The suppression of Antarctic bottom water formation by melting ice shelves in Prydz Bay.

A fourth production region for the globally important Antarctic bottom water has been attributed to dense shelf water formation in the Cape Darnley Polynya, adjoining Prydz Bay in East Antarctica. Here we show new observations from CTD-instrumented elephant seals in 2011-2013 that provide the first complete assessment of dense shelf water formation in Prydz Bay. After a complex evolution involving opposing contributions from three polynyas (positive) and two ice shelves (negative), dense shelf water (salinity 34.65-34.7) is exported through Prydz Channel. This provides a distinct, relatively fresh contribution to Cape Darnley bottom water. Elsewhere, dense water formation is hindered by the freshwater input from the Amery and West Ice Shelves into the Prydz Bay Gyre. This study highlights the susceptibility of Antarctic bottom water to increased freshwater input from the enhanced melting of ice shelves, and ultimately the potential collapse of Antarctic bottom water formation in a warming climate.

Potential regime shift in decreased sea ice production after the Mertz Glacier calving.

Variability in dense shelf water formation can potentially impact Antarctic Bottom Water (AABW) production, a vital component of the global climate system. In East Antarctica, the George V Land polynya system (142-150°E) is structured by the local 'icescape', promoting sea ice formation that is driven by the offshore wind regime. Here we present the first observations of this region after the repositioning of a large iceberg (B9B) precipitated the calving of the Mertz Glacier Tongue in 2010. Using satellite data, we find that the total sea ice production for the region in 2010 and 2011 was 144 and 134 km(3), respectively, representing a 14-20% decrease from a value of 168 km(3) averaged from 2000-2009. This abrupt change to the regional icescape could result in decreased polynya activity, sea ice production, and ultimately the dense shelf water export and AABW production from this region for the coming decades.

Real life experience confirms sustained response to long-term biologics and switching in ankylosing spondylitis.

OBJECTIVE: To investigate the long-term response to biological therapies in AS in a real life clinical setting and to quantify non-response and response to 'switching' therapies in these cases. METHODS: All patients prescribed TNF-blocking therapies for AS between 1999 and 2006 were studied. Response was evaluated using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and CRP results. RESULTS: A total of 113 patients (84 males: 29 females, mean age 45 yrs, median disease duration 16 yrs, 87% HLA-B27 positive) were identified. At baseline they had a mean BASDAI of 6.57, BASFI 6.57 and CRP of 31 g/dl. At the end of follow-up, these values had reduced to mean BASDAI of 3.12, BASFI 4.16 and CRP of 7 g/dl. Improvements were sustained for 24 months and beyond with no loss of effect. Only nine patients (8%) suffered side-effects leading to cessation or switching of first-line therapy and non-response occurred in 15 patients (13%) in the long term. Fifteen patients (13%) switched to a second drug and 14 of these (93%) had a significant and sustained response. Outcomes were similar regardless of drug used, duration of disease and HLA-B27 status. CONCLUSION: Treatment of active AS with TNF blockers according to the British Society of Rheumatology guidelines leads to a sustained response for over 2 yrs with most patients tolerating the drugs well. The rate of non-response is significantly lower than that seen in RA and nearly all of these patients respond well to a second-line agent.

Sustained response to long-term biologics and switching in psoriatic arthritis: results from real life experience.

OBJECTIVE: To investigate the response to biologic drugs in psoriatic arthritis and to quantify non-response and outcome from switching agents. METHODS: 60 patients (33 men and 27 women, mean age 46 years, median disease duration 16 years) prescribed biologic drugs for psoriatic arthritis between 2001 and 2006 were studied. Response was evaluated using joint counts, C-reactive protein levels and disease activity scores (using 28 joints; DAS28). RESULTS: The mean percentage improvements seen were 56% in tender joint count, 70% in swollen joint count, 64% in C-reactive protein level and 36% in the overall disease activity score. Improvements were sustained beyond 24 months with no loss of effect. Side-effects leading to cessation or switching of first-line therapy were only seen in 5% of patients and non-response occurred in 20% long term. Overall, 90% of patients achieved a significant response, using switching in 20% of cases. Outcomes were similar regardless of drug used, duration of disease and subtype of arthritis. CONCLUSIONS: Treatment of active psoriatic arthritis with anti-tumour necrosis factor agents leads to a sustained response over 3 years with most patients tolerating these drugs well. The rate of non-response is low with the majority of patients responding to second- and third-line therapies.

