Long-Term Persistence of an Anxiolytic Drug (Oxazepam) in a Large Freshwater Lake.

Production and human consumption of pharmaceuticals result in contamination of surface waters worldwide. Little is known about the long-term (i.e., over decades) fate of pharmaceuticals in aquatic systems. Here, we show that the most prescribed anxiolytic in Sweden (oxazepam) persists in its therapeutic form for several decades after being deposited in a large freshwater lake. By comparing sediment cores collected in 1995 and 2013, we demonstrate that oxazepam inputs from the early 1970s remained in the sediments until sampling in 2013, despite in situ degradation processes and sediment diagenesis. In laboratory and pond experiments, we further reveal that therapeutic forms of oxazepam can persist over several months in cold (5 °C) lake water free from UV light. We conclude that oxazepam can persist in lakes over a time scale much longer than previously realized and that levels can build up in lakes due to both a legacy of past inputs and a growing urban population.

Lake eutrophication and its implications for organic carbon sequestration in Europe.

The eutrophication of lowland lakes in Europe by excess nitrogen (N) and phosphorus (P) is severe because of the long history of land-cover change and agricultural intensification. The ecological and socio-economic effects of eutrophication are well understood but its effect on organic carbon (OC) sequestration by lakes and its change overtime has not been determined. Here, we compile data from ~90 culturally impacted European lakes [~60% are eutrophic, Total P (TP) >30 µg P l(-1) ] and determine the extent to which OC burial rates have increased over the past 100-150 years. The average focussing corrected, OC accumulation rate (C ARFC ) for the period 1950-1990 was ~60 g C m(-2) yr(-1) , and for lakes with >100 µg TP l(-1) the average was ~100 g C m(-2) yr(-1) . The ratio of post-1950 to 1900-1950 C AR is low (~1.5) indicating that C accumulation rates have been high throughout the 20th century. Compared to background estimates of OC burial (~5-10 g C m(-2) yr(-1) ), contemporary rates have increased by at least four to fivefold. The statistical relationship between C ARFC and TP derived from this study (r(2) = 0.5) can be used to estimate OC burial at sites lacking estimates of sediment C-burial. The implications of eutrophication, diagenesis, lake morphometry and sediment focussing as controls of OC burial rates are considered. A conservative interpretation of the results of the this study suggests that lowland European meso- to eutrophic lakes with >30 µg TP l(-1) had OC burial rates in excess of 50 g C m(-2) yr(-1) over the past century, indicating that previous estimates of regional lake OC burial have seriously underestimated their contribution to European carbon sequestration. Enhanced OC burial by lakes is one positive side-effect of the otherwise negative impact of the anthropogenic disruption of nutrient cycles.

Land-use change, not climate, controls organic carbon burial in lakes.

Lakes are a central component of the carbon cycle, both mineralizing terrestrially derived organic matter and storing substantial amounts of organic carbon (OC) in their sediments. However, the rates and controls on OC burial by lakes remain uncertain, as do the possible effects of future global change processes. To address these issues, we derived OC burial rates in (210)Pb-dated sediment cores from 116 small Minnesota lakes that cover major climate and land-use gradients. Rates for individual lakes presently range from 7 to 127 g C m(-2) yr(-1) and have increased by up to a factor of 8 since Euro-American settlement (mean increase: 2.8×). Mean pre-disturbance OC burial rates were similar (14-22 g C m(-2) yr(-1)) across all land-cover categories (prairie, mixed deciduous and boreal forest), indicating minimal effect of the regional temperature gradient (approx. 4 °C) on background carbon burial. The relationship between modern OC burial rates and temperature was also not significant after removal of the effect of total phosphorus. Contemporary burial rates were strongly correlated with lake-water nutrients and the extent of agricultural land cover in the catchment. Increased OC burial, documented even in relatively undisturbed boreal lake ecosystems, indicates a possible role for atmospheric nitrogen deposition. Our results suggest that globally, future land-cover change, intensification of agriculture and associated nutrient loading together with atmospheric N-deposition will enhance OC sequestration by lakes.

