The first application of wastewater-based drug epidemiology in five South Korean cities

Illicit drug consumption in five cities in South Korea was estimated by analyzing 17 drug residues in untreated wastewater samples collected during the Christmas and New Year period of 2012-13. Only methamphetamine, amphetamine, and codeine were detected at concentrations of tens of nanograms per liter or even lower concentrations in more than 90% of the samples. Other illicit drug residues (including cocaine, methadone, and benzoylecgonine) that have been detected frequently in wastewater from other countries were not found in this study. Methamphetamine was found to be the most widely used illicit drug in South Korea, and the estimated average consumption rate was 22 mg d−1 (1000 people)−1. This rate is, for example, 2-5 times lower than the estimated average consumption rates in Hong Kong and other parts of China and 4-80 times lower than the estimated average consumption rates in cities in Western countries. It should be noted that the wastewater samples analyzed in this study were collected during a holiday season, when daily consumption of illicit drugs is often higher than on an average day. The methamphetamine usage rates were calculated for different cities in South Korea, and the usage rates in smaller cities was higher (2-4 times) than the average.

Measuring drug use patterns in Queensland through wastewater analysis

Estimating the use of illicit drugs in the general community is an important task with ramifications for law enforcement agencies, as well as health portfolios. Australia has four ongoing drug monitoring systems, including the AIC’s DUMA program, the National Drug Strategy Household Survey, the Illicit Drug Reporting System and the Ecstasy and Related Drug Reporting System. The systems vary in methods, but broadly they are reliant upon self-report data and may be subject to selection biases. The present study employed a completely different method. By chemically analysing sewerage water, the study produced daily estimates of consumption of methamphetamine, MDMA and cocaine. Samples were collected in November 2009 and November 2010 from a municipality in Queensland, with an population of over 150,000 people. Estimates were made of the average daily dose and average daily street value per 1,000 people. On the basis of estimated dose and price, the methamphetamine market appeared considerably stronger than either MDMA or cocaine. This paper explains the strengths and weaknesses of wastewater analysis. It considers the potential value of wastewater analysis in measuring net consumption of illicit drugs and the effectiveness of law enforcement agency strategies.

Adverse childhood experiences and the health of university students in eight provinces of Vietnam

Recent systematic reviews have emphasized the need for more research into the health and social impacts of adverse childhood experiences (ACEs) in the Asia-Pacific region. This cross-sectional study was conducted with 2099 young adult students in 8 medical universities throughout Vietnam. An anonymous, self-report questionnaire included the World Health Organization ACE-International Questionnaire and standardized measures of mental and physical health. Three quarters (76%) of the students reported at least one exposure to ACEs; 21% had 4 or more ACEs. The most commonly reported adversities were emotional abuse, physical abuse, and witnessing a household member being treated violently (42.3%, 39.9%, and 34.6%, respectively). Co-occurrence of ACEs had dose–response relationships with poor mental health, suicidal ideation, and low physical health–related quality of life. This first multisite study of ACEs among Vietnamese university students provided evidence that childhood adversity is common and is significantly linked with impaired health and well-being into the early adult years

Adverse weather effects on bus ridership

This study focuses on the effects of weather on daily bus ridership in Brisbane, given the dominance of buses in that city. The weather pattern of Brisbane varies by season according to its subtropical climate characteristics. Bus operation is affected by inclement weather conditions, as buses share the road system with general traffic. Moreover, bus stops generally offer little, or sometimes no, protection from adverse weather. Hence, adverse weather conditions such as rain are thought to directly impact on daily travel behaviour patterns. There has been limited Australian research on the impact of weather on daily transit ridership. This study investigates the relationship between rainy days and daily bus ridership for the period 2010 to 2012. Overall, rainfall has a negative effect, with varying impacts on different transit groups. However, this analysis confirmed a positive relationship between consecutive rainy days (rain continuing for 3 or more days). A possible explanation could be that people switch their transport mode to bus to avoid high traffic congestion and higher accident potentiality on rainy days. Also, Brisbane’s segregated busway corridor works favourably towards this mode choice. The findings of our study enhance the fundamental understanding of traveller behaviour, particularly mode-choice behaviour, under adverse weather conditions.

Single nucleotide polymorphisms in clinics: Fantasy or reality for cancer?

