Environmental contamination of arsenic and its toxicological impact on humans

Inorganic arsenic compounds are known carcinogens. The human epidemiologic evidence of arsenic-induced skin, lung, and bladder cancers is strong. However, the evidence of arsenic carcinogenicity in animals is very limited. Lack of a suitable animal model until recent years has inhibited studies of the mechanism of arsenic carcinogenesis. The toxicity and bioavailability of arsenic depend on its solubility and chemical forms. Therefore, it is critical to be able to measure arsenic speciation accurately and reliably. However, speciation of arsenic in more complex matrices remains a real challenge. There are tens of millions of people who are being exposed to excessive levels of arsenic in the drinking water alone. The source of contamination is mainly of natural origin and the mass poisoning is occurring worldwide, particularly in developing countries. Chronic arsenicosis resulting in cancer and non-cancer diseases will impact significantly on the public health systems in their respective countries. Effective watershed management and remediation technologies in addition to medical treatment are urgently needed in order to avoid what has been regarded as the largest calamity of chemical poisoning in the world.

Relationships of tacrolimus pharmacokinetic measures and adverse outcomes in stable adult liver transplant recipients

Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration-time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients. The associations between tacrolimus trough concentrations (C-0), non-trough concentrations (C-1, C-2, C-4, C-6/8), and AUC(0-12) and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients. The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C-0, C-1, C-2, C-4, C-6/8 or AUC(0-12) and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects. Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range.

Referral patterns in a global store-and-forward telemedicine system

We examined the nature of the referral patterns in the email telemedicine network operated by the Swinfen Charitable Trust with a view to informing long-term resource planning. Over the first six years of operation, 62 hospitals from 19 countries registered with the Trust in order to be able to refer cases for specialist advice; 55 of these hospitals (89%) actually referred cases during this period. During the first six years of operation, nearly 1000 referrals were submitted and answered, from a wide range of specialty areas. Between July 2002 and March 2005 the referral rate rose from 127 to 318 cases per year. The median length of time required to provide a specialist's response was 2.3 days during the first 12 months and 1.8 days during the last 12 months. Five hospitals submitted cases for more than four years (together sending a total of 493 cases). Their activity data showed a trend to declining referral rates over the four-year period, which may represent successful knowledge transfer. There is some evidence that over the last three years the growth in demand has been exponential, while the growth in resources available (i.e. specialists) has been linear, a situation which cannot continue for very long before demand outstrips supply.

Protein adduct species in muscle and liver of rats following acute ethanol administration

Aims: Previous immunohistochemical studies have shown that the post-translational formation of aldehyde-protein adducts may be an important process in the aetiology of alcohol-induced muscle disease. However, other studies have shown that in a variety of tissues, alcohol induces the formation of various other adduct species, including hybrid acetaldehyde-malondialdehyde-protein adducts and adducts with free radicals themselves, e.g. hydroxyethyl radical (HER)-protein adducts. Furthermore, acetaldehyde-protein adducts may be formed in reducing or non-reducing environments resulting in distinct molecular entities, each with unique features of stability and immunogenicity. Some in vitro studies have also suggested that unreduced adducts may be converted to reduced adducts in situ. Our objective was to test the hypothesis that in muscle a variety of different adduct species are formed after acute alcohol exposure and that unreduced adducts predominate. Methods: Rabbit polyclonal antibodies were raised against unreduced and reduced aldehydes and the HER-protein adducts. These were used to assay different adduct species in soleus (type I fibre-predominant) and plantaris (type II fibre-predominant) muscles and liver in four groups of rats administered acutely with either [A] saline (control); [B] cyanamide (an aldehyde dehydrogenase inhibitor); [C] ethanol; [D] cyanamide+ethanol. Results: Amounts of unreduced acetaldehyde and malondialdehyde adducts were increased in both muscles of alcohol-dosed rats. However there was no increase in the amounts of reduced acetaldehyde adducts, as detected by both the rabbit polyclonal antibody and the RT1.1 mouse monoclonal antibody. Furthermore, there was no detectable increase in malondialdehyde-acetaldehyde and HER-protein adducts. Similar results were obtained in the liver. Conclusions: Adducts formed in skeletal muscle and liver of rats exposed acutely to ethanol are mainly unreduced acetaldehyde and malondialdehyde species.

Aquatic passive sampling of herbicides on naked particle loaded membranes: Accelerated measurement and empirical estimation of kinetic parameters

Water-sampler equilibrium partitioning coefficients and aqueous boundary layer mass transfer coefficients for atrazine, diuron, hexazionone and fluometuron onto C18 and SDB-RPS Empore disk-based aquatic passive samplers have been determined experimentally under a laminar flow regime (Re = 5400). The method involved accelerating the time to equilibrium of the samplers by exposing them to three water concentrations, decreasing stepwise to 50% and then 25% of the original concentration. Assuming first-order Fickian kinetics across a rate-limiting aqueous boundary layer, both parameters are determined computationally by unconstrained nonlinear optimization. In addition, a method of estimation of mass transfer coefficients-therefore sampling rates-using the dimensionless Sherwood correlation developed for laminar flow over a flat plate is applied. For each of the herbicides, this correlation is validated to within 40% of the experimental data. The study demonstrates that for trace concentrations (sub 0.1 mu g/L) and these flow conditions, a naked Empore disk performs well as an integrative sampler over short deployments (up to 7 days) for the range of polar herbicides investigated. The SDB-RPS disk allows a longer integrative period than the C18 disk due to its higher sorbent mass and/or its more polar sorbent chemistry. This work also suggests that for certain passive sampler designs, empirical estimation of sampling rates may be possible using correlations that have been available in the chemical engineering literature for some time.

