Standardised survey method for identifying catchment risks to water quality.

This paper describes the development and application of a systematic methodology to identify and quantify risks in drinking water and recreational catchments. The methodology assesses microbial and chemical contaminants from both diffuse and point sources within a catchment using Escherichia coli, protozoan pathogens and chemicals (including fuel and pesticides) as index contaminants. Hazard source information is gathered by a defined sanitary survey process involving use of a software tool which groups hazards into six types: sewage infrastructure, on-site sewage systems, industrial, stormwater, agriculture and recreational sites. The survey estimates the likelihood of the site affecting catchment water quality, and the potential consequences, enabling the calculation of risk for individual sites. These risks are integrated to calculate a cumulative risk for each sub-catchment and the whole catchment. The cumulative risks process accounts for the proportion of potential input sources surveyed and for transfer of contaminants from upstream to downstream sub-catchments. The output risk matrices show the relative risk sources for each of the index contaminants, highlighting those with the greatest impact on water quality at a sub-catchment and catchment level. Verification of the sanitary survey assessments and prioritisation is achieved by comparison with water quality data and microbial source tracking.

Long-term clinical and functional outcome following treatment for Paget-Schroetter syndrome.

BACKGROUND: Effort-related thrombosis of the axillosubclavian vein (Paget-Schroetter syndrome, PSS) is uncommon. It tends to affect young, active individuals and yet consensus on management is lacking. The aim here was to analyse late outcomes in a series of patients treated for PSS using a standard protocol. METHODS: The medical records of patients treated for PSS over 16 years were analysed. Patients were divided into four groups according to their management. Clinical and functional outcomes were analysed regarding residual venous defects after treatment, and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scores, respectively. RESULTS: Some 117 patients (52 men and 65 women, mean age 32 years) were included. Catheter-directed thrombolysis was successful in 42 of 56 treated patients. Thoracic outlet decompression surgery was performed in 95 patients. DASH scores improved significantly in patients treated surgically (P < 0.001 to P = 0·009); early surgery had a better outcome than delayed surgery (P = 0·040). Patients who were managed conservatively showed no improvement (P = 0·116). Where venoplasty was necessary, it was successful in 18 of 25 patients. A short duration of lysis (less than 24 h) increased the risk of rethrombosis (P = 0·020). The method of postoperative anticoagulation had no influence on the rate of rethrombosis. CONCLUSION: Patients treated surgically for PSS had better functional outcomes than those managed conservatively. Prompt thrombolysis and surgery was superior to delayed management with respect to rethrombosis and functional outcome.

Modelling skin penetration using the Laplace transform technique.

The Laplace transform is a convenient mathematical tool for solving ordinary and partial differential equations. The application of this technique to problems arising in drug penetration through the skin is reviewed in this paper.

Assessment of the lateral diffusion and penetration of topically applied drugs in humans using a novel concentric tape stripping design.

PURPOSE: To determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique. METHOD: Ethanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin. RESULTS: CAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3 mins ranged between 83.0 and 92.9 % and decreased to between 64.5 and 66.9 % at 3 h. IBU recovery further decreased to 47.7 ± 5.6 % at 6 h, correlating with greater in vitro penetration relative to CAF and HC. CONCLUSION: Drug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time.

Predicting skin penetration of actives from complex cosmetic formulations: an evaluation of inter formulation and inter active effects during formulation optimization for transdermal delivery.

Twenty products, containing a radiolabelled form of each active in typical cosmetic formulations, were made and applied to female human epidermal membranes mounted in Franz diffusion cells for 48 h under 'in use' conditions. The products consisted of combinations of five formulations (a hydro-alcoholic gel, an oil in water emulsion, a water in oil emulsion, a microemulsion and an oil) with four model drug actives (testosterone, hydrocortisone, 5-fluorouracil and ketoconazole). Steady-state flux appeared to be reached by 8 h and maintained for all products, other than for the microemulsions, consistent with the actives being present in the residual formulation on the skin at saturation. The recovery for each active at the end of the 48-h study (from a series of stratum corneum tape strips, the remaining skin, cumulative amount penetrating into the receptor solution, product washed from the skin and on the donor chamber cap) ranged from 86.5% to 100.6%. The rank order of the fluxes for the actives from the hydro-alcoholic gel is consistent with the known active molecular size and polarity determinants for maximum epidermal flux. Actives with similar steady-state (maximum) fluxes from a range of formulations had retention in the stratum corneum and similar transport rate constants through the stratum corneum. The microemulsion formulation significantly enhanced both the stratum corneum steady-state flux and transport rate constant for 5-fluorouracil, hydrocortisone and testosterone. The penetration flux of each active could be related to its size and polarity and appeared maximal when the actives in the different cosmetic formulations applied to the skin under 'in use' conditions were likely to remain in the residual product on the skin as a saturated solution after solvent evaporation. Enhanced penetration fluxes can be achieved by formulation selection and an appropriate choice/mix of emollients/adjuvants. The principles described here provide a framework for understanding the delivery of cosmetic ingredients from various formulations.