Anthropogenic alteration of nutrient supply increases the global freshwater carbon sink.

Lakes have a disproportionate effect on the global carbon (C) cycle relative to their area, mediating C transfer from land to atmosphere, and burying organic-C in their sediments. The magnitude and temporal variability of C burial is, however, poorly constrained, and the degree to which humans have influenced lake C cycling through landscape alteration has not been systematically assessed. Here, we report global and biome specific trajectories of lake C sequestration based on 516 lakes and show that some lake C burial rates (i.e., those in tropical forest and grassland biomes) have quadrupled over the last 100 years. Global lake C-sequestration (~0.12 Pg year-1) has increased by ~72 Tg year-1 since 1900, offsetting 20% of annual CO2 freshwater emissions rising to ~30% if reservoirs are included and contributing to the residual continental C sink. Nutrient availability explains ~70% of the observed increase, while rising temperatures have a minimal effect.

Marine resource abundance drove pre-agricultural population increase in Stone Age Scandinavia.

How climate and ecology affect key cultural transformations remains debated in the context of long-term socio-cultural development because of spatially and temporally disjunct climate and archaeological records. The introduction of agriculture triggered a major population increase across Europe. However, in Southern Scandinavia it was preceded by ~500 years of sustained population growth. Here we show that this growth was driven by long-term enhanced marine production conditioned by the Holocene Thermal Maximum, a time of elevated temperature, sea level and salinity across coastal waters. We identify two periods of increased marine production across trophic levels (P1 7600-7100 and P2 6400-5900 cal. yr BP) that coincide with markedly increased mollusc collection and accumulation of shell middens, indicating greater marine resource availability. Between ~7600-5900 BP, intense exploitation of a warmer, more productive marine environment by Mesolithic hunter-gatherers drove cultural development, including maritime technological innovation, and from ca. 6400-5900 BP, underpinned a ~four-fold human population growth.

Valacyclovir for the management of herpes viral infections.

The Herpesviridae family (Types 1-8) continues to inflict considerable morbidity and social stigma upon humanity. Once infected with the herpes viruses, especially Types 1-3, they establish permanent residence within our nervous system and reactivate during periods of stress, trauma, and/or other precipitating factors. To date, there is no cure for herpes viral infections but antivirals can attenuate the symptoms and duration of episodic outbreaks. Prophylactic therapy can suppress recurrences. The first antiviral with selective activity against virus-infected cells is considered to be acyclovir. Our article will highlight the clinical indications of the current generation, valacyclovir, which is a prodrug of acyclovir. We consider valacyclovir as a second-generation antiviral, having taken into account the initial selectivity and safety profile of its progenitor, acyclovir.

The ecology of the planktonic diatom Cyclotella and its implications for global environmental change studies.

The fossil record of diatoms in lake sediments can be used to assess the effects of climate variability on lake ecosystems if ecological relationships between diatom community structure and environmental parameters are well understood. Cyclotella sensu lato taxa are a key group of diatoms that are frequently dominant members of phytoplankton communities in low- to moderate-productivity lakes. Their relative abundances have fluctuated significantly in palaeolimnological records spanning over a century in arctic, alpine, boreal and temperate lakes. This suggests that these species are sensitive to environmental change and may serve as early indicators of ecosystem effects of global change. Yet patterns of change in Cyclotella species are not synchronous or unidirectional across, or even within, regions, raising the question of how to interpret these widespread changes in diatom community structure. We suggest that the path forward in resolving seemingly disparate records is to identify clearly the autecology of Cyclotella species, notably the role of nutrients, dissolved organic carbon and light, coupled with better consideration of both the mechanisms controlling lake thermal stratification processes and the resulting effects of changing lake thermal regimes on light and nutrients. Here we begin by reviewing the literature on the resource requirements of common Cyclotella taxa, illustrating that many studies reveal the importance of light, nitrogen, phosphorus, and interactions among these resources in controlling relative abundances. We then discuss how these resource requirements can be linked to shifts in limnological processes driven by environmental change, including climate-driven change in lakewater temperature, thermal stratification and nutrient loading, as well as acidification-driven shifts in nutrients and water clarity. We examine three case studies, each involving two lakes from the same region that have disparate trends in the relative abundances of the same species, and illustrate how the mechanisms by which these species abundances are changing can be deciphered. Ultimately, changes in resource availability and water clarity are key factors leading to shifts in Cyclotella abundances. Tighter integration of the autecology of this important group of diatoms with environmental change and subsequent alterations in limnological processes will improve interpretations of palaeolimnological records, and clarify the drivers of seemingly disparate patterns in fossil records showing widespread and rapid changes across the northern hemisphere.

