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Aims: To identify clinical features and protein biomarkers associated with bladder cancer (BC) in individuals with type 2 diabetes mellitus presenting with haematuria., Materials and Methods: Data collected from the Haematuria Biomarker (HaBio) study was used in this analysis. A matched sub-cohort of patients with type 2 diabetes and patients without diabetes was created based on age, sex, and BC diagnosis, using approximately a 1:2 fixed ratio. Randox Biochip Array Technology and ELISA were applied for measurement of 66 candidate serum and urine protein biomarkers. Hazard ratios and 95% confidence intervals were estimated by chi-squared and Wilcoxon rank sum test for clinical features and candidate protein biomarkers. Diagnostic protein biomarker models were identified using Lasso-based binominal regression analysis., Results: There was no difference in BC grade, stage, and severity between individuals with type 2 diabetes and matched controls. Incidence of chronic kidney disease (CKD) was significantly higher in patients with type 2 diabetes (p = 0.008), and CKD was significantly associated with BC in patients with type 2 diabetes (p = 0.032). A biomarker model, incorporating two serum (monocyte chemoattractant protein 1 and vascular endothelial growth factor) and three urine (interleukin 6, cytokeratin 18, and cytokeratin 8) proteins, predicted incidence of BC with an Area Under the Curve (AUC) of 0.84 in individuals with type 2 diabetes. In people without diabetes, the AUC was 0.66., Conclusions: We demonstrate the potential clinical utility of a biomarker panel, which includes proteins related to BC pathogenesis and type 2 diabetes, for monitoring risk of BC in patients with type 2 diabetes. Earlier urology referral of patients with type 2 diabetes will improve outcomes for these patients., Trial Registration: http://www.isrctn.com/ISRCTN25823942., (© 2022 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

The present study investigates the bioaccumulation of the insensitive munition compounds 2,4-dinitroanisole (DNAN) and 3-nitro-1,2,4-triazol-5-one (NTO), developed for future weapons systems to replace current munitions containing sensitive explosives. The earthworm Eisenia andrei was exposed to sublethal concentrations of DNAN or NTO amended in Sassafras sandy loam. Chemical analysis indicated that 2- and 4-amino-nitroanisole (2-ANAN and 4-ANAN, respectively) were formed in DNAN-amended soils. The SumDNAN (sum of DNAN, 2-ANAN, and 4-ANAN concentrations) in soil decreased by 40% during the 14-d exposure period. The SumDNAN in the earthworm body residue increased until day 3 and decreased thereafter. Between days 3 and 14, there was a 73% decrease in tissue uptake that was greater than the 23% decrease in the soil concentration, suggesting that the bioavailable fraction may have decreased over time. By day 14, the DNAN concentration accounted for only 45% of the SumDNAN soil concentration, indicating substantial DNAN transformation in the presence of earthworms. The highest bioaccumulation factor (BAF; the tissue-to-soil concentration ratio) was 6.2 ± 1.0 kg/kg (dry wt) on day 3 and decreased to 3.8 ± 0.8 kg/kg by day 14. Kinetic studies indicated a BAF of 2.3 kg/kg, based on the earthworm DNAN uptake rate of 2.0 ± 0.24 kg/kg/d, compared with the SumDNAN elimination rate of 0.87 d -1 (half-life = 0.79 d). The compound DNAN has a similar potential to bioaccumulate from soil compared with trinitrotoluene. The NTO concentration in amended soil decreased by 57% from the initial concentration (837 mg NTO/kg dry soil) during 14 d, likely due to the formation of unknown transformation products. The bioaccumulation of NTO was negligible (BAF ≤ 0.018 kg/kg dry wt). Environ Toxicol Chem 2021;40:1713-1725. © 2021 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2021 SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