The history of a transdermal product: From innovation to generic.

The development, registration and successful launch of a novel, innovative transdermal pharmaceutical product requires an idea, structured planning and a highly skilled, specialist team. It is not often that the opportunity arises to document this activity. This paper demonstrates the multidisciplinary effort required to take such a product (Axiron®, a transdermal testosterone product) from innovation to market and also describes its ultimate fate after the generic drug industry took an interest in its commercial success. Although many understand various aspects of this drug development process this understanding is often, by necessity, limited to the specialities of each of the individuals involved. It is hoped that this paper will provide an interesting overview of the entire process from beginning (innovation) to end (genericization).

Predictions of biodiversity response to genetically modified herbicide-tolerant crops.

We simulated the effects of the introduction of genetically modified herbicide-tolerant (GMHT) crops on weed populations and the consequences for seed-eating birds. We predict that weed populations might be reduced to low levels or practically eradicated, depending on the exact form of management. Consequent effects on the local use of fields by birds might be severe, because such reductions represent a major loss of food resources. The regional impacts of GMHT crops are shown to depend on whether the adoption of GMHT crops by farmers covaries with current weed levels.

One hundred questions of importance to the conservation of global biological diversity.

We identified 100 scientific questions that, if answered, would have the greatest impact on conservation practice and policy. Representatives from 21 international organizations, regional sections and working groups of the Society for Conservation Biology, and 12 academics, from all continents except Antarctica, compiled 2291 questions of relevance to conservation of biological diversity worldwide. The questions were gathered from 761 individuals through workshops, email requests, and discussions. Voting by email to short-list questions, followed by a 2-day workshop, was used to derive the final list of 100 questions. Most of the final questions were derived through a process of modification and combination as the workshop progressed. The questions are divided into 12 sections: ecosystem functions and services, climate change, technological change, protected areas, ecosystem management and restoration, terrestrial ecosystems, marine ecosystems, freshwater ecosystems, species management, organizational systems and processes, societal context and change, and impacts of conservation interventions. We anticipate that these questions will help identify new directions for researchers and assist funders in directing funds.

Audit of the use of IVC filters in the UK: experience from three centres over 12 years.

AIM: To audit the use of inferior vena cava (IVC) filter insertions at three UK centres over 12 years to assess whether trends in filter use in the UK mirrored those seen elsewhere. MATERIALS AND METHODS: Radiology department databases were interrogated for IVC filter insertions and removals between 1994 and 2006. Reports for these interventions, along with prior and subsequent imaging reports, were analysed. Follow-up data were obtained when available. RESULTS: Five hundred and sixteen filters were placed with a significant year-on-year trend towards increasing use. Fifty-seven percent of filters placed were for absolute indications and 37% for relative indications. The filters were used for prophylaxis in 6% of patients in the absence of proven pulmonary embolism (PE) or deep vein thrombosis (DVT). A retrievable filter was used in 74% of cases with retrieval attempted in 40% of these and no evidence of an increasing rate of retrieval over time. A significant complication related to insertion or retrieval was encountered in 0.4 and 1% of procedures, respectively. Mean 24 h and 30 day mortalities were 1 and 8%, respectively. There was an absence of organized follow-up at all three centres. CONCLUSION: IVC filter use in the UK is increasing. The use of retrievable filters has not resulted in increased filter retrieval. Filter insertion and retrieval is associated with a low risk of significant complication, but lack of systematic follow-up limits conclusions regarding safety and efficacy.

The occurrence of antibiotics in an urban watershed: from wastewater to drinking water.

