Co-enrichment of cancer-associated bacterial taxa is correlated with immune cell infiltrates in esophageal tumor tissue.

Esophageal carcinoma (ESCA) is a leading cause of cancer-related death worldwide, and certain oral and intestinal pathogens have been associated with cancer development and progression. We asked if esophageal microbiomes had shared alterations that could provide novel biomarkers for ESCA risk. We extracted DNA from tumor and non-tumor tissue of 212 patients in the NCI-MD case control study and sequenced the 16S rRNA gene (V3-4), with TCGA ESCA RNA-seq (n = 172) and WGS (n = 123) non-human reads used as validation. We identified four taxa, Campylobacter, Prevotella, Streptococcus, and Fusobacterium as highly enriched in esophageal cancer across all cohorts. Using SparCC, we discovered that Fusobacterium and Prevotella were also co-enriched across all cohorts. We then analyzed immune cell infiltration to determine if these dysbiotic taxa were associated with immune signatures. Using xCell to obtain predicted immune infiltrates, we identified a depletion of megakaryocyte-erythroid progenitor (MEP) cells in tumors with presence of any of the four taxa, along with enrichment of platelets in tumors with Campylobactor or Fusobacterium. Taken together, our results suggest that intratumoral presence of these co-occurring bacterial genera may confer tumor promoting immune alterations that allow disease progression in esophageal cancer.

Surface water temperature impacts on coastal wetland denitrification: Implications for river reconnection.

Louisiana, located in the southeast United States, is home to 40% of the continental US's coastal wetlands yet accounts for 80% of the nation's coastal wetland loss. This loss is generally attributed to decreased sediment supply, hydrologic alteration from levees, channelization, subsidence, sea-level rise, and wave and tidal induced marsh edge erosion. The Mid-Barataria Sediment Diversion is a US $1.3 billion coastal restoration project that will divert up to 2100 m3 s-1 of sediment-laden Mississippi River water directly into Barataria Basin. The influx of colder, nutrient-rich, springtime river water could negatively impact water quality of the receiving basin. We quantified the effects of colder, surface water temperature on the nitrate (NO3-) reduction rate in vegetated marsh and open water bay sediments. Colder water limited NO3- removal processes averaging 17.1 mg N m-2 d-1 in the range of 5-14 °C, before increasing almost 3-fold in the 20 °C treatments at 50.6 mg N m-2 d-1. Low N removal rates, especially near the project inflow where temperatures will be coldest will favor transport of NO3- further into Barataria Basin where eutrophic conditions could become expressed. These results will inform coastal managers around the world of the potential ecosystem response to coastal restoration aimed at river reconnection where colder waters enter warmer, shallow basins.

Are viruses associated with disc herniation? A clinical case series.

BACKGROUND: There is some limited evidence for the presence of viruses in herniated disc material including a previous case series that claimed to provide "unequivocal evidence of the presence of herpes virus DNA in intervertebral disc specimens of patients with lumbar disc herniation suggesting the potential role of herpes viruses as a contributing factor to the pathogenesis of degenerative disc disease". This study has not been replicated. The objective of our study was to determine if viruses were present in herniated disc fragments in participants with a prior history of back pain. METHODS: We recruited fifteen participants with a history of prior low-back pain prior to undergoing disc herniation surgery in the lumbar spine. Harvested disc samples were subject to next generation sequencing for detection of both RNA and DNA viral pathogens. Additionally, samples were analysed by a broadly reactive PCR targeting herpesviral DNA. Ethics approval was granted by the Human Research Ethics Committees of both Murdoch University, and St John of God Hospital, Western Australia. RESULTS: Of the fifteen research participants, 8 were female. Mean age was 49.4 years (SD 14.5 yrs) with a range of 24-70 years. All participants had prior back pain with mean time since first ever attack being 8.8 years (SD 8.8 yrs). No samples contained significant DNA sequences relating to known human viral agents. Inconsequential retroviral sequences were commonly found and were a mixture of putative animal and human retroviral protein coding segments. All samples were negative for herpesvirus DNA when analysed by pan-herpesvirus PCR. CONCLUSIONS: This study found no viral pathogens in any intervertebral disc fragments of patients who had previous back pain and underwent discectomy for disc herniation and thus it is unlikely that viruses are associated with disc herniation, however given the contradiction between key studies enhanced replication of this experiment is recommended.