Single nucleotide polymorphisms (SNPs) have been classically used for dissecting various human complex disorders using candidate gene studies. During the last decade, large scale SNP analysis i.e. genome-wide association studies (GWAS) have provided an agnostic approach to identify possible genetic loci associated with heterogeneous disease such as cancer susceptibility, prognosis of survival or drug response. Further, the advent of new technologies, including microarray based genotyping as well as high throughput next generation sequencing has opened new avenues for SNPs to be used in clinical practice. It is speculated that the utility of SNPs to understand the mechanisms, biology of variable drug response and ultimately treatment individualization based on the individual’s genome composition will be indispensable in the near future. In the current review, we discuss the advantages and disadvantages of the clinical utility of genetic variants in disease risk-prediction, prognosis, clinical outcome and pharmacogenomics. The lessons and challenges for the utility of SNP based biomarkers are also discussed, including the need for additional functional validation studies.

Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes

INTRODUCTION Although the high heritability of BMD variation has long been established, few genes have been conclusively shown to affect the variation of BMD in the general population. Extreme truncate selection has been proposed as a more powerful alternative to unselected cohort designs in quantitative trait association studies. We sought to test these theoretical predictions in studies of the bone densitometry measures BMD, BMC, and femoral neck area, by investigating their association with members of the Wnt pathway, some of which have previously been shown to be associated with BMD in much larger cohorts, in a moderate-sized extreme truncate selected cohort (absolute value BMD Z-scores = 1.5-4.0; n = 344). MATERIALS AND METHODS Ninety-six tag-single nucleotide polymorphism (SNPs) lying in 13 Wnt signaling pathway genes were selected to tag common genetic variation (minor allele frequency [MAF] > 5% with an r(2) > 0.8) within 5 kb of all exons of 13 Wnt signaling pathway genes. The genes studied included LRP1, LRP5, LRP6, Wnt3a, Wnt7b, Wnt10b, SFRP1, SFRP2, DKK1, DKK2, FZD7, WISP3, and SOST. Three hundred forty-four cases with either high or low BMD were genotyped by Illumina Goldengate microarray SNP genotyping methods. Association was tested either by Cochrane-Armitage test for dichotomous variables or by linear regression for quantitative traits. RESULTS Strong association was shown with LRP5, polymorphisms of which have previously been shown to influence total hip BMD (minimum p = 0.0006). In addition, polymorphisms of the Wnt antagonist, SFRP1, were significantly associated with BMD and BMC (minimum p = 0.00042). Previously reported associations of LRP1, LRP6, and SOST with BMD were confirmed. Two other Wnt pathway genes, Wnt3a and DKK2, also showed nominal association with BMD. CONCLUSIONS This study shows that polymorphisms of multiple members of the Wnt pathway are associated with BMD variation. Furthermore, this study shows in a practical trial that study designs involving extreme truncate selection and moderate sample sizes can robustly identify genes of relevant effect sizes involved in BMD variation in the general population. This has implications for the design of future genome-wide studies of quantitative bone phenotypes relevant to osteoporosis.

Growth hormone resistance and somatomedins in children with end-stage liver disease awaiting transplantation

Background: The success of orthotopic liver transplantation as treatment for end-stage liver disease has prompted investigation of strategies to maintain or improve nutrition and growth in children awaiting transplantation, because malnutrition is an adverse prognostic factor. The purpose of this study was to evaluate the effect of recombinant human growth hormone therapy on body composition and indices of liver function in patients awaiting transplant. Methods: The study was designed as a placebo- controlled, double-blind, crossover trial. Patients received 0.2 U/kg growth hormone, subcutaneously, or placebo daily for 28 days during two treatment periods, separated by a 2-week washout period. Ten patients (mean age, 3.06 ± 1.15 years; range, 0.51-11.65 years, five men), with extrahepatic biliary atresia (n = 8) or two with Alagille's syndrome (n = 2), with end-stage liver disease, completed the trial while awaiting orthotopic liver transplantation. Height, weight, total body potassium, total body fat, resting energy expenditure, respiratory quotient, hematologic and multiple biochemical profile, number of albumin infusions, insulin-like growth factor-1 and 1, growth hormone binding protein (GHBP), and insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein (IGFBP-3) were measured at the beginning and end of each treatment period. Results: Growth hormone treatment was associated with a significant decline in serum bilirubin (-34.6 ± 16.5 μmol/l vs. 18.2 ± 11.59 μmol/l; p < 0.02) but there was no significant effect on any anthropometric or body composition measurements, or on any biochemical or hematologic parameters. Conclusions: These children with end-stage liver disease displayed growth hormone resistance, particularly in relation to the somatomedin axis. Exogenous growth hormone administration may be of limited value in these patients

