6 months after surgery. Complete recovery of otitis was observed 1 month after surgery without another treatment in 9 (42.8%) of 21 patients who were detected to have serous otitis media preoperatively. Tension-free closure, lower risk of fistula, good restoration of velopharyngeal functions, ability to be performed on all types of cleft palate, ability to provide a good intraoperative exposure, and being a single stage seem to be the most important advantages of this technique.


Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline.
What is the role of medical cannabis or cannabinoids for people living with chronic pain due to cancer or non-cancer causes? Chronic pain is common and distressing and associated with considerable socioeconomic burden globally. Medical cannabis is increasingly used to manage chronic pain, particularly in jurisdictions that have enacted policies to reduce use of opioids; however, existing guideline recommendations are inconsistent, and cannabis remains illegal for therapeutic use in many countries. The guideline expert panel issued a weak recommendation to offer a trial of non-inhaled medical cannabis or cannabinoids, in addition to standard care and management (if not sufficient), for people living with chronic cancer or non-cancer pain. An international guideline development panel including patients, clinicians with content expertise, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach. The MAGIC Evidence Ecosystem Foundation (MAGIC) provided methodological support. The panel applied an individual patient perspective. This recommendation is informed by a linked series of four systematic reviews summarising the current body of evidence for benefits and harms, as well as patient values and preferences, regarding medical cannabis or cannabinoids for chronic pain. The recommendation is weak because of the close balance between benefits and harms of medical cannabis for chronic pain. It reflects a high value placed on small to very small improvements in self reported pain intensity, physical functioning, and sleep quality, and willingness to accept a small to modest risk of mostly self limited and transient harms. Shared decision making is required to ensure patients make choices that reflect their values and personal context. Further research is warranted and may alter this recommendation.


An evaluation of a heroin overdose prevention and education campaign.
Following detection of an upward trend in the frequency of fatal heroin overdoses in Victoria between 2001 and 2003, Victoria's Department of Human Services planned a campaign aimed at increasing injecting drug users' (IDU) awareness of overdose risks and prevention strategies. Stickers, wallet cards and posters featuring five key messages were distributed via needle and syringe programs (NSP) and other drug and alcohol services between November 2005 and April 2006. An evaluation of the campaign was commissioned to be conducted in late 2006. The evaluation consisted of analysis of three independent data sets--quantitative data collected from IDU during the campaign period (n = 855 at baseline; and a range of 146-656 at follow up); qualitative interviews with IDU who were NSP clients during the campaign period (n = 16) and qualitative interviews with NSP staff and other key stakeholders (n = 9). While key experts felt that the campaign messages had engendered lasting impact for at least some IDU, these positive impressions were not borne out by the NSP client data, with less than one quarter of all campaign messages being mentioned by a significantly higher proportion of clients during the post-campaign period compared with baseline. Key experts perceived the greatest weakness of the campaign to be the delay between issue identification and the introduction of campaign materials. While IDU are generally responsive to health promotion campaigns, future initiatives in this domain should be designed and implemented rapidly and in ways that are sufficiently flexible to cope with shifts in drug markets which could influence the reception of key messages.


Pythagorean Self Awareness Intervention in Caregivers of Patients with Motor Disabilities.
Caregiving for disabled people is a strenuous task often provided by family members, with adverse repercussions on the caregivers' health. The aim of this study was to evaluate, for the first time, the effects of a novel cognitive-based stress management technique, the Pythagorean Self-Awareness Intervention (PSAI) on the stress levels and other cognitive and psychological characteristics of non-paid caregivers of patients with motor disability. In this quasi-experimental study, 59 caregivers of first-degree relatives with motor disabilities due to chronic neurological diseases, inpatients at a Rehabilitation Center, in Athens, Greece, were assigned to an intervention (PSAI, n=28) and a control group (received unstructured consultation, n=31). Psychological, cognitive, and sleep-related measurements (Zarit Burden Interview tool, Pittsburgh Sleep Quality Index, Self-Efficacy Scale, Depression, Anxiety and Stress Scale, Symbol Digit Modalities Test, California Verbal Learning Test-II, Brief Visuospatial Memory Test-Revised) were held at baseline and after 8 weeks (at completion of PSAI) in both groups. PSAI was found to decrease caregivers' stress, depressive symptoms and anxiety and improve their sleep quality, visual memory, self-efficacy, and cognitive speed processing. Future randomized controlled studies are needed to investigate the effects of this novel intervention in larger samples of caregivers.