Treatment of wastewater ammonium under varying salinity conditions within the marshland upwelling system.

Coastal wetlands and estuaries are impacted by nutrient loads from a variety of sources including infrequently occupied hunting and fishing camps. The marshland upwelling system (MUS) was designed to treat wastewater in the coastal environment where traditional septic systems or centralized wastewater collection and treatment are not viable. A laboratory macrocosm study was designed to simulate field conditions in which domestic wastewater is treated via injection into a marsh subsurface. Treatment of wastewater nitrogen (N) utilizing the MUS was examined under high (∼20 ppt) and low (∼2 ppt) salinity conditions. Two N wastewater solutions were used, one treatment consisted of 100 mg NH4-N L-1, while a second treatment consisted of 80 mg NH4-N L-1/20 mg NO3-N L-1. The 20 ppt salinity treatment was found to have a negative impact on NH4-N sorption. The potentially mineralizable N rate was higher in the low salinity treatment, which could potentially be offset by the higher sorption capacity at lower salinities. The background salinity of the local groundwater should be considered as the salinity will play a role in the longevity of the system.

Optimization and diagnostic evaluation of monoclonal antibody-based blocking ELISA formats for detection of neutralizing antibodies to Hendra virus in mammalian sera.

Maintenance of Hendra virus (HeV) in pteropid bat populations has been associated with spillover events in horses, humans and dogs. Experimental studies have demonstrated infections for several other species including guinea pigs, cats and ferrets. The criteria of a sensitive and specific serological test that is effective for a range of species, but which does not require use of live virus, has not been satisfactorily addressed by currently available tests. We have evaluated the use of two HeV neutralizing monoclonal antibodies (mAbs) in a blocking format enzyme-linked immunosorbent assay (bELISA) to detect serum antibody against a recombinant expressed HeV G protein (sol G) in several animal species. The human mAb m102.4 neutralises both HeV and the closely related Nipah virus (NiV); the mouse mAb 1.2 neutralises only HeV. Given these functional differences, we have investigated both antibodies using a bELISA format. Diagnostic sensitivity (DSe) and diagnostic specificity (DSp) were optimized using individual thresholds for mAb 1.2 and m102.4. For mAb 1.2 the positive threshold of >33% inhibition yielded DSe and DSp values of 100% (95% CI 95.3-100.0) and 99.5 (95% CI 98.8-99.8) respectively; for mAb m102.4 a positive threshold of >49% inhibition gave DSe and DSp values of 100 (95% CI 95.3-100.0) and 99.8 (95% CI 99.2-100.0) respectively. At these thresholds the DSe was 100% for both tests relative to the virus neutralization test. Importantly, the occurrence of false positive reactions did not overlap across the assays. Therefore, by sequential and selective application of these assays, it is possible to identify false positive reactions and achieve a DSp that approximates 100% in the test population.

Review article: novel oral-targeted therapies in inflammatory bowel disease.