Estimating the cost and health status consequences of treatment with TNF antagonists in patients with psoriatic arthritis.

OBJECTIVES: Tumour necrosis factor (TNF) has been shown to improve the outcomes in patients with psoriatic arthritis (PsA). We estimate the long-term impact on health status of prescribing the TNF antagonist etanercept, and evaluate the cost-effectiveness in a health economic model. METHODS: The relationship between disability (Health Assessment Questionnaire) and health state utility was explored to estimate the quality-adjusted life years (QALYs) gained from the TNF antagonist etanercept. A model was then used to compare sequences of treatments for PsA after failure of two conventional disease modifying anti-rheumatic drugs (DMARDs). One arm commences on etanercept therapy and this is compared with a strategy commencing with combination therapy of methotrexate and ciclosporin and another commencing with leflunomide. Individual patient data from Phase III etanercept trials is used to populate the model supported by published evidence from extensive literature searches. By incorporating a life table specific for a PsA population, and using a number of evidence- and expert opinion-based assumptions for disease progression, the model was extended beyond the trial duration to a 10-yr time horizon. Cost offsets were produced by avoiding surgery through delayed progression; drug and monitoring costs were also modelled. RESULTS: Over the 10 yrs, modelled etanercept treatment gave 0.82 more QALYs when compared with combination therapy with methotrexate and ciclosporin, and 0.65 more QALYs in comparison with leflunomide. This equates to a central estimate for the cost per QALY of pound28 189 and pound28 189 for ciclosporin and leflunomide, respectively. Sensitivity analyses demonstrated this could vary by as much as +/-28%. CONCLUSIONS: With limited data currently available, the potential cost-effectiveness of etanercept in DMARD failures for adults with PsA appears encouraging. The result for other TNF antagonists will depend on how their relative efficacy and drug price compares with etanercept. A number of limitations are described and priorities for further research suggested.

A randomised, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus ciclosporin in patients with active psoriatic arthritis.

OBJECTIVES: To evaluate the safety and efficacy of adding ciclosporin A (CSA) to the treatment of patients with psoriatic arthritis (PsA) demonstrating an incomplete response to methotrexate (MTX) monotherapy. METHODS: In a 12 month, randomised, double blind, placebo controlled trial at five centres in three countries, 72 patients with active PsA with an incomplete response to MTX were randomised to receive either CSA (n = 38) or placebo (n = 34). Patients underwent full clinical and radiological assessment and, in addition, high resolution ultrasound (HRUS) was performed at one centre. An intention to treat (last observation carried forward) analysis was employed. RESULTS: Some significant improvements were noted at 12 months in both groups. However, in the active but not the placebo arm there were significant improvements in swollen joint count, mean (SD), from 11.7 (9.7) to 6.7 (6.5) (p<0.001) and C reactive protein, from 17.4 (14.5) to 12.7 (14.3) mg/l (p<0.05) as compared with baseline. The Psoriasis Area and Severity Index (PASI) score improved in the active group (2 (2.3) to 0.8 (1.3)) as compared with placebo (2.2 (2.7) to 1.9 (2.8)), p<0.001, and synovitis detected by HRUS (33 patients, 285 joints) was reduced by 33% in the active group compared with 6% in the placebo group (p<0.05). No improvement in Health Assessment Questionnaire or pain scores was detected. CONCLUSIONS: Synovitis detected by HRUS was significantly reduced. Combining CSA and MTX treatment in patients with active PsA, and a partial response to MTX, significantly improves the signs of inflammation but not pain or quality of life.

Adequate early cyclosporin exposure is critical to prevent renal allograft rejection: patients monitored by absorption profiling.