The presence of 28 antibiotics in three hospital effluents, five wastewater treatment plants (WWTPs), six rivers and a drinking water storage catchment were investigated within watersheds of South-East Queensland, Australia. All antibiotics were detected at least once, with the exception of the polypeptide bacitracin which was not detected at all. Antibiotics were found in hospital effluent ranging from 0.01-14.5 microg L(-1), dominated by the beta-lactam, quinolone and sulphonamide groups. Antibiotics were found in WWTP influent up to 64 microg L(-1), dominated by the beta-lactam, quinolone and sulphonamide groups. Investigated WWTPs were highly effective in removing antibiotics from the water phase, with an average removal rate of greater than 80% for all targeted antibiotics. However, antibiotics were still detected in WWTP effluents in the low ng L(-1) range up to a maximum of 3.4 microg L(-1), with the macrolide, quinolone and sulphonamide antibiotics most prevalent. Similarly, antibiotics were detected quite frequently in the low ng L(-1) range, up to 2 microg L(-1) in the surface waters of six investigated rivers including freshwater, estuarine and marine samples. The total investigated antibiotic concentration (TIAC) within the Nerang River was significantly lower (p<0.05) than all other rivers sampled. The absence of WWTP discharge to this river is a likely explanation for the significantly lower TIAC and suggests that WWTP discharges are a dominant source of antibiotics to investigated surface waters. A significant difference (p<0.001) was identified between TIACs at surface water sites with WWTP discharge compared to sites with no WWTP discharge, providing further evidence that WWTPs are an important source of antibiotics to streams. Despite the presence of antibiotics in surface waters used for drinking water extraction, no targeted antibiotics were detected in any drinking water samples.

Navigating transdermal diffusion with multiphoton fluorescence lifetime imaging.

We demonstrate the potential of fluorescence lifetime imaging by time-correlated single-photon counting as a method for monitoring the transdermal diffusion pathway and diffusion rate of pharmaceuticals in human skin. The current application relies on observing subtle changes in the fluorescence lifetime of the intrinsic fluorophores present in the intracellular region between corneocytes of the stratum corneum. We have comprehensively characterized the measured fluorescence lifetimes from intracorneocyte junctions in three skin section types (dermatomed skin, epidermal membranes and stratum corneum) revealing statistically significant differences of the short lifetime component between each of the types, which we attribute to the sample preparation and imaging method. We show using epidermal membrane sections that application of a drug/solvent formulation consisting of ethinyl estradiol and spectroscopic grade ethanol to the surface gives rise to a slight but statistically significant shortening of the fluorescence lifetime of the long-lived emitting species present in the sample, from approximately 2.8 ns to 2.5 ns. The method may be useful for future studies where the kinetics and pathways of a variety of applied formulations could be investigated.

Embolization of renal angiomyolipoma: immediate complications and long-term outcomes.

AIMS: To report the outcomes of elective and emergency embolization of renal angiomyolipoma and describe an angiographic sign that will help localize the symptomatic aneurysm in emergency cases. MATERIALS AND METHODS: A retrospective review of all patients undergoing embolization of renal angiomyolipoma at a two centres between 1998-2007. Indications for treatment and angiographic images were reviewed. Incidence of acute rupture during embolization was noted. RESULTS: Seventeen patients underwent 23 episodes of embolization using polyvinyl alcohol (PVA) particles, bead block, and coils. Thirteen were elective procedures for large or symptomatic angiomyolipoma and 10 were acute procedures for patients presenting with retroperitoneal haemorrhage. Patients presenting acutely with haemorrhage tended to have extensive multifocal renal involvement. Active bleeding on diagnostic angiography was seen in a single patient who presented with retroperitoneal haemorrhage 48h after elective embolization with PVA alone. Seven out of 10 (70%) of the acute cases displayed splaying of adjacent vessels due to peri-aneurysmal haematoma, known locally as the "light bulb sign". This allowed treatment to be focused on the symptomatic aneurysm. The light bulb sign was not present in any patient undergoing elective embolization. Aneurysm rupture with active extravasation occurred following embolization of the distal tumour circulation with PVA in four of 10 (40%) of the patients in the acute group and three of 13 (23%) patients in the elective group. Five patients required a subsequent embolization, three at a different site. Two patients in the elective group required repeat embolization of the target site, one for delayed haemorrhage and the other whose tumour did not shrink following the initial incomplete treatment. CONCLUSIONS: Embolization of renal angiomyolipoma produces durable results. The presence of the light bulb sign is a strong indicator of the site of haemorrhage within the kidney. We advocate using a combination of particulate material and coils, as embolization with PVA alone may predispose to acute haemorrhage occurring during or after embolization.

Application of microemulsions in dermal and transdermal drug delivery.