BACKGROUND: There is a great unmet clinical need for efficacious, tolerable, economical and orally administrated drugs for the treatment of inflammatory bowel disease (IBD). New therapeutic avenues have become possible including the development of medications that target specific genetic pathways found to be relevant in other immune mediated diseases. AIMS: To provide an overview of recent clinical trials for new generation oral targeted medications that may have a future role in IBD management. METHODS: Pubmed and Medline searches were performed up to 1 March 2018 using keywords: "IBD", "UC", "CD", "inflammatory bowel disease" "ulcerative colitis", "Crohn's disease" in combination with "phase", "study", "trial" and "oral". A manual search of the clinical trial register, article reference lists, abstracts from meetings of Digestive Disease Week, United European Gastroenterology Week and ECCO congress were also conducted. RESULTS: In randomised controlled trials primary efficacy endpoints were met for tofacitinib (JAK 1/3 inhibitor-phase III), upadacitinib (JAK 1 inhibitor-phase II) and AJM300 (α4-integrin antagonist-phase II) in ulcerative colitis. Ozanimod (S1P receptor agonist-phase II) also demonstrated clinical remission. For Crohn's disease, filgotinib (JAK1 inhibitor-phase II) met primary endpoints and laquinimod (quinolone-3-carboxide small molecule-phase II) was also efficacious. Trials using mongersen (SMAD7 inhibitor) and vidofludimus (dihydroorotate dehydrogenase inhibitor) have been halted. CONCLUSIONS: This is potentially the start of an exciting new era in which multiple therapeutic options are at the disposal of physicians to treat IBD on an individualised basis. Head-to-head studies with existing treatments and longer term safety data are needed for this to be possible.

Comparison of a New Intranasal Naloxone Formulation to Intramuscular Naloxone: Results from Hypothesis-generating Small Clinical Studies.

Easy-to-use naloxone formulations are needed to help address the opioid overdose epidemic. The pharmacokinetics of i.v., i.m., and a new i.n. naloxone formulation (2 mg) were compared in six healthy volunteers. Relative to i.m. naloxone, geometric mean (90% confidence interval [CI]) absolute bioavailability of i.n. naloxone was modestly lower (55%; 90% CI, 43-70% vs. 41%; 90% CI, 27-62%), whereas average (±SE) mean absorption time was substantially shorter (74 ± 8.8 vs. 6.7 ± 4.9 min). The opioid-attenuating effects of i.n. naloxone were compared with i.m. naloxone (2 mg) after administration of oral alfentanil (4 mg) to a separate group of six healthy volunteers pretreated with 240 mL of water or grapefruit juice. The i.m. and i.n. naloxone attenuated miosis by similar extents after water (40 ± 15 vs. 41 ± 21 h*%) and grapefruit juice (49 ± 18 vs. 50 ± 22 h*%) pretreatment. Results merit further testing of this new naloxone formulation.

Hydrogen Isotopic Composition of Arctic and Atmospheric CH4 Determined by a Portable Near-Infrared Cavity Ring-Down Spectrometer with a Cryogenic Pre-Concentrator.

In this study, near-infrared continuous wave cavity ring-down spectroscopy was applied to the measurement of the δ2H of methane (CH4). The cavity ring-down spectrometer (CRDS) system consisted of multiple DFB laser diodes to optimize selection of spectral line pairs. By rapidly switching measurements between spectral line peaks and the baseline regions, the long-term instrumental drift was minimized, substantially increasing measurement precision. The CRDS system coupled with a cryogenic pre-concentrator measured the δ2H of terrestrial atmospheric CH4 from 3 standard liters of air with a precision of ±1.7‰. The rapidity with which both C and H isotopic measurements of CH4 can be made with the CRDS will enable hourly monitoring of diurnal variations in terrestrial atmospheric CH4 signatures that can be used to increase the resolution of global climate models for the CH4 cycle. Although the current instrument is not capable of measuring the δ2H of 10 ppbv of martian CH4, current technology does exist that could make this feasible for future spaceflight missions. As biological and abiotic CH4 sources have overlapping carbon isotope signatures, dual-element (C and H) analysis is key to reliable differentiation of these sources. Such an instrument package would therefore offer improved ability to determine whether or not the CH4 recently detected in the martian atmosphere is biogenic in origin. Key Words: Arctic-Hydrogen isotopes-Atmospheric CH4-CRDS-Laser. Astrobiology 16, 787-797.