Site-directed mutagenesis and kinetic studies of the West Nile virus NS3 protease identify key enzyme-substrate interactions

The flavivirus West Nile virus (WNV) has spread rapidly throughout the world in recent years causing fever, meningitis, encephalitis, and fatalities. Because the viral protease NS2B/NS3 is essential for replication, it is attracting attention as a potential therapeutic target, although there are currently no antiviral inhibitors for any flavivirus. This paper focuses on elucidating interactions between a hexapeptide substrate (Ae-KPGLKR-p-nitroanilide) and residues at S1 and S2 in the active site of WNV protease by comparing the catalytic activities of selected mutant recombinant proteases in vitro. Homology modeling enabled the predictions of key mutations in VWNV NS3 protease at S1 (V115A/F, D129A/ E/N, S135A, Y150A/F, S160A, and S163A) and S2 (N152A) that might influence substrate recognition and catalytic efficiency. Key conclusions are that the substrate P1 Arg strongly interacts with S1 residues Asp-129, Tyr-150, and Ser-163 and, to a lesser extent, Ser-160, and P2 Lys makes an essential interaction with Asn-152 at S2. The inferred substrate-enzyme interactions provide a basis for rational protease inhibitor design and optimization. High sequence conservation within flavivirus proteases means that this study may also be relevant to design of protease inhibitors for other flavivirus proteases.

Assessing moth migration and population structuring in Helicoverpa annigera (Lepidoptera : Noctuidae) at the regional scale: Example from the Darling Downs, Australia

Analysis of gene flow and migration of Helicoverpa armigera (Hubner) in a major cropping region of Australia identified substantial genetic structuring, migration events, and significant population genotype changes over the 38-mo sample period from November 1999 to January 2003. Five highly variable microsatellite markers were used to analyze 916 individuals from 77 collections across 10 localities in the Darling Downs. The molecular data indicate that in some years (e.g., April 2002-March 2003), low levels of H. armigera migration and high differentiation between populations occurred, whereas in other years (e.g., April 2001-March 2002), there were higher levels of adult moth movement resulting in little local structuring of populations. Analysis of populations in other Australian cropping regions provided insight into the quantity and direction of immigration of H. armigera adults into the Darling Downs growing region of Australia. These data provide evidence adult moth movement differs from season to season, highlighting the importance of studies in groups such as the Lepidoptera extending over consecutive years, because short-term sampling may be misleading when population dynamics and migration change so significantly. This research demonstrates the importance of maintaining a coordinated insecticide resistance management strategy, because in some years H. armigera populations may be independent within a region and thus significantly influenced by local management practices; however, periods with high migration will occur and resistance may rapidly spread.

Renal structural and functional repair in a mouse model of reversal of ureteral obstruction

The end point of immune and nonimmune renal injury typically involves glomerular and tubulointerstitial fibrosis. Although numerous studies have focused on the events that lead to renal fibrosis, less is known about the mechanisms that promote cellular repair and tissue remodeling. Described is a model of renal injury and repair after the reversal of unilateral ureteral obstruction (UUO) in male C57b1/6J mice. Male mice (20 to 25 g) underwent 10 d of UUO with or without 1, 2, 4, or 6 wk of reversal of UUO (R-UUO). UUO resulted in cortical tubular cell atrophy and tubular dilation in conjunction with an almost complete ablation of the outer medulla. This was associated with interstitial macrophage infiltration; increased hydroxyproline content; and upregulated type I, III, IV, and V collagen expression. The volume density of kidney occupied by renal tubules that exhibited a brush border was measured as an assessment of the degree of repair after R-UUO. After 6 wk of R-UUO, there was an increase in the area of kidney occupied by repaired tubules (83.7 +/- 5.9%), compared with 10 d UUO kidneys (32.6 +/- 7.3%). This coincided with reduced macrophage numbers, decreased hydroxyproline content, and reduced collagen accumulation and interstitial matrix expansion, compared with obstructed kidneys from UUO mice. GFR in the 6-wk R-UUO kidneys was restored to 43 to 88% of the GFR in the contralateral unobstructed kidneys. This study describes the regenerative potential of the kidney after the established interstitial matrix expansion and medullary ablation associated with UUO in the adult mouse.

New concepts for distinguishing the hidden patterns of linkage disequilibrium which underlie association between genotypes and complex phenotypes

A disappointing feature of conventional methods for detecting association between DNA variation and a phenotype of interest is that they tell us little about the hidden pattern of linkage disequilibrium (LD) with the functional variant that is actually responsible for the association. This limitation applies to case-control studies and also to the transmission/disequilibrium test (TDT) and other family-based association methods. Here we present a fresh perspective on genetic association based on two novel concepts called 'LD squares' and 'equi-risk alleles'. These describe and characterize the different patterns of gametic LD which underlie genetic association. These concepts lead to a general principle - the Equi-Risk Allele Segregation Principle - which captures the way in which underlying LD patterns affect the transmission patterns of genetic variants associated with a phenotype. This provides a basis for distinguishing the hidden LD patterns and might help to locate the functional variants responsible for the association.