Role of coenzyme Q(10) as an antioxidant and bioenergizer in periodontal diseases.
Periodontal disease is an inflammatory disease process resulting from the interaction of a bacterial attack and host inflammatory response. Arrays of molecules are considered to mediate the inflammatory response at one time or another, among these are free radicals and reactive oxygen species (ROS). Periodontal pathogens can induce ROS overproduction and thus may cause collagen and periodontal cell breakdown. When ROS are scavenged by antioxidants, there can be a reduction of collagen degradation. Ubiquinol (reduced form coenzyme Q(10)) serves as an endogenous antioxidant which increases the concentration of CoQ(10) in the diseased gingiva and effectively suppresses advanced periodontal inflammation.


Feasibility of gadofosveset-enhanced steady-state magnetic resonance angiography of the peripheral vessels at 3 Tesla with Dixon fat saturation.
To investigate the feasibility and image quality of gadofosveset-enhanced steady-state peripheral MR-angiography using Dixon fat saturation in comparison to spectral fat saturation. After Institutional Review Board (IRB) approval, 10 healthy volunteers underwent peripheral MR-angiography at 3.0 T during the steady state 50 minutes after gadofosveset injection. A steady-state-adapted volume interpolated breathhold examination sequence with an isotropic spatial resolution of 1 mm was acquired with 2-point Dixon fat saturation (DixFS, acquisition time 52 seconds) and with conventional, spectral fat saturation (SFS, acquisition time 58 seconds). The quality of the images was rated on an ordinal 4-point scale (4, very good) by 2 radiologists in consensus. The signal-to-noise ratios (SNRs) of the vessels, the fat, and the muscles as well as the contrast-to-noise-ratio (CNR) between vessels, fat, and muscle were determined. Paired P tests were performed for statistical analysis with a significance level of P < 0.05. Diagnostic image quality was achieved in all examinations. The image quality of the DixFS images was rated superior (median 4) over the SFS images (median 3; P = 0.03). The SNR of muscles and vessels was 40% higher with DixFS (P < 0.008), whereas the SNR of fat was decreased by 40.3% from 40.7 with SFS to 22.4 with DixFS (P < 0.0001). The CNR (fat/muscle) of the DixFS images of 84.1/71.7 was significantly higher than the CNR of the SFS images of 47.7/47.4 (P < 0.001). Two-point Dixon fat suppression for MR-angiography during the steady state after the administration of gadofosveset is feasible with superior image quality and more than 50% increase in CNR (fat/muscle) compared with spectral fat saturation without an additional time penalty.


Reconstructing the lower urinary tract: The Mitrofanoff principle.
Since the original description of the trans-appendicular continent cystostomy by Mitrofanoff in 1980, a variety of techniques have been described for creating a continent catheterisable channel leading to the bladder, which avoids the native urethra. The Mitrofanoff principle involves the creation of a conduit going into a low pressure reservoir, which can emptied through clean intermittent catheterization through an easily accessible stoma. A variety of tissue segments have been used for creating the conduit, but the two popular options in current urological practice remain the appendix and Yang-Monti transverse ileal tube. The Mitrofanoff procedure has an early reoperation rate for bleeding, bowel obstruction, anastomotic leak or conduit breakdown of up to 8% and the most common long-term complication noted is stomal stenosis resulting in difficulty catheterizing the conduit. However, in both pediatric and adult setting, reports imply that the procedure is durable although it is associated with an overall re-operation rate of up to 32% in contemporary series. Initial reports of laparoscopic and robotic-assisted Mitrofanoff procedures are encouraging, but long-term outcomes are still awaited.