Bridged systems via radical cyclization reactions. Stereospecific synthesis of chiral tricyclo[6.2.1.0(1,5)]undecanes

The application of radical-mediated cyclizations and annulations in organic synthesis has grown in importance steadily over the years to reach the present status where they are now routinely used in the strategy-level planning.2 The presence of a quaternary carbon atom is frequently encountered in terpenoid natural products, and it often creates a synthetic challenge when two or more quaternary carbon atoms are present in a contiguous manner.3 Even though creation of a quaternary carbon atom by employing a tertiary radical is very facile, creation of a quaternary carbon atom (or a spiro carbon atom) via radical addition onto a fully substituted olefinic carbon atom is not that common but of synthetic importance. For example, the primary radical derived from the bromide 1 failed to cyclize to generate the two vicinal quaternary carbon atoms and resulted in only the reduced product 2.4 The tricyclic carbon framework tricyclo[6.2.1.01,5]undecane (3) is present in a number of sesquiterpenoids e.g. zizzanes, prelacinanes, etc.5

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Developing novel drugs against the unicellular parasite Plasmodium is complicated by the paucity of simple screening systems. Heat-shock proteins are an essential class of proteins for the parasite's cyclical life style between different cellular milieus and temperatures. The molecular chaperone Hsp90 assists a large variety of proteins, but its supporting functions for many proteins that are important for cancer have made it into a well-studied drug target. With a better understanding of the differences between Hsp90 of the malarial parasite and Hsp90 of its human host, new therapeutic options might become available. We have generated a set of isogenic strains of the budding yeast Saccharomyces cerevisiae where the essential yeast Hsp90 proteins have been replaced with either of the two human cytosolic isoforms Hsp90 alpha or Hsp90 beta, or with Hsp90 from Plasmodium falciparum (Pf). All strains express large amounts of the Flag-tagged Hsp90 proteins and are viable. Even though the strain with Pf Hsp90 grows more poorly, it provides a tool to reconstitute additional aspects of the parasite Hsp90 complex and its interactions with substrates in yeast as a living test tube. Upon exposure of the set of Hsp90 test strains to the two Hsp90 inhibitors radicicol (Rd) and geldanamycin (GA), we found that the strain with Pf Hsp90 is relatively more sensitive to GA than to Rd compared to the strains with human Hsp90's. This indicates that this set of yeast strains could be used to screen for new Pf Hsp90 inhibitors with a wider therapeutic window.

Is there such a thing as a love drug?

This paper considers recent discussion of the possible use of ‘love drugs’ and ‘anti-love drugs’ as a way of enhancing or diminishing romantic relationships. The primary focus is on the question of whether the idea of using such products commits its proponents to an excessively reductionist conception of love, and on whether the resulting ‘love’ in the use of ‘love drugs’ would be authentic, to the extent that it would be brought about artificially.

Characterization of Ion-Exchange Fibers for Controlled Drug Delivery

Increasing attention has been focused on methods that deliver pharmacologically active compounds (e.g. drugs, peptides and proteins) in a controlled fashion, so that constant, sustained, site-specific or pulsatile action can be attained. Ion-exchange resins have been widely studied in medical and pharmaceutical applications, including controlled drug delivery, leading to commercialisation of some resin based formulations. Ion-exchangers provide an efficient means to adjust and control drug delivery, as the electrostatic interactions enable precise control of the ion-exchange process and, thus, a more uniform and accurate control of drug release compared to systems that are based only on physical interactions. Unlike the resins, only few studies have been reported on ion-exchange fibers in drug delivery. However, the ion-exchange fibers have many advantageous properties compared to the conventional ion-exchange resins, such as more efficient compound loading into and release from the ion-exchanger, easier incorporation of drug-sized compounds, enhanced control of the ion-exchange process, better mechanical, chemical and thermal stability, and good formulation properties, which make the fibers attractive materials for controlled drug delivery systems. In this study, the factors affecting the nature and strength of the binding/loading of drug-sized model compounds into the ion-exchange fibers was evaluated comprehensively and, moreover, the controllability of subsequent drug release/delivery from the fibers was assessed by modifying the conditions of external solutions. Also the feasibility of ion-exchange fibers for simultaneous delivery of two drugs in combination was studied by dual loading. Donnan theory and theoretical modelling were applied to gain mechanistic understanding on these factors. The experimental results imply that incorporation of model compounds into the ion-exchange fibers was attained mainly as a result of ionic bonding, with additional contribution of non-specific interactions. Increasing the ion-exchange capacity of the fiber or decreasing the valence of loaded compounds increased the molar loading, while more efficient release of the compounds was observed consistently at conditions where the valence or concentration of the extracting counter-ion was increased. Donnan theory was capable of fully interpreting the ion-exchange equilibria and the theoretical modelling supported precisely the experimental observations. The physico-chemical characteristics (lipophilicity, hydrogen bonding ability) of the model compounds and the framework of the fibrous ion-exchanger influenced the affinity of the drugs towards the fibers and may, thus, affect both drug loading and release. It was concluded that precisely controlled drug delivery may be tailored for each compound, in particularly, by choosing a suitable ion-exchange fiber and optimizing the delivery system to take into account the external conditions, also when delivering two drugs simultaneously.