The synthesis of carbon-based nanomaterials is often inefficient, generating large amounts of soot with metals as waste by-product. Currently, there are no specific regulations for disposal of engineered nanomaterials or the waste by-products resulting from their synthesis, so it is presumed that by-products are disposed of in the same way as the parent (bulk) materials. We studied the terrestrial toxicity of soot from gadolinium metallofullerene nanomanufacturing on earthworms (Eisenia fetida) and isopods (Porcellio scaber). The metallofullerene soot consisted of carbon particle agglomerates in the nanometer and submicrometer ranges (1-100 and 101-999 nm, respectively), with metals used during nanomanufacturing detectable on the particles. Despite high metal concentrations (>100 000 mg/kg) in the soot, only a relatively small amount of metals leached out of a spiked field soil, suggesting only moderate mobility. Seven- and 14-d exposures in field soil demonstrated that the soot was only toxic to earthworms at high concentrations (>10 000 mg/kg); however, earthworms avoided spiked soils at lower concentrations (as low as 500 mg/kg) and at lower soil pH. The presence of soot in food and soil did not cause isopod avoidance. These data demonstrate that metallofullerene soot from nanomanufacturing may only be toxic to earthworms at high concentrations representative of improper disposal or accidental spills. However, our results indicate that terrestrial invertebrates may avoid soils contaminated with soot at sublethal concentrations. Environ Toxicol Chem 2018;9999:1-12. Published 2018 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work, and as such, is in the public domain in the United States of America., (Published 2018 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work, and as such, is in the public domain in the United States of America.)

This investigation builds on previous studies on military-relevant tungsten (W) to more thoroughly explore environmental pathways and bioaccumulation kinetics during direct soil exposure versus trophic transfer and elucidate its relative accumulation and speciation in different snail organs. The modeled steady-state concentration and bioaccumulation factor (BAF) of W from soil into cabbage were 302 mg/kg and 0.55, respectively. Steady-state concentrations (34 mg/kg) and BAF values (0.05) obtained for the snail directly exposed to contaminated soil were lower than trophic transfer by consumption of W-contaminated cabbage (tissue concentration of 86 mg/kg; BAF of 0.36). Thus, consumption of contaminated food is the most important pathway for W mobility in this food chain. The highest concentrations of W compartmentalization were in the snail's hepatopancreas based on wet chemistry and synchrotron-based investigations. Chemical speciation via inductively couple plasma mass spectrometry showed a higher degree of polytungstate partitioning in the hepatopancreas relative to the rest of the body. Based on synchrotron analysis, W was incorporated into the shell matrix during exposure, particularly during the regeneration of damaged shell. This offers the potential for application of the shell as a longer-term biomonitoring and forensics tool for historic exposure.

Gaucher disease (GD) is caused by mutations in the GBA1 gene that encodes the lysosomal enzyme acid β-glucosidase (GCase). Reduced GCase activity primarily leads to the accumulation of two substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Current treatment options have not been shown to ameliorate the neurological pathology observed in the most severe forms of GD, clearly representing an unmet medical need. To better understand the relationship between GlcCer and GlcSph accumulation and ultimately their connection with the progression of neurological pathology, we developed LC-MS/MS methods to quantify GlcCer and GlcSph in mouse brain tissue. A significant challenge in developing these methods was the chromatographic separation of GlcCer and GlcSph from the far more abundant isobaric galactosyl epimers naturally occurring in white matter. After validation of both methods, we evaluated the levels of both substrates in five different GD mouse models, and found significant elevation of brain GlcSph in all five, while GlcCer was elevated in only one of the five models. In addition, we measured GlcCer and GlcSph levels in the brains of wild-type mice after administration of the GCase inhibitor conduritol β-epoxide (CBE), as well as the nonlysosomal β-glucosidase (GBA2) inhibitor N-butyldeoxygalactonojirimycin (NB-DGJ). Inhibition of GCase by CBE resulted in elevation of both sphingolipids; however, inhibition of GBA2 by NB-DGJ resulted in elevation of GlcCer only. Taken together, these data support the idea that GlcSph is a more selective and sensitive biomarker than GlcCer for neuronopathic GD in preclinical models.