Teriparatide (rhPTH 1-34) for the treatment of osteoporosis.
Osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Osteoporosis develops through an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts resulting in increased bone loss. Numerous agents used for the prevention and treatment of osteoporosis slow bone loss by decreasing both bone resorption and formation. These include bisphosphonates, hormone replacement therapy, selective oestrogen receptor modulators and calcitonins. All reduce vertebral fracture risk and some reduce non-vertebral fracture risk, but none routinely increases bone mass and strength or restores lost bone architecture. In many respects, antiresorptive therapies halt the progression of osteoporosis. However, for patients who have osteoporosis, particularly those who have sustained their first fracture and are at high risk for subsequent fractures, there is a need to develop agents that stimulate bone formation and, thus, reverse osteoporosis. Teriparatide is the recombinant human 1-34 amino acid sequence of parathyroid hormone recently approved in the US for the treatment of men and postmenopausal women at high risk for osteoporotic fracture and in Europe for the treatment of postmenopausal women with osteoporosis. When given by once-daily injection, teriparatide increases bone mass by stimulating formation of new bone, resulting in the restoration of bone architecture.


Modeling the Effect of Replacing Sugar-Sweetened Beverage Consumption with Water on Energy Intake, HBI Score, and Obesity Prevalence.
Sugar-sweetened beverages (SSB) contribute to excessive weight gain through added energy intake. Replacing SSB with water is one strategy that has shown promise in helping lower excessive energy intake. Using nationally representative data from US adults (n = 19,718) from NHANES 2007-2012 we examine the impact of replacing SSB with water on Healthy Beverage Index (HBI) scores and obesity prevalence. Replacing an 8-ounce serving of SSB with water lowered the percent of energy from beverages from 17% to 11% (among those consuming 1 serving SSB/day). Reductions in the percent energy from beverages were observed across all SSB consumption groups (1-2 servings/day and >2 servings/day). Among adults there was a 9% to 21% improvement in HBI score when one serving of water replaced one serving of SSB. Using previously published randomized controlled trials (RCT) and meta-analyses of measured weight loss we also predicted a reduction in the prevalence of obesity (observed: 35.2%; predicted 33.5%-34.9%, p < 0.05) and increase in the prevalence of normal weight (observed: 29.7%; high weight loss: 31.3%, p < 0.05). Our findings provide further epidemiologic evidence that water in the place of SSB can be used as a strategy to limit energy intake and help individuals meet beverage intake recommendations.


The Impact of Interactivity on Comprehending 2D and 3D Visualizations of Movement Data.
GPS, RFID, and other technologies have made it increasingly common to track the positions of people and objects over time as they move through two-dimensional spaces. Visualizing such spatio-temporal movement data is challenging because each person or object involves three variables (two spatial variables as a function of the time variable), and simply plotting the data on a 2D geographic map can result in overplotting and occlusion that hides details. This also makes it difficult to understand correlations between space and time. Software such as GeoTime can display such data with a three-dimensional visualization, where the 3rd dimension is used for time. This allows for the disambiguation of spatially overlapping trajectories, and in theory, should make the data clearer. However, previous experimental comparisons of 2D and 3D visualizations have so far found little advantage in 3D visualizations, possibly due to the increased complexity of navigating and understanding a 3D view. We present a new controlled experimental comparison of 2D and 3D visualizations, involving commonly performed tasks that have not been tested before, and find advantages in 3D visualizations for more complex tasks. In particular, we tease out the effects of various basic interactions and find that the 2D view relies significantly on "scrubbing" the timeline, whereas the 3D view relies mainly on 3D camera navigation. Our work helps to improve understanding of 2D and 3D visualizations of spatio-temporal data, particularly with respect to interactivity.


Cardiac Mechanoperception: A Life-Long Story from Early Beats to Aging and Failure.
The life-long story of the heart starts concomitantly with primary differentiation events occurring in multipotent progenitors located in the so-called heart tube. This initially tubular structure starts a looping process, which leads to formation of the final four-chambered heart with a primary contribution of geometric and position-associated cell sensing. While this establishes the correct patterning of the final cardiac structure, it also provides feedbacks to fundamental cellular machineries controlling proliferation and differentiation, thus ensuring a coordinated restriction of cell growth and a myocyte terminal differentiation. Novel evidences provided by embryological and cell engineering studies have clarified the relevance of mechanics-supported position sensing for the correct recognition of cell fate inside developing embryos and multicellular aggregates. One of the main components of this pathway, the Hippo-dependent signal transduction machinery, is responsible for cell mechanics intracellular transduction with important consequences for gene transcription and cell growth control. Being the Hippo pathway also directly connected to stress responses and altered metabolism, it is tempting to speculate that permanent alterations of mechanosensing may account for modifying self-renewal control in tissue homeostasis. In the present contribution, we translate these concepts to the aging process and the failing of the human heart, two pathophysiologic conditions that are strongly affected by stress responses and altered metabolism.