This study used receiver operating characteristic analysis to investigate the properties of area under the concentration-time curve during the first 4h after cyclosporin-microemulsion dosing (AUC0-4) and cyclosporin (CyA) levels immediately before and at 2 and 3h after dosing (C0, C2 and C3) to predict the risk of biopsy-proven acute rejection (AR) at 6 months. Ninety-eight kidney transplant recipients treated with CyA-microemulsion-based triple therapy immunosuppression were studied on post-transplant days 3, 5, and 7, and at increasing intervals thereafter. The most sensitive and specific predictor of AR was AUC0-4. Of the single time-point measurements, the measurement properties of C2 were closest to those of AUC0-4, and superior to those of C3. The relationship between C0 and subsequent AR was weak and did not reach statistical significance. On day 3, CyA AUC0-4 > or = 4,400 ng.h/mL and C2 > or = 1,700 ng/mL were each associated with a 92% negative predictive value for rejection in the first 6months. Pharmacokinetic measurements on or after day 5, and measurements on day 3 in patients with delayed graft function, were not predictive of AR. Adequate exposure within the first 3days post transplantation may be critically important in preventing subsequent rejection.

Sertraline-induced hypoglycemia.

OBJECTIVE: To report a case of hypoglycemia that occurred in a patient treated with the selective serotonin-reuptake inhibitor, sertraline. CASE SUMMARY: An 82-year-old white woman with mild cardiovascular disease and no history of glucose intolerance was seen in the emergency department for a presyncopal episode associated with a blood glucose of 32 mg/dL as measured by the ambulance attendant. She had similar symptoms the day before. Despite repeated administration of oral and intravenous glucose, the patient had recurrent episodes of hypoglycemia and was hospitalized for four days. She had started taking sertraline 50 mg once daily for mild depression 25 days prior to presentation. Other medications included furosemide 20 mg/d, ramipril 5 mg/d, clopidogrel 75 mg/d, nitroglycerin patch 0.4 mg/h, and lorazepam 1 mg taken occasionally for agitation. She had never been prescribed any oral hypoglycemic agents. Serum sertraline and desmethylsertraline concentrations measured two, three, and four days after discontinuing sertraline were within the expected range, but the rate of decline was consistent with a moderately prolonged half-life. DISCUSSION: Sertraline has been shown to blunt postprandial hyperglycemia in rats and to potentiate the hypoglycemic effects of sulfonylurea agents in humans. It has not been reported to cause hypoglycemia independently, but in this case, a nondiabetic patient experienced multiple episodes of hypoglycemia that resolved after discontinuation of sertraline. CONCLUSIONS: This report and another implicating fluoxetine in a case of hypoglycemia suggest that healthcare professionals should consider these medications among the possible causes of hypoglycemia occurring in patients receiving selective serotonin-reuptake inhibitors.

A simple method to estimate the required dialysis time for cases of alcohol poisoning.

BACKGROUND: Conventional dialysis management of ethylene glycol and methanol poisoning includes frequent intradialytic determinations of serum toxin concentration. Dialysis is continued until a target toxin concentration is reached. Initially, the required dialysis duration is unknown, making planning difficult. We devised a simple method to estimate the duration of dialysis required and avoid quantitation of multiple toxin samples. METHODS: Using the assumption that toxic alcohols would have a dialysis clearance similar to urea, we proposed that required dialysis time (hours) to reach a 5 mmol/L toxin concentration target would be: [-V ln(5/A)]/0.06k, where V (liters) is the Watson estimate of total body water, A is the initial toxin concentration (mmol/L), and k is 80% of the manufacturer-specified dialyzer urea clearance (mL/min) at the initial observed blood flow rate. Directly measured dialysis and renal toxin clearance, and true dialysis requirement by conventional treatment protocol were compared with our estimate in two methanol and three ethylene glycol poisonings treated with Fresenius F8 dialyzers. RESULTS: There were no clinically or statistically significant differences between predicted dialysis duration (7.6 +/- 1.9 hours, +/-SD) and that actually provided using hourly toxin concentration sampling (7.4 +/- 1.9 hours). Renal toxin clearance was negligible compared to that of dialysis, and predicted dialysis clearance did not differ significantly from that observed. CONCLUSIONS: The simple estimate method is sufficiently valid to guide the prescription of dialysis for toxic alcohol poisoning. Data required at dialysis start include only the initial toxin concentration, dialyzer manufacturer's specified urea clearance at initial observed blood pump speed, and patient demographics to estimate total body water. This approach allows for planned dialysis therapy, without the need for additional toxin concentration measurements until dialysis is completed.