Microemulsions are thermodynamically stable colloidal dispersions of water and oil stabilized by a surfactant and, in many cases, also a cosurfactant. In the pharmaceutical field, microemulsions have been used as drug carriers for percutaneous, ocular, oral and parenteral administration. This review discusses some of the applications of microemulsions specifically for topical and transdermal applications. Microemulsion nomenclature and composition, with particular emphasis on choice of surfactant and cosurfactant, is discussed. Methods used to characterize microemulsions are reviewed. Microemulsion formulations for dermal and transdermal delivery of pharmaceutical agents with particular emphasis on anti-inflammatory and anaesthetic agents are critically evaluated. Finally, the issues which warrant further investigation by researchers in order to realize the full potential of the technology are discussed.

Removal of antibiotics in conventional and advanced wastewater treatment: implications for environmental discharge and wastewater recycling.

Removal of 28 human and veterinary antibiotics was assessed in a conventional (activated sludge) and advanced (microfiltration/reverse osmosis) wastewater treatment plant (WWTP) in Brisbane, Australia. The dominant antibiotics detected in wastewater influents were cephalexin (med. 4.6 microg L(-1), freq. 100%), ciprofloxacin (med. 3.8 microg L(-1), freq. 100%), cefaclor (med. 0.5 microg L(-1), freq. 100%), sulphamethoxazole (med. 0.36 microg L(-1), freq. 100%) and trimethoprim (med. 0.34 microg L(-1), freq. 100%). Results indicated that both treatment plants significantly reduced antibiotic concentrations with an average removal rate from the liquid phase of 92%. However, antibiotics were still detected in both effluents from the low-to-mid ng L(-1) range. Antibiotics detected in effluent from the activated sludge WWTP included ciprofloxacin (med. 0.6 microg L(-1), freq. 100%), sulphamethoxazole (med. 0.27 microg L(-1), freq. 100%) lincomycin (med. 0.05 microg L(-1), freq. 100%) and trimethoprim (med. 0.05 microg L(-1), freq. 100%). Antibiotics identified in microfiltration/reverse osmosis product water included naladixic acid (med. 0.045 microg L(-1), freq. 100%), enrofloxacin (med. 0.01 microg L(-1), freq. 100%), roxithromycin (med. 0.01 microg L(-1), freq. 100%), norfloxacin (med. 0.005 microg L(-1), freq. 100%), oleandomycin (med. 0.005 microg L(-1), freq. 100%), trimethoprim (med. 0.005 microg L(-1), freq. 100%), tylosin (med. 0.001 microg L(-1), freq. 100%), and lincomycin (med. 0.001 microg L(-1), freq. 66%). Certain traditional parameters, including nitrate concentration, conductivity and turbidity of the effluent were assessed as predictors of total antibiotic concentration, however only conductivity demonstrated any correlation with total antibiotic concentration (p=0.018, r=0.7). There is currently a lack of information concerning the effects of these chemicals to critically assess potential risks for environmental discharge and water recycling.

Is there a risk associated with the insect repellent DEET (N,N-diethyl-m-toluamide) commonly found in aquatic environments?

DEET (N,N-diethyl-m-toluamide) is the active ingredient of most commercial insect repellents. This compound has commonly been detected in aquatic water samples from around the world indicating that DEET is both mobile and persistent, despite earlier assumptions that DEET was unlikely to enter aquatic ecosystems. DEET's registration category does not require an ecological risk assessment, thus information on the ecological toxicity of DEET is sparse. This paper reviews the presence of DEET in aqueous samples from around the world (e.g. drinking water, streams, open seawater, groundwater and treated effluent) with reported DEET concentrations ranging from 40-3000 ng L(-1). In addition, new DEET data collected from 36 sites in coastal waterways from eastern Australia (detections ranging from 8 to 1500 ng L(-1)) are examined. A summary of new and existing toxicity data are discussed with an emphasis on preparing a preliminary risk assessment for DEET in the aquatic environment. Collated information on DEET in the aquatic environment suggests risk to aquatic biota at observed environmental concentrations is minimal. However, the information available was not sufficient to conduct a full risk assessment due to data deficiencies in source characterisation, transport mechanisms, fate, and ecotoxicity studies. These risks warrant further investigation due to the high frequency that this organic contaminant is detected in aquatic environments around the world.

Complex iliac and bilateral common femoral artery aneurysms: a novel hybrid procedure.