Activation of the insulin-signaling pathway in sciatic nerve and hippocampus of type 1 diabetic rats.

Peripheral neuropathy is a major complication associated with diabetes and central neuropathy characterized by Alzheimer's disease-like features in the brain is associated with increased dementia risk for patients with diabetes. Although glucose uptake into the cells of the nervous system is insulin-independent, contribution of impaired insulin support is clearly recognized to play a role, however not yet fully understood, in the development of neuropathy. In this study, we assessed the direct role of insulin on the peripheral nervous system (PNS) and central nervous system (CNS) of insulin-dependent type 1 diabetic rats. Fresh sciatic nerve and hippocampus from control and diabetic rats were incubated with varied ex vivo concentrations of insulin and phosphorylation levels of insulin receptor and glycogen synthase kinase-3 (GSK3ß) were assessed by Western blot analysis. Both the sciatic nerve and hippocampus from type 1 diabetic rats were highly responsive to exogenous insulin with a significantly increased phosphorylation of insulin receptor and GSK3 compared to tissues from control rats. Further, sustained in vivo insulin delivery, not sufficient to restore normal blood glucose, normalized the activation of both insulin receptor and GSK3 in both PNS and CNS tissues. These results suggest that the insulin-signaling pathway is responsive to exogenous insulin in the nervous system of insulin-deficient type 1 diabetic rats and that constant insulin delivery restore normal nerve function and may protect PNS and CNS from damage.

Intracameral anesthesia: in vitro iris and corneal uptake and washout of 1% lidocaine hydrochloride.

OBJECTIVES: To characterize the uptake, washout, and metabolism of lidocaine hydrochloride in the iris/ciliary body and cornea. METHODS: Iris/ciliary body uptake of lidocaine hydrochloride was measured by incubating human and rabbit irides in radiolabeled carbon 14-1% lidocaine hydrochloride for 2 to 60 minutes. Washout was determined by incubating the iris in 14C-1% lidocaine hydrochloride for 5 minutes and transferring the iris to a series of wells. The wells contained a common intraocular irrigating solution of essential ions, glucose, and glutathione buffered with bicarbonate (an enriched balanced salt solution [BSS PLUS]), which is similar to aqueous humor. Corneal uptake was measured by exposing the endothelial surface to 14C-1% lidocaine hydrochloride for 5 or 15 minutes. Corneal washout was performed after 5-minute exposure to 14C-1% lidocaine hydrochloride using a 2-chambered diffusion apparatus. Samples of the iris, cornea, and BSS PLUS washout solution were analyzed by high-performance liquid chromatography and liquid scintillation spectrometry. RESULTS: In vitro iris/ciliary body uptake of 14C-1% lidocaine hydrochloride follows a logarithmic curve, with 50% to 60% of maximum lidocaine hydrochloride uptake present at 5 minutes. There was no difference in uptake between human, albino rabbit, and pigmented rabbit irides. Washout of lidocaine from the iris occurs with a halflife of 8 to 9 minutes. Corneal uptake of lidocaine was greater after incubation for 15 vs. 5 minutes. The washout of lidocaine from the cornea had a half-life of 5 minutes. Results of high-performance liquid chromatography confirmed that there were no metabolites or breakdown products in the iris, cornea, or washout solution. CONCLUSIONS: Lidocaine is taken up quickly by the iris/ ciliary body and cornea and rapidly removed from these tissues after BSS PLUS washout. Irrigation during phacoemulsification seems to limit lidocaine exposure to the ocular tissues, resulting in a short duration of anesthesia. Lidocaine is not metabolized or broken down by the iris or cornea during this short period.