A 6-year experience with urine drug testing by family service agencies in Nova Scotia, Canada.

The objective of this study is to describe a urine drug-testing program implemented for parents with a history of substance abuse by family service agencies in the province of Nova Scotia, Canada. Nurse collectors went to the parents' home to obtain urine specimens under direct observation and then delivered the specimens to the toxicology laboratory or arranged shipment by courier under chain of custody. Each urine specimen was screened for cannabinoids, cocaine metabolite, opiates, amphetamines and benzodiazepines, ethyl alcohol and creatinine. All positive screening tests were confirmed by another method such as gas chromatography-mass spectrometry (GC-MS). In 15,979 urine specimens collected from 1994 to 1999, the percent positive rate for one (or more) drugs/metabolites ranged from 45.6% (1994-1996) to 30.0% (1998, 1999). A total of 575 specimens (3.7%) were dilute (urine creatinine <25mg/dl). Positive rates in 15,404 non-dilute specimens from 1994 to 1999 were as follows: cannabinoids - 11.7%, benzodiazepines - 11.3%, cocaine metabolite - 3.7%, and ethyl alcohol - 2.6%. Most clients provided less than 20 urine specimens for testing but some individuals submitted urine specimens more than 100 times in a 12-15-month period. Urine drug screening in parents with a history of substance abuse provided an objective and reliable indication of recent drug use in this population.

Experience with urine drug testing by the Correctional Service of Canada.

The Correctional Service of Canada implemented a urine drug-screening program over 10 years ago. The objective of this report is to describe the program and drug test results in this program for 1999. Offenders in Canadian federal correctional institutions and those living in the community on conditional release were subject to urine drug testing. Urine specimens were collected at correctional facilities and shipped by courier to MAXXAM Analytics Inc. laboratory. All urine specimens were analyzed for amphetamines, cannabinoids, cocaine metabolite (benzoylecgonine), opiates, phencyclidine, benzodiazepines, methyl phenidate, meperidine, pentazocine and fluoxetine by immunoassay screening (homogeneous EIA and ELISA assays) followed by GC-MS confirmation. Ethyl alcohol was analyzed when specifically requested. Alternative screening and confirmation methods with lower cut-off values were used, whenever urine specimens were dilute (creatinine <20mg/dl and specific gravity

Urinary excretion profiles of 11-nor-9-carboxy-delta9-tetrahydrocannabinol: a delta9-THCCOOH to creatinine ratio study.

Monitoring the major cannabinoid metabolite (delta9-THCCOOH) to creatinine ratio (M/C) has been used to predict new drug use. According to Huestis and Cone, the best accuracy (85.4%) for predicting new marijuana use was a ratio > or = 0.5 from two urine specimens collected at least 24 h apart. Manno et al. recommended an M/C ratio of > or = 1.5. Subjects with a history of chronic marijuana use were screened for cannabinoid use by immunoassay (50-ng/mL cutoff), and presumptive positives were confirmed by gas chromatography-mass spectrometry for delta9-THCCOOH (15-ng/mL cutoff). Creatinine was analyzed with a cutoff concentration of 25 mg/dL. The study objective was to apply the criteria from both groups of workers to determine if consecutive urine specimens (collected at least 24 h apart) positive for cannabinoids could be used to differentiate new marijuana use from the excretion of residual cannabinoid metabolite (delta9-THCCOOH) in an uncontrolled setting. Serial urine specimens (826) were collected from 26 individuals. Huestis and Cone and Manno et al. ratios indicated new drug use in 83% and 33% of serial urine specimens collected at least 24 h apart, respectively. Clinically, the Huestis and Cone ratio is recommended because of a lower false-negative rate (7.4%) than the Manno et al. false-negative rate (24%). In legal situations, we recommend using the Manno et al. ratio because of its lower false-positive rate (0.1%) as stated by Huestis and Cone.