Hendra Virus Infection Dynamics in the Grey-Headed Flying Fox (Pteropus poliocephalus) at the Southern-Most Extent of Its Range: Further Evidence This Species Does Not Readily Transmit the Virus to Horses.

Hendra virus (HeV) is an important emergent virus in Australia known to infect horses and humans in certain regions of the east coast. Whilst pteropid bats ("flying foxes") are considered the natural reservoir of HeV, which of the four mainland species is the principal reservoir has been a source of ongoing debate, particularly as shared roosting is common. To help resolve this, we sampled a colony consisting of just one of these species, the grey-headed flying fox, (Pteropus poliocephalus), at the southernmost extent of its range. Using the pooled urine sampling technique at approximately weekly intervals over a two year period, we determined the prevalence of HeV and related paramyxoviruses using a novel multiplex (Luminex) platform. Whilst all the pooled urine samples were negative for HeV nucleic acid, we successfully identified four other paramyxoviruses, including Cedar virus; a henipavirus closely related to HeV. Collection of serum from individually caught bats from the colony showed that antibodies to HeV, as estimated by a serological Luminex assay, were present in between 14.6% and 44.5% of animals. The wide range of the estimate reflects uncertainties in interpreting intermediate results. Interpreting the study in the context of HeV studies from states to the north, we add support for an arising consensus that it is the black flying fox and not the grey-headed flying fox that is the principal source of HeV in spillover events to horses.

Quantitative prediction and clinical evaluation of an unexplored herb-drug interaction mechanism in healthy volunteers.

Quantitative prediction of herb-drug interaction risk remains challenging. A quantitative framework to assess a potential interaction was used to evaluate a mechanism not previously tested in humans. The semipurified milk thistle product, silibinin, was selected as an exemplar herbal product inhibitor of raloxifene intestinal glucuronidation. Physiologically based pharmacokinetic (PBPK) model simulations of the silibinin-raloxifene interaction predicted up to 30% increases in raloxifene area under the curve (AUC0-inf) and maximal concentration (Cmax). Model-informed clinical evaluation of the silibinin-raloxifene interaction indicated minimal clinical interaction liability, with observed geometric mean raloxifene AUC0-inf and Cmax ratios lying within the predefined no effect range (0.75-1.33). Further refinement of PBPK modeling and simulation approaches will enhance confidence in predictions and facilitate generalizability to additional herb-drug combinations. This quantitative framework can be used to develop guidances to evaluate potential herb-drug interactions prospectively, providing evidenced-based information about the risk or safety of these interactions.

The cost of treatment failure: resource use and costs incurred by hepatitis C virus genotype 1-infected patients who do or do not achieve sustained virological response to therapy.

Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost-effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium-term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2 months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS 'Payment by Results' database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non-SVR) with mean follow-up of 3.5 (SVR) and 4.9 (non-SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non-SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5-year post-treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13-fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56-fold, equating to more than £10 000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real-life data for future cost-effectiveness analyses related to the treatment for chronic HCV infection.

Dapagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes.

Dapagliflozin is a selective, competitive inhibitor of sodium/glucose cotransporter 2 (SGLT2) acting to block reabsorption of filtered glucose in the kidney. Independent of pancreatic ß cell function or the modulation of insulin sensitivity, this novel treatment strategy promotes glucosuria and direct lowering of plasma glucose concentrations. Dapagliflozin has been approved for the treatment of type 2 diabetes in the European Union; however, the United States Food and Drug Administration rejected the approval of dapagliflozin based on lack of clinical data to effectively assess the benefit-to-risk profile. This manuscript will highlight the physiology of renal glucose regulation and reabsorption, briefly outline the pharmacology of dapagliflozin and discuss the results of completed clinical trials as well as the current status of the drug.

Steady-state carbamazepine pharmacokinetics following oral and stable-labeled intravenous administration in epilepsy patients: effects of race and sex.