A 74-year-old man presented with a right common iliac artery aneurysm and bilateral common femoral artery aneurysms. These aneurysms were repaired by a hybrid procedure. A one-stage approach was chosen including an endovascular stent-graft and femoro-iliaco-femoral Y-bypass grafting. The authors describe a novel combined open and endovascular approach to repair these complex aneurysms.

Characterisation of N-terminally extended met-enkephalin Arg6Gly7Leu8 variants in the porcine upper digestive tract.

Proenkephalin A-derived peptides are known to occur in the gut, but their precise identity is uncertain. We report here the isolation of N-terminally extended forms of Met-enkephalin Arg6Gly7Leu8 from porcine upper digestive tract monitored by radioimmunoassay. A single major form was identified in pyloric antral muscle and mucosa, but in the duodenum two major forms were detected. Microsequence analysis together with immunological data revealed that the antral mucosal peptide and the most acidic duodenal peptide had identical amino-acid sequences, corresponding to a 5.3 kDa peptide terminating in Met-enkephalin Arg6Gly7Leu8. The data indicate that high-molecular-weight peptides may constitute a major proportion of gut opioid peptide immunoactivity.

Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer.

PURPOSE: The prognosis for advanced pancreatic cancer remains poor. Gastrin acts as a growth factor for pancreatic cancer. We describe the first study of the antigastrin immunogen G17DT in pancreatic cancer. Our aims were to determine the antibody response, safety, tolerability, and preliminary evidence of efficacy of G17DT in advanced pancreatic cancer. PATIENTS AND METHODS: Thirty patients with advanced pancreatic cancer were immunized with three doses of either 100 micro g or 250 micro g of G17DT. RESULTS: In the whole group, 20 (67%) of 30 patients produced an antibody response. The 250- micro g dose resulted in a significantly greater response rate of 82% compared with 46% for the 100- micro g group (P =.018). The most significant side effects, seen in three patients, were local abscess and/or fever. The median survival for the whole group from the date of the first immunization was 187 days; median survival was 217 days for the antibody responders and 121 days for the antibody nonresponders. The difference in survival between the antibody responders and nonresponders was significant (P =.0023). CONCLUSION: Patients with advanced pancreatic cancer are able to mount an adequate antibody response to G17DT. The 250- micro g dose is superior to the 100- micro g dose, and it appears to be generally well tolerated. Antibody responders demonstrate significantly greater survival than antibody nonresponders. Phase III studies are currently underway in order to determine efficacy.

Growth hormone-induced insulin resistance and its relationship to lipid availability in the rat.

The role of increased lipid availability in the generation of insulin resistance by growth hormone has not been established. We investigated this in rats infused with saline (controls) or human growth hormone (hGH) (500 micrograms x kg-1 x 24 h-1) for 5 h or 3 days. hGH infusion increased basal plasma insulin at 5 h (335 +/- 33 vs. 197 +/- 15 [controls]; P < 0.005) and at 3 days (396 +/- 34 vs. 218 +/- 14 pmol/l; P < 0.0001). Plasma nonesterified fatty acid (0.26 +/- 0.01 vs. 0.21 +/- 0.01 [controls] g/l) and liver long-chain acyl-CoA (21.2 +/- 1.9 vs. 14.1 +/- 1.1 [controls] nmol/g wet wt) were elevated at 5 h (P < 0.01 for both) but were below control levels after 3 days of hGH infusion (P < 0.01 for both); indirect calorimetry after 3 days demonstrated decreased lipid oxidation. Clamp studies showed similar degrees of peripheral insulin resistance at 5-h and 3-day hGH infusion (glucose disposal reduced by 25% versus controls). Insulin-stimulated glucose metabolic index (Rg') in red gastrocnemius muscle (red muscle) was reduced (P < 0.05 and P < 0.01) at 5 h and 3 days of hGH infusion, respectively (e.g., 5 h, 10.0 +/- 1.8 vs. 24.1 +/- 4.4 [controls] micromol x 100 g-1 x min-1), whereas insulin-mediated muscle glycogen synthesis was reduced (P < 0.03) only in rats infused with hGH for 3 days. We conclude that in the rat, hGH rapidly induces persistent peripheral insulin resistance and basal hyperinsulinemia. However, the transient nature of increased lipid mobilization suggests that it is not an important factor in the manifestation of muscle insulin resistance during prolonged hGH elevation. The persistent insulin resistance is not associated with increased lipid oxidation but is associated with hyperinsulinemia and reduced insulin-mediated muscle glycogen synthesis.