LipidIMMS Analyzer: integrating multi-dimensional information to support lipid identification in ion mobility-mass spectrometry based lipidomics.
Ion mobility-mass spectrometry (IM-MS) has showed great application potential for lipidomics. However, IM-MS based lipidomics is significantly restricted by the available software for lipid structural identification. Here, we developed a software tool, namely, LipidIMMS Analyzer, to support the accurate identification of lipids in IM-MS. For the first time, the software incorporates a large-scale database covering over 260 000 lipids and four-dimensional structural information for each lipid [i.e. m/z, retention time (RT), collision cross-section (CCS) and MS/MS spectra]. Therefore, multi-dimensional information can be readily integrated to support lipid identifications, and significantly improve the coverage and confidence of identification. Currently, the software supports different IM-MS instruments and data acquisition approaches. The software is freely available at: http://imms.zhulab.cn/LipidIMMS/. Supplementary data are available at Bioinformatics online.


The effects of chelidonine on tubulin polymerisation, cell cycle progression and selected signal transmission pathways.
Chelidonine is a tertiary benzophenanthridine alkaloid known to cause mitotic arrest and to interact weakly with tubulin. Our interest in chelidonine began when we found it to be a major contaminant of Ukrain, which is a compound reported to be selectively toxic to malignant cells. The effects of chelidonine in two normal (monkey kidney and Hs27), two transformed (Vero and Graham 293) and two malignant (WHCO5 and HeLa) cell lines, were examined. Chelidonine proved to be a weak inhibitor of cell growth, but no evidence for selective cytotoxicity was found in this study. It was confirmed that chelidonine inhibits tubulin polymerisation (IC50 = 24 microM), explaining its ability to disrupt microtubular structure in cells. A G2/M arrest results, which is characterised by abnormal metaphase morphology, increased levels of cyclin B1 and enhanced cdc2 kinase activity. Exposure of all cell lines examined to chelidonine leads to activation of the stress-activated protein kinase/jun kinase pathway (SAPK/JNK).


Characteristics and treatment response of self-identified problematic Internet users in a behavioral addiction outpatient clinic.
Controversies remain about the validity of the diagnosis of problematic Internet use. This might be due in part to the lack of longitudinal naturalistic studies that have followed a cohort of patients who self-identify as having Internet-related problems. This retrospective study included 57 patients who consulted the Geneva Addiction Outpatient Clinic from January 1, 2007, to January 1, 2010. Patients underwent an initial clinical psychiatric evaluation that included collection of data on socio-demographics, method of referral, specific Internet usage, psychiatric diagnosis, and Internet Addiction Test (IAT) and Clinical Global Impression Scale (CGI) scores. Treatment consisted of individual psychotherapeutic sessions. Of these patients, 98% were male and 37% were 18 years or younger. Most patients were online gamers (46% playing massively multiplayer online role-playing games). The mean IAT score was 52.9 (range 20-90). Sixty-eight percent of patients had a co-morbid psychiatric diagnosis, with social phobia being the most prevalent (17.8%). Patients who remained in treatment (dropout rate 24%) showed an overall improvement of symptoms: 38.6% showed significant or average improvement on their CGI score, 26.3% showed minimal improvement, and 14% showed no change. Our results support the hypothesis that there are specific types of Internet use, with online gaming mainly affecting young male patients. As Internet addiction is not yet an official diagnosis, better instruments are needed to screen patients and to avoid false-negative and false-positive diagnoses. Successful care should integrate the treatment of co-morbid symptoms and involve families and relatives in the therapeutic process.