Endogenous beta-carbolines as clonidine-displacing substances.

Endogenous beta-carbolines, such as harmane, are known to occur in mammalian species including humans. Radioligand binding studies have revealed that certain beta-carbolines display high affinity for both I(1) and I(2) imidazoline-binding sites (IBS). Functional studies have shown that the beta-carboline harmane elicits many characteristics expected of an endogenous ligand IBS. This article discusses the evidence relating to beta-carbolines as endogenous ligands and presents a case for harmane and related compounds as endogenous ligands for IBS.

Characterization of [(3)H]harmane binding to rat whole brain membranes.

This study investigates the binding of [(3)H]harmane to rat whole brain homogenates. Saturation studies revealed [(3)H]harmane labels a single, saturable, high-capacity population with high affinity. All the test compounds displaced [(3)H]harmane completely and in an apparently monophasic manner. The displacement profile of the test ligands indicated labeling of MAO-A. Given the high level of MAO-A binding, it is unlikely that a low-capacity I(2) site would be distinguishable from the total [(3)H]harmane population.

Pharmacokinetics of norelgestromin and ethinyl estradiol from two consecutive contraceptive patches.

The primary objective of this open-label study was to determine the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE)following two consecutive applications of a contraceptive patch (ORTHO EVRA/EVRA). Twelve healthy women wore the first patch on their abdomen for 7 days and, after removal at 168 hours (day 7), wore a second patch for 10 days (i.e., 3 days beyond the intended 7-day wear period). Blood samples were collected before and at various times up to 456 hours (day 19) after application of the first patch for analysis of NGMN and EE. Mean serum concentrations of NGMN and EE remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, during the entire 7-day wear period after application of the first patch and for 10 days after application of the second patch; reference ranges are based on studies with ORTHO-CYCLEN/ Cilest. No patch detached spontaneously. No subject discontinued or experienced a serious adverse event.

Comparison of preservative-free bupivacaine vs. lidocaine for intracameral anesthesia: a randomized clinical trial and in vitro analysis.

PURPOSE: To determine whether intracameral bupivacaine hydrochloride 0.5% is as effective as lidocaine hydrochloride 1.0% in controlling discomfort of patients during phacoemulsification and posterior chamber intraocular lens implantation. In rabbits, corneal endothelial cell function, ultrastructure, and viability were evaluated after in vitro perfusion of bupivacaine 0.5%. METHODS: In a double-masked, controlled trial, 48 eyes of 48 patients with uncomplicated age-related cataract were randomly assigned to receive bupivacaine 0.5% or lidocaine 1.0% intracamerally before phacoemulsification with a posterior chamber intraocular lens. Outcome measures such as pain, visual acuity, amount of sedation, length of surgery, pupil size, intraocular pressure, corneal clarity, and anterior chamber reaction were compared. In laboratory studies, paired rabbit corneas were evaluated by endothelial cell perfusion with either bupivacaine 0.5%, bupivacaine 0.5% and glutathione bicarbonate Ringer solution in a 1:1 ratio or bupivacaine 0.5% buffered to a pH of 7.0. The paired control corneas were perfused with glutathione bicarbonate Ringer solution and rates of corneal swelling were determined. Cell ultrastructure and viability were also evaluated. RESULTS: In the randomized trial, there was no significant difference in the pain patients had during surgery or in the early or late postoperative period. No statistically significant difference was seen between the two groups in terms of pupil size, intraocular pressure, corneal edema, anterior chamber reaction, or visual acuity immediately after the operation or on postoperative day 1. Paired rabbit corneas perfused with bupivacaine 0.5% and bupivacaine 0.5% buffered to a pH of 7.0 swelled significantly (P<.001, P = .009, respectively), and had corneal endothelial cell damage. Dilution of the bupivacaine 1:1 with glutathione bicarbonate Ringer solution prevented corneal edema and damage to the corneal endothelium. Endothelial cell viability was also decreased after perfusion of bupivacaine 0.5% (P<.001). CONCLUSIONS: Clinically, bupivacaine 0.5% is as effective as lidocaine 1.0% for anesthesia during phacoemulsification and posterior chamber intraocular lens implantation. However, in vitro perfusion of bupivacaine 0.5% damaged the corneal endothelium of rabbits except when the drug was diluted 1:1 with glutathione bicarbonate Ringer solution. Surgeons who use 0.2 to 0.5 ml of intracameral bupivacaine 0.5% should be aware of its potential to cause endothelial cell damage because of its lipid solubility. The bupivacaine 0.5% should be diluted at least 1:1 with balanced salt solution before intracameral injection, followed immediately by phacoemulsification. The surgeon should ensure that the bupivacaine 0.5% is nonpreserved and packaged in single-use vials or flip-top containers.