Synthesis and Reactions of Binuclear Diolefin Rhodium(I) Compounds bridged by Nitrogen Heterocycles, Crystal Structure of Dichloro-Di-1,5-Cyclooctadiene(Mu-Pyrazine)-Dirhodium(I) [[Rh(1,5-C8h12)Cl]2(Mu-C4h4n2)]

Binuclear complexes of rhodium(I) of the type [(dien)(X)Rh(μ-N-N)Rh(X)(dien)] (dien = 1,5-cyclooctadiene or norbornadiene; N-N = pyrazine, 4,4′-bipyridine or Phenazine and X = Cl or Br) with bridging heterocycles have been isolated and their reactions with carbon monoxide, 2,2′-bipyridine and 1,10-phenanthroline investigated. The crystal structure of [(COD)(Cl)Rh(μ-pyrazine)Rh(Cl)(COD)] has been determined.

Kinetic analysis of nitroxide radical coupling reactions mediated by CuBr

In a previous paper, we described the room temperature rapid, selective, reversible, and near quantitative Cu-activated nitroxide radical coupling (NRC) technique to prepare 3-arm polystyrene stars. In this work, we evaluated the Cu-activation mechanism, either conventional atom transfer or single electron transfer (SET), through kinetic simulations. Simulation data showed that one can describe the system by either activation mechanism. We also found through simulations that bimolecular radical termination, regardless of activation mechanism, was extremely low and could be considered negligible in an NRC reaction. Experiments were carried out to form 2- and 3-arm PSTY stars using two ligands, PMDETA and Me6TREN, in a range of solvent conditions by varying the ratio of DMSO to toluene, and over a wide temperature range. The rate of 2- or 3-arm star formation was governed by the choice of solvent and ligand. The combination of Me6TREN and toluene/DMSO showed a relatively temperature independent rate, and remarkably reached near quantitative yields for 2-arm star formation after only 1 min at 25 °C.

Studies of Phosphazenes. Part 13.' Thermal Rearrangement Reactions of Some Met hoxycyclo phosp hazenes

The methoxycyclophosphazenes [NP(OMe),], (n = 3-6) rearrange on heating to give oxocyclophosphazanes, [N(Me)PO(OMe)],. Isomeric products are formed when n = 4-6. The lH, ,lP, and 13C n.m.r. data for the starting materials and the products are presented. The ethoxy- and n-propoxy-derivatives N,P,( OR)* do not undergo the above rearrangement. The geminal derivatives N,P,R,(OMe), (R = Ph or NHBut) on heating yield both fully and partially rearranged products, namely dioxophosphaz-1 -enes and oxophosphazadienes, as shown by 270- MHz lH n.m.r. spectroscopy. The non-geminal derivative N,P,( NMe,),(OMe), gives only the fully rearranged product N,Me,P,(NMe,),O,(OMe), whose structure has been established from its lH and 31P n.m.r. spectra.

Preparation of Hexafluorodisilane and Reactions of Hexafluorodisilane and Hexachlorodisilane with Sulfur Trioxide

Hexafluorodisilane has been prepared by the fluorination of hexachlorodisilane or hexabromodisilane by potassium fluoride in boiling acetonitrile, in yields approximating 45 and 60% respectively. Hexafluorodisilane has been characterised by infrared spectral data, vapour density measurements and analytical data. Both hexafluorodisilane and hexachlorodisilane are found to react with sulfur trioxide when heated to 400°C for 12 h. The products of reaction are silicon tetrafluoride, silica and sulfur dioxide with hexafluorodisilane while hexachlorodisilane in addition gives rise to hexachlorodisiloxane.