Effects of Bos taurus autosome 9-located quantitative trait loci haplotypes on the disease phenotypes of dairy cows with experimentally induced Escherichia coli mastitis.
Several quantitative trait loci (QTL) affecting mastitis incidence and mastitis-related traits such as somatic cell score exist in dairy cows. Previously, QTL haplotypes associated with susceptibility to Escherichia coli mastitis in Nordic Holstein-Friesian (HF) cows were identified on Bos taurus autosome 9. In the present study, we induced experimental E. coli mastitis in Danish HF cows to investigate the effect of 2 E. coli mastitis-associated QTL haplotypes on the cows' disease phenotypes and recovery in early lactation. Thirty-two cows were divided in 2 groups bearing haplotypes with either low (HL) or high (HH) susceptibility to E. coli. In addition, biopsies (liver and udder) were collected from half of the cows (n=16), resulting in a 2 × 2 factorial design, with haplotype being one factor (HL vs. HH) and biopsy being the other factor (biopsies vs. no biopsies). Each cow was inoculated with a low E. coli dose (20 to 40 cfu) in one front quarter at time 0 h. Liver biopsies were collected at -144, 12, 24, and 192 h; udder biopsies were collected at 24h and 192 h post-E. coli inoculation. The clinical parameters: feed intake, milk yield, body temperature, heart rate, respiration rate, rumen motility; and the paraclinical parameters: bacterial counts, somatic cell count (SCC), and milk amyloid A levels in milk; and white blood cell count, polymorphonuclear neutrophilic leukocyte (PMNL) count, and serum amyloid A levels in blood were recorded at different time points post-E. coli inoculation. Escherichia coli inoculation changed the clinical and paraclinical parameters in all cows except one that was not infected. Clinically, the HH group tended to have higher body temperature and heart rate than the HL group did. Paraclinically, the HL group had faster PMNL recruitment and SCC recovery than the HH group did. However, we also found interactions between the effects of haplotype and biopsy for body temperature, heart rate, and PMNL. In conclusion, when challenged with E. coli mastitis, HF cows with the specific Bos taurus autosome 9-located QTL haplotypes were associated with differences in leukocyte kinetics, with low-susceptibility cows having faster blood PMNL recruitment and SCC recovery and a tendency for a milder clinical response than the high-susceptibility cows did.


Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes.
Ketone bodies are produced by the liver and used peripherally as an energy source when glucose is not readily available. The two main ketone bodies are acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB), while acetone is the third, and least abundant, ketone body. Ketones are always present in the blood and their levels increase during fasting and prolonged exercise. They are also found in the blood of neonates and pregnant women. Diabetes is the most common pathological cause of elevated blood ketones. In diabetic ketoacidosis (DKA), high levels of ketones are produced in response to low insulin levels and high levels of counterregulatory hormones. In acute DKA, the ketone body ratio (3HB:AcAc) rises from normal (1:1) to as high as 10:1. In response to insulin therapy, 3HB levels commonly decrease long before AcAc levels. The frequently employed nitroprusside test only detects AcAc in blood and urine. This test is inconvenient, does not assess the best indicator of ketone body levels (3HB), provides only a semiquantitative assessment of ketone levels and is associated with false-positive results. Recently, inexpensive quantitative tests of 3HB levels have become available for use with small blood samples (5-25 microl). These tests offer new options for monitoring and treating diabetes and other states characterized by the abnormal metabolism of ketone bodies.


The Potential Benefits of Non-skills Training (Mental Toughness) for Elite Athletes: Coping With the Negative Psychological Effects of the COVID-19 Pandemic.
The spread of COVID-19 has had a significant impact on global sport. This is especially true at the elite level, where it has disrupted training and competition. Concomitantly, restrictions have disrupted long-term event planning. Many elite athletes remain unsure when major events will occur and worry about further interruptions. Although some athletes have successfully adapted to the demands of the COVID-19 crisis, many have experienced difficulties adjusting. This has resulted in psychological complications including increased stress, anxiety, and depression. This article critically examines the extent to which non-cognitive skills training, in the form of increased awareness of Mental Toughness, can help elite athletes inoculate against and cope with negative psychological effects arising from the COVID-19 pandemic. Non-cognitive skills encompass intrapersonal (motivations, learning strategies, and self-regulation) and interpersonal (interactions with others) domains not directly affected by intellectual capacity. Previous research indicates that enhancement of these spheres can assist performance and enhance mental well-being. Moreover, it suggests that training in the form of increased awareness of Mental Toughness, can improve the ability to cope with COVID-19 related challenges. In this context, Mental Toughness encompasses a broad set of enabling attributes (i.e., inherent and evolved values, attitudes, emotions, and cognitions). Indeed, academics commonly regard Mental Toughness as a resistance resource that protects against stress. Accordingly, this article advocates the use of the 4/6Cs model of Mental Toughness (i.e., Challenge, Commitment, Control, and Confidence) to counter negative psychological effects arising from COVID-19.