Carbamazepine is a widely prescribed antiepileptic drug. Owing to the lack of an intravenous formulation, its absolute bioavailability, absolute clearance, and half-life in patients at steady state have not been determined. We developed an intravenous, stable-labeled (SL) formulation in order to characterize carbamazepine pharmacokinetics in patients. Ninety-two patients received a 100-mg infusion of SL-carbamazepine as part of their morning dose. Blood samples were collected up to 96 hours after drug administration. Plasma drug concentrations were measured with liquid chromatography-mass spectrometry, and concentration-time data were analyzed using a noncompartmental approach. Absolute clearance (l/hr/kg) was significantly lower in men (0.039 ± 0.017) than in women (0.049 ± 0.018; P = 0.007) and in African Americans (0.039 ± 0.017) when compared with Caucasians (0.048 ± 0.018; P = 0.019). Half-life was significantly longer in men than in women as well as in African Americans as compared with Caucasians. The absolute bioavailability was 0.78. Sex and racial differences in clearance may contribute to variable dosing requirements and clinical response.

Disruption of Abi1/Hssh3bp1 expression induces prostatic intraepithelial neoplasia in the conditional Abi1/Hssh3bp1 KO mice.

Prostate cancer is one of the leading causes of cancer-related deaths in the United States and a leading diagnosed non-skin cancer in American men. Genetic mutations underlying prostate tumorigenesis include alterations of tumor suppressor genes. We tested the tumor suppressor hypothesis for ABI1/hSSH3BP1 by searching for gene mutations in primary prostate tumors from patients, and by analyzing the consequences of prostate-specific disruption of the mouse Abi1/Hssh3bp1 ortholog. We sequenced the ABI1/hSSH3BP1 gene and identified recurring mutations in 6 out of 35 prostate tumors. Moreover, complementation and anchorage-independent growth, proliferation, cellular adhesion and xenograft assays using the LNCaP cell line, which contains a loss-of-function Abi1 mutation, and a stably expressed wild-type or mutated ABI gene, were consistent with the tumor suppressor hypothesis. To test the hypothesis further, we disrupted the gene in the mouse prostate by breeding the Abi1 floxed strain with the probasin promoter-driven Cre recombinase strain. Histopathological evaluation of mice indicated development of prostatic intraepithelial neoplasia (PIN) in Abi1/Hssh3bp1 knockout mouse as early as the eighth month, but no progression beyond PIN was observed in mice as old as 12 months. Observed decreased levels of E-cadherin, ß-catenin and WAVE2 in mouse prostate suggest abnormal cellular adhesion as the mechanism underlying PIN development owing to Abi1 disruption. Analysis of syngeneic cell lines point to the possibility that upregulation of phospho-Akt underlies the enhanced cellular proliferation phenotype of cells lacking Abi1. This study provides proof-of-concept for the hypothesis that Abi1 downregulation has a role in the development of prostate cancer.

Alogliptin for the treatment of type 2 diabetes.

The pharmacologic management of type 2 diabetes has changed dramatically in the past two decades. We have moved from a situation of only having two choices, insulin and sulfonylureas, to a position of myriad choices from 11 categories of medications (insulin, sulfonylureas, biguanides, α-glucosidase inhibitors, gliptins (dipeptidyl peptidase 4 [DPP IV] inhibitors), bromocriptine, glucagon-like peptide analogues, thiazolidinediones, glinides, amylin analogues and bile acid sequestrants. One of the most recent additions to this list are the DPP IV inhibitors commonly known as gliptins. Currently, there are four DPP IV inhibitors available in various countries-alogliptin, sitagliptin, vildagliptin and saxagliptin (1). Of these, two have been approved for clinical use in the United States: sitagliptin and saxagliptin. Additionally, linagliptin, vildagliptin and alogliptin are currently in phase III development in the United States while studies with another DPP IV inhibitor, dutogliptin, have been terminated (2). Alogliptin was approved for use in Japan under the trade name Nesina® in April 2010 (3). This manuscript will review alogliptin, its chemistry, pharmacokinetics/pharmacodynamics, drug interactions, clinical trials and its current state of FDA review. Preclinical animal data have been reviewed elsewhere and will not be outlined in this manuscript. The interested reader is referred to those recent reviews (4, 5).