Experience with a urine opiate screening and confirmation cutoff of 2000 ng/mL.

Until recently, most laboratories used an opiate immunoassay screening and confirmation cutoff value of 300 ng/mL for codeine and morphine detection by gas chromatography-mass spectrometry (GC-MS). The cutoff value for opiates was increased to 2000 ng/mL or higher in various laboratories because of concerns that small doses of codeine and foods containing poppy seeds would give a positive opiate-screening result. Workplace drug-testing programs in the U.S. raised the opiate cutoff value to 2000 ng/mL on 30 November 1998. The objective of this study is to describe the results of opiate testing of 8600 urine specimens collected over 24 months with a 2000-ng/mL screening and confirmation (codeine and morphine) cutoff value. Specimens were screened by the EMITdau opiate assay using an in-house 2000-ng/mL morphine calibrator. Presumptive positive findings (N = 621) were analyzed quantitatively by GC-MS for codeine and morphine. One hundred and eighty six urine specimens were positive for codeine and morphine (> 2000 ng/mL), 298 specimens were positive for codeine only (> 2000 ng/mL) and 26 specimens were positive for morphine only (> 2000 ng/mL). All remaining specimens had codeine and morphine values < 2000 ng/mL. The codeine and morphine confirmation rate in this program reduced from 7.1% in 1994-1996 (300-ng/mL cutoff) to 2.1% in 1997-1998 with a 2000-ng/mL cutoff value. The codeine-only confirmation rate lowered from 6.6% (300-ng/mL cutoff) to 3.4% (2000-ng/mL cutoff). It was concluded that increasing opiate screening and codeine and morphine confirmation cutoff values led to > 300% reduction in the confirmed-positive rate for codeine and morphine and a 47% reduction in codeine-only confirmations in a urine drug-testing program where codeine was the major opiate used.

Glucose protection from MPP+-induced apoptosis depends on mitochondrial membrane potential and ATP synthase.

MPP+ inhibits mitochondrial complex I and alpha-ketoglutarate dehydrogenase causing necrosis or apoptosis of catecholaminergic neurons. Low glucose levels or glycolytic blockade has been shown to potentiate MPP+ toxicity. We found that MPP+ caused concentration-dependent apoptosis of neuronally differentiated PC12 cells and that glucose, but not pyruvate, supplementation reduced apoptosis. Oligomycin concentrations sufficient to inhibit ATP synthase blocked the decreased apoptosis afforded by glucose supplementation. Laser-scanning confocal microscope imaging of chloromethyl-tetramethylrosamine methyl ester fluorescence to estimate DeltaPsiM showed that MPP+ and atractyloside reduced DeltaPsiM, while cyclosporin A (CSA) and glucose supplementation reversed decreases in DeltaPsiM caused by MPP+. Oligomycin blocked the effect of glucose supplementation on DeltaPsiM. These findings show that (i) MPP+-induced and atractyloside-induced apoptosis are associated with reduced DeltaPsiM; (ii) CSA maintains DeltaPsiM and reduces MPP+-induced apoptosis; and (iii) glucose supplementation maintains DeltaPsiM, likely by glycolytic ATP-dependent proton pumping at ATP synthase and reduces MPP+-induced apoptosis.

Comparison of four immunoassays for the detection of lorazepam in urine.

Four healthy patient subjects were each given a single, 1-mg lorazepam tablet. Urine samples from all patient subjects were collected at 12 intervals (0-2, 2-5, 5-8, 8-11, 11-14, 14-24, 24-26, 26-29, 29-32, 32-35, 35-38, and 38-48 hours). An aliquot from each urine collection was screened using cloned enzyme donor immunoassay (CEDIA), enzyme-multiplied immunoassay technique (EMIT) II, EMIT dau, and fluorescence polarization immunoassay (FPIA) without and with hydrolysis using beta-glucuronidase. Using a 200 ng/mL calibrator cut-off, none of the four immunoassays gave a positive response before hydrolyzation of the urine samples. For offline hydrolysis using Helix pomatia beta-glucuronidase, 35, 3, 0, and 4 of 48 urine samples gave positive responses on the previously listed immunoassays. The CEDIA method also gave 32 of 48 positive responses for online hydrolysis using Escherichia coli beta-glucuronidase. Online hydrolysis can be conveniently automated by including the beta-glucuronidase in the first of the two reagents combined with the urine sample.