The experience of cancer.

The illness career of the person with cancer has been characterized as a 'living-dying' experience in which, faced with the intolerable incompatibility of life and death, the individual and his or her family attempt to maintain control and 'normalize' everyday activity. Unfortunately, in their everyday struggles, families in North America appear to face social isolation from existing community services and networks that might assist them. Perhaps because the illness is so heavily medicalized and stigmatized, most persons with cancer and their families do not participate in them. A minority benefit from self-help organizations such as Cancer Society groups and survivor coalitions. The palliative care and hospice/home care movements provide an alternative to dying in the acute-care hospital, again, for a minority. Half of those with cancer survive more than 5 years; for these persons, the ordeal has just begun. Survivors must cope with physical disabilities due to surgery and the side effects of other treatments, the psychological traumas of fear of recurrence and social stigma, and the disappointment of a considerably reduced range of future possibilities for career and development. The fact that their relationships with others are negatively affected is well documented, particularly with intimate relationships. In a sense, a person never really 'gets over' cancer: it is a sword of Damocles that continues to hang over the individual and his or her family for the rest of the person's life.(ABSTRACT TRUNCATED AT 250 WORDS)

Posthaemorrhagic ventricular dilatation in the premature infant: natural history and predictors of outcome.

OBJECTIVE: To investigate the natural history and predictors of outcome of posthaemorrhagic ventriculomegaly in the very low birthweight (VLBW) infant. METHODS: All VLBW infants admitted between September 1994 and September 1997 to the neonatal intensive care units of Brigham and Women's Hospital (Boston), Children's Hospital (Boston), and Christchurch Women's Hospital (New Zealand) with germinal matrix intraventricular haemorrhage (IVH) were identified. All charts and ultrasound scans were reviewed to define the natural history and perinatal and/or postnatal factors of value in prediction of the course of posthaemorrhagic ventriculomegaly. Progressive ventricular dilatation (PVD) was defined from the results of serial cranial ultrasound scans. RESULTS: A total of 248 VLBW infants had evidence of IVH (22% of all VLBW infants, mean (SD) gestational age 26.8 (2.6) weeks). A quarter of the infants exhibited PVD. Spontaneous arrest of PVD occurred without treatment in 38% of infants with PVD. Of the remaining 62% with persistent PVD, 48% received non-surgical treatment only (pharmacological and/or drainage of cerebrospinal fluid by serial lumbar punctures), 34% received surgical treatment with insertion of a ventriculoperitoneal reservoir and/or shunt, and 18% died. The development of PVD after IVH and adverse short term outcome, such as the requirement for surgery, were predicted most strongly by the severity of IVH. CONCLUSIONS: These data reflect the natural history of PVD in the 1990s and show that, despite a slight reduction in its overall incidence, there appears to be a more aggressive course, with appreciable mortality and morbidity in the extremely premature infant. The major predictor of adverse short term outcome, defined as death or need for surgical intervention, was the severity of IVH. These findings may be valuable for the management of very small premature infants.

The determination of RWJ-38705 (tramadol N-oxide) and its metabolites in preclinical pharmacokinetic studies using LC-MS/MS.