Seeking a way to promote the use of constructed wetlands for domestic wastewater treatment in developing countries.

The aim of this study was to evaluate the domestic wastewater treatment efficiency as well as the survivability of commercially valuable ornamental plants in subsurface flow wetlands (SSFW) for domestic wastewater (DWW) treatment in laboratory and pilot wetland studies. The laboratory scale study included five different species (Zantedeschia aethiopica, Strelitzia reginae, Anthurium andreanum, Canna hybrids and Hemmerocallis dumortieri) that were evaluated in horizontal flow subsurface treatment cells. All the plants survived during the 6-month experimental period demonstrating high wetland nutrient treatment efficiency. In order to validate and expand these preliminary results, a pilot-scale wetland study was carried out in SSFWs under two different flow regimes (horizontal and vertical flow). Four ornamental species were tested during a 1-year period: Zantedeschia aethiopica, Strelitzia reginae, Anthurium andreanum and Agapanthus africanus. The removal efficiencies were significantly higher in the vertical subsurface-flow constructed wetlands (VFCW) for all pollutants, except for nitrate (NO(3)-N), total nitrogen (TN) and total suspended solids (TSS). These results show that it is feasible to use select non-wetland plants with high market value in SSFWs without reducing the efficiency of the wastewater treatment system, although future work should continue in order to apply this technology in a large scale. The added value of floriculture in treatment wetlands can help to promote the use of constructed wetlands (CW) for domestic wastewater treatment in developing countries where economical resources are scarce and water pollution with DWW is common.

Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case-control study.

OBJECTIVES: Zonisamide (ZNS) is an antiepileptic drug (AED) that has been associated with psychiatric adverse events (PAE) and cognitive adverse events (CAE); controlled studies evaluating these adverse events are limited. Our objectives were to 1) determine the incidence of PAE and CAE leading to the discontinuation of ZNS and 2) identify risk factors for PAE and CAE associated with the discontinuation of ZNS. METHODS: All patients exposed to ZNS at MINCEP Epilepsy Care between March 2000 and September 2008 were identified. Reasons for discontinuing ZNS were documented. Separate case-control studies were performed to identify risk factors associated with the discontinuation of ZNS due to PAE or CAE via multivariate binary logistic regression. RESULTS: A total of 544 patients were exposed to ZNS during the study period. PAE and CAE were the most frequently identified reasons for terminating ZNS therapy. The incidence of PAE severe enough to be associated with the discontinuation of ZNS was 6.9%; the incidence of CAE was 5.8%. Factors associated with termination of ZNS therapy due to PAE were past psychiatric history (p = 0.005), symptomatic generalized epilepsy (p = 0.027), and lower maximum ZNS serum concentration (mean = 17.9 mg/L vs 34.7 mg/L, p < 0.001). Independent variables associated with discontinuing ZNS due to CAE were greater number of concomitant AEDs (p = 0.011) and lower maximum ZNS serum concentration (mean = 16.6 mg/L vs 30.6 mg/L, p = 0.002). CONCLUSIONS: We have identified clinically relevant risk factors associated with the discontinuation of ZNS. Our findings support the concept that selected patients are relatively more vulnerable to CNS adverse events when exposed to ZNS.

Mississippi River flood of 2008: observations of a large freshwater diversion on physical, chemical, and biological characteristics of a shallow estuarine lake.