Use and abuse of the benzodiazepines.

Since chlordiazepoxide was introduced in 1961, the benzodiazepines have had many important roles in the pharmacotherapy of various disorders. This drug class for the central nervous system has been considered one of the safest in use for 35 years, especially when the benzodiazepines are compared with the barbiturates they often replaced. The objective of this article is to provide an update on the availability and distribution of benzodiazepines around the world and to discuss their most common clinical applications. Adverse effects of benzodiazepines, observed after long-term therapeutic use and after overdoses, are also presented. Triazolam is discussed because this benzodiazepine was removed from the market by regulatory authorities in the United Kingdom in 1991. Benzodiazepines will continue to have an important role in clinical medicine. Their clinical use, however, should be monitored more closely because of the greater awareness of their adverse effects after long-term use and because of the potential for misuse and abuse.

CEDIA dau Benzodiazepine screening assay: a reformulation.

The CEDIA dau Benzodiazepine assay has been reformulated to include online hydrolysis of urinary benzodiazepine glucuronide conjugates. The new antibody possesses enhanced cross-reactivities toward the low-dose benzodiazepines, which are excreted at low urinary drug-metabolite concentrations. The screening method was evaluated using lorazepam as the probe benzodiazepine. Four subjects each consumed a 1-mg lorazepam tablet. Sequential urine voids over the same time intervals were collected for the next 48 h. Twelve postdose urine samples were collected from each subject. Positive results were obtained from 5-24 h to 2-35 h using a 200-ng/mL nitrazepam calibration cutoff. There was no practical difference between hydrolyzing online with the supplied E. coli beta-glucuronidase or offline with Helix pomatia beta-glucuronidase purchased separately. Without hydrolysis, all urine samples tested negative. The cross-reactivities of lorazepam in terms of nitrazepam calibration equivalents, varied from 108 to 178% for lorazepam concentrations between 50 and 2500 ng/mL. Lorazepam glucuronide gave cross-reactivities (expressed as lorazepam base) between 72 and 136% using the online hydrolysis procedure with E. coli beta-glucuronidase. Offline hydrolysis with Helix pomatia gave cross-reactivities between 84 and 134%. Without hydrolysis, lorazepam glucuronide gave less than 4% cross-reactivity in the assay.

Improved cross-reactivity to alpha OH triazolam in the BMC CEDIA DAU urine benzodiazepine assay.

Immunoassays designed to detect use of older benzodiazepines such as oxazepam or diazepam often cannot detect triazolam use because of the low doses of triazolam administered, rapid biotransformation to metabolites with poor cross-reactivities, and the small amount of alpha OH triazolam glucuronide excreted in the urine. Previous studies have demonstrated that certain immunoassays have high cross-reactivity to alpha OH triazolam but are unable to detect therapeutic triazolam use in urine. The objectives of this study were to characterize the immunoreactivity toward alpha OH triazolam in the reformulated cloned enzyme donor immunoassay (CEDIA) drug abuse urine benzodiazepine assay and to measure the immunoreactivity of urine specimens from subjects who were administered single oral doses of triazolam. Alpha OH triazolam standards were prepared in drug-free urine and the new CEDIA assay gave a positive result at concentrations from 100 to 200 ng/ml, which indicates an eight-fold improvement in CEDIA cross-reactivity to alpha OH triazolam standards in the reformulated CEDIA assay. With a 200 ng/ml cut-off, 4/30 of the urine specimens screened positive for benzodiazepines without enzymatic hydrolysis and 6/30 after enzymatic hydrolysis. When using an in-house 100 ng/ml nitrazepam cut-off calibrator, 10/30 urine specimens were positive in the reformulated CEDIA assay without hydrolysis and 22/30 were positive with enzymatic hydrolysis before screening.