A rapid and reliable analytical method is described for the simultaneous determination of RWJ-38705 (tramadol N-oxide) and several of its major metabolites in the plasma of Sprague-Dawley rats and Beagle dogs. Sample preparation using solid phase extraction was followed by reversed phase liquid chromatography (LC) coupled with tandem mass spectrometric (MS/MS) detection in the positive ionization mode. The assay was linear for all analytes over concentrations ranging from approximately 6 to 2000 ng/ml. The inter-assay reproducibility was generally less than 15% while accuracy values were within 13% of theoretical. The overall recovery of the analytes ranged from approximately 40 to 64% in rat plasma and 53-75% in dog plasma. This assay has proven to be sensitive, specific and reproducible, and it has been readily implemented in preclinical PK studies. Representative plasma concentration versus time profiles resulting from administration of TNO to rats and dogs are presented in this communication.

A palaeolimnological assessment of diatom production responses to lake acidification.

To quantify diatom palaeoproduction responses to lake acidification, a whole-basin diatom accumulation rate was calculated for the small acidified lake Gaffeln, in the Gårdsjön catchment in south-west Sweden. Changes in the relative frequency of diatom assemblages to acidification were typical of other lakes in the area, notably a decline in planktonic diatoms after approximately 1900 and increase in acid-tolerant benthic species (e.g. Eunotia spp. and Tabellaria binalis). Single deep-water cores could be used to infer past changes in diatom production because of changed sediment-microfossil deposition patterns, probably due to the development of a benthic algal mat in the littoral zone. The basin mean total diatom accumulation rate (based on eight cores) was approximately constant over the last 150 years, while planktonic diatoms decreased from 0.3 x 10(6) frustules cm(-2) year(-1) prior to 1900 to trace levels in the 1970s. There was, however, a corresponding increase in the accumulation of benthic diatoms over the same period, from 0.5 to 1 x 10(6) frustules cm(-2) year(-1) between 1950 and the present, together with changed community structure. The increase in benthic species probably reflects an expansion of the littoral zone as light transparency increased.

Toxicity of ocular surgical solutions.

Intraocular medications, solutions, and instruments are an integral component of intraocular surgery. The ionic composition, pH, and osmolality should approximate aqueous humor to prevent damage to the corneal endothelium. Intraocular medications should be evaluated for their intrinsic properties and presence of vehicles or preservatives. Many new cleaning procedures and promising new intraocular drugs are likely to be introduced in the future. The responsibility of ocular surgeons is to protect their patients from drug-, solution-, or instrument-related toxicity.

Complete characterisation of thermally treated sludges.

As disposal options for sludges become more difficult to find and more expensive to operate, those relying on some form of thermal treatment are becoming more commercially attractive. The incentive, especially for more heavily populated countries, is the production of treated solids suitable for beneficial application to land. It is the level of treatment required to achieve this cost effectively which has been the focus of much of the research in this field. There are now several commercially available plants designed to thermally treat sludges and many have been in full scale operation for a number of years. One of the auxiliary claims often made by proponents of such treatments, is that the resultant sludges are more amenable to dewatering and therefore easier and cheaper to handle. In this work we have used a novel filtration rig to obtain complete sets of filtration data for different sludges. Historically sludge characterisation has been achieved by measurement of an empirical Capillary Suction Time (CST) parameter, however with the new filtration apparatus it is now possible to obtain fundamental sludge characteristics across a wide range of volume fractions in hours not days. We have applied this technology to characterise different sludge samples before and after thermal treatment under different sets of operating conditions (pH, temperature and pressure) to simulate some of the commercially available thermal treatment technologies. We have also examined the effects of various chemical oxidants (hydrogen peroxide and Fenton's reagent) used as pretreatments to the thermal process and attempted to compare their cost efficiencies. The results show that the physical structure of the sludge is irreversibly altered by decreasing the pH or heating to temperatures in excess of 150 degrees C in a way which significantly enhances the dewaterability of the material. The treated sludge not only has a higher permeability but also has a higher final per cent solids (often in the autothermal region). In contrast the amounts of chemical additives used in pretreatment to achieve similar effects are cost prohibitive.