High nitrogen (N) loading to coastal aquatic systems can be expressed as increased algal production and subsequent low dissolved oxygen. In April, 2008, predictions for extreme flood stage for the Lower Mississippi River triggered the opening of the Bonnet Carré Spillway, a major release valve for the river. The spillway diverted approximately 8 km3 of water over one month of operation into Lake Pontchartrain with a concomitant 10000 t of NO3-N. Satellite imagery, physical, water quality, and chlorophyll a (chl a) measurements show that the Mississippi River plume mixed with < 40% of the lake during this time, and much of the nutrient load was transported to the coastal ocean. Nitrate, dissolved reactive phosphorus (P), and dissolved silica (Si) concentrations were 4.8, 5.0, and 3.2 times higher, respectively, within the river plume when compared with those of the lake water. Despite the high nutrient concentrations within the river plume, phytoplankton biomass, evidenced by chl a concentrations, was low. Much of the nutrient load appeared to bypass the lake and was transported to the coastal ocean during the opening of the diversion. The potential removal of a total of 7.6% of the N load from the Mississippi River during the one month of flood level flow may have been a contributing factor in the lower than predicted hypoxia zone off the Louisiana coast during the summer of 2008.

The short-term effects of prescribed burning on biomass removal and the release of nitrogen and phosphorus in a treatment wetland.

Nutrient removal by constructed wetlands can decline over time due to the accumulation of organic matter. A prescribed burn is one of many management strategies used to remove detritus in macrophyte-dominated systems. We quantified the short-term effects on effluent water quality and the amount of aboveground detritus removed from a prescribed burn event. Surface water outflow concentrations were approximately three times higher for P and 1.5 times higher for total Kjeldhal nitrogen (TKN) following the burn event when compared to the control. The length of time over which the fire effect was significant (P < 0.05), 3 d for TKN and up to 23 d for P fractions. Over time, the concentration of soluble reactive phosphorus (SRP) in the effluent decreased, but was compensated with increases in dissolved organic phosphorus (DOP) and particulate phosphorus (PP), such that net total P remained the same. Total aboveground biomass decreased by 68.5% as a result of the burn, however, much of the live vegetation was converted to standing dead material. These results demonstrate that a prescribed burn can significantly decrease the amount of senescent organic matter in a constructed wetland. However, short-term nutrient releases following the burn could increase effluent nutrient concentrations. Therefore, management strategies should include hydraulically isolating the burned area immediately following the burn event to prevent nutrient export.

Phenytoin half-life and clearance during maintenance therapy in adults and elderly patients with epilepsy.

BACKGROUND: Phenytoin (PHT) is widely used to treat epilepsy in elderly patients, but information on its pharmacokinetics in this population is limited. OBJECTIVE: The purpose of this study was to investigate the effects of age and sex on PHT pharmacokinetics using stable-labeled (SL) isotopes of PHT or fosphenytoin (FOS) administered IV or IM while patients remained on their oral maintenance regimen. METHODS: Subjects were patients 18 years or older with epilepsy, but otherwise healthy, on a maintenance regimen of PHT who were not taking interacting medications. Subjects were given a single injection of a 100 mg dose of SL-PHT or SL-FOS followed by their usual morning PHT dose less 100 mg. Serial blood samples were collected up to 196 hours after the SL dose. Plasma PHT and SL-PHT concentrations were measured by a gas chromatographic-mass spectrometric assay. PHT pharmacokinetics were characterized using a population-based, nonlinear, mixed-effects model. RESULTS: Sixty-three subjects completed the study, 45 of whom were 65 years or older. There was no difference between adult and elderly or men and women in PHT clearance, distribution volume, and elimination half-life. The mean elimination half-life was 40 hours. CONCLUSIONS: Healthy elderly adults appear to have the same phenytoin (PHT) pharmacokinetics as younger adults. Reduced PHT dosage requirements may be due to age-related changes in patients' sensitivity to the therapeutic and toxic effects of the drug. The prolonged elimination half-life suggests that most patients can take PHT once daily and the time to reach steady-state may extend to 2-3 weeks.