Background: Chemical bioavailability is an important dose metric in environmental risk assessment. Although many approaches have been used to evaluate bioavailability, not a single approach is free from limitations. Previously, we developed a new genomics-based approach that integrated microarray technology and regression modeling for predicting bioavailability (tissue residue) of explosives compounds in exposed earthworms. In the present study, we further compared 18 different regression models and performed variable selection simultaneously with parameter estimation., Results: This refined approach was applied to both previously collected and newly acquired earthworm microarray gene expression datasets for three explosive compounds. Our results demonstrate that a prediction accuracy of R(2) = 0.71-0.82 was achievable at a relatively low model complexity with as few as 3-10 predictor genes per model. These results are much more encouraging than our previous ones., Conclusion: This study has demonstrated that our approach is promising for bioavailability measurement, which warrants further studies of mixed contamination scenarios in field settings.

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A and is characterized by pathological accumulation of globotriaosylceramide and globotriaosylsphingosine. Earlier, the authors demonstrated that oral coadministration of the pharmacological chaperone AT1001 (migalastat HCl; 1-deoxygalactonojirimycin HCl) prior to intravenous administration of enzyme replacement therapy improved the pharmacological properties of the enzyme. In this study, the authors investigated the effects of coformulating AT1001 with a proprietary recombinant human α-galactosidase A (ATB100) into a single intravenous formulation. AT1001 increased the physical stability and reduced aggregation of ATB100 at neutral pH in vitro, and increased the potency for ATB100-mediated globotriaosylceramide reduction in cultured Fabry fibroblasts. In Fabry mice, AT1001 coformulation increased the total exposure of active enzyme, and increased ATB100 levels in cardiomyocytes, cardiac vascular endothelial cells, renal distal tubular epithelial cells, and glomerular cells, cell types that do not show substantial uptake with enzyme replacement therapy alone. Notably, AT1001 coformulation also leads to greater tissue globotriaosylceramide reduction when compared with ATB100 alone, which was positively correlated with reductions in plasma globotriaosylsphingosine. Collectively, these data indicate that intravenous administration of ATB100 coformulated with AT1001 may provide an improved therapy for Fabry disease and thus warrants further investigation.

Certain mutant Alzheimer's amyloid-β (Aβ) peptides (that is, Dutch mutant APP(E693Q)) form complexes with gangliosides (GAβ). These mutant Aβ peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing β-hexosaminidase (β-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in Aβ aggregation and accumulation. The small molecule OT1001 is a β-hex-targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for β-hex and low cytotoxicity. Dutch APP(E693Q) transgenic mice accumulate oligomeric Aβ as they age, as well as Aβ oligomer-dose-dependent anxiety and impaired novel object recognition (NOR). Treatment of Dutch APP(E693Q) mice with OT1001 caused a dose-dependent increase in brain β-hex levels up to threefold over those observed at baseline. OT1001 treatment was associated with reduced anxiety, improved learning behavior in the NOR task and dramatically reduced GAβ accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase β-hex activity may be useful in reducing accumulation of certain mutant species of Aβ and in preventing the associated behavioral pathology., Competing Interests: Within the past 5 years, SG has held research grants from Baxter Pharmaceuticals and Amicus Therapeutics. SG is also a member of the Data and Safety Monitoring Board for the Pfizer-Janssen Alzheimer's Immunotherapy Alliance. BAW, ACS, DJL, JWS and ERS are employees or shareholders of OrPhi Therapeutics. HNW and REB are employees and shareholders of Amicus Therapeutics.

Mutations in the gene that encodes the lysosomal enzyme acid β-glucosidase lead to reduced cellular activity and accumulation of glycosphingolipid substrates, biochemical hallmarks of the lysosomal storage disorder Gaucher disease (GD). Recently such mutations have been identified as risk factors for Parkinson's disease (PD) and related disorders. Both gain-of-function (due to toxic cellular accumulation of mutant enzyme) and loss-of-function (due to accumulation of lipid substrates) hypotheses have been put forth to address the biochemical link between GD and PD. Similarly, links between Alzheimer's disease and other lysosomal enzyme deficiencies have begun to emerge. The use of pharmacological chaperones to restore the cellular trafficking and activity of mutant lysosomal enzymes may offer a novel approach to treat these debilitating neurodegenerative diseases., (Copyright © 2014. Published by Elsevier Ltd.)

Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzymes are unable to efficiently pass the quality control mechanisms of the endoplasmic reticulum, resulting in reduced lysosomal trafficking, substrate accumulation, and cellular dysfunction. Pharmacological chaperones (PCs) are small molecules that bind and stabilize mutant lysosomal enzymes, thereby allowing proper cellular translocation. Such compounds have been shown to increase enzyme activity and reduce substrate burden in a number of preclinical models and clinical studies. In this Perspective, we review several of the lysosomal diseases for which PCs have been studied and the SAR of the various classes of molecules.

Metallic tungsten has civil and military applications and was considered a green alternative to lead. Recent reports of contamination in drinking water and soil have raised scrutiny and suspended some applications. This investigation employed the cabbage Brassica oleracae and snail Otala lactea as models to determine the toxicological implications of sodium tungstate and an aged tungsten powder-spiked soil containing monomeric and polymeric tungstates. Aged soil bioassays indicated cabbage growth was impaired at 436 mg of W/kg, while snail survival was not impacted up to 3793 mg of W/kg. In a dermal exposure, sodium tungstate was more toxic to the snail, with a lethal median concentration of 859 mg of W/kg. While the snail significantly bioaccumulated tungsten, predominately in the hepatopancreas, cabbage leaves bioaccumulated much higher concentrations. Synchrotron-based mapping indicated the highest levels of W were in the veins of cabbage leaves. Our results suggest snails consuming contaminated cabbage accumulated higher tungsten concentrations relative to the concentrations directly bioaccumulated from soil, indicating the importance of robust trophic transfer investigations. Finally, synchrotron mapping provided evidence of tungsten in the inner layer of the snail shell, suggesting potential use of snail shells as a biomonitoring tool for metal contamination.

Background: We appraised 23 biomarkers previously associated with urothelial cancer in a case-control study. Our aim was to determine whether single biomarkers and/or multivariate algorithms significantly improved on the predictive power of an algorithm based on demographics for prediction of urothelial cancer in patients presenting with hematuria., Methods: Twenty-two biomarkers in urine and carcinoembryonic antigen (CEA) in serum were evaluated using enzyme-linked immunosorbent assays (ELISAs) and biochip array technology in 2 patient cohorts: 80 patients with urothelial cancer, and 77 controls with confounding pathologies. We used Forward Wald binary logistic regression analyses to create algorithms based on demographic variables designated prior predicted probability (PPP) and multivariate algorithms, which included PPP as a single variable. Areas under the curve (AUC) were determined after receiver-operator characteristic (ROC) analysis for single biomarkers and algorithms., Results: After univariate analysis, 9 biomarkers were differentially expressed (t test; P < .05). CEA AUC 0.74; bladder tumor antigen (BTA) AUC 0.74; and nuclear matrix protein (NMP22) 0.79. PPP included age and smoking years; AUC 0.76. An algorithm including PPP, NMP22, and epidermal growth factor (EGF) significantly improved AUC to 0.90 when compared with PPP. The algorithm including PPP, BTA, CEA, and thrombomodulin (TM) increased AUC to 0.86. Sensitivities = 91%, 91%; and specificities = 80%, 71%, respectively, for the algorithms., Conclusions: Addition of biomarkers representing diverse carcinogenic pathways can significantly impact on the ROC statistic based on demographics. Benign prostate hyperplasia was a significant confounding pathology and identification of nonmuscle invasive urothelial cancer remains a challenge., (Copyright © 2011 American Cancer Society.)

To determine if trinitrotoluene (TNT) forms nonextractable residues in earthworms and to measure the relative degree of accumulation as compared to TNT and its deaminated metabolites, Eisenia fetida was exposed to 14C-TNT using dermal contact to filter paper or exposure to soil. Nonextractable residues made up 32-68% of total body burden depending on exposure media and depuration time. Parent TNT accounted for less than 3% of radioactivity, while ADNTs accounted for 7-38%. Elimination half-lives were 61-120 h for TNT, ADNTs, and DANTs, which was significantly lower than the half-lives found for nonextractable residues, 201-240 h. However, over 80% of the nonextractable residue was solubilized using weak acid (pH 2). Based on our findings that TNT accumulation occurs primarily as nonextractable residues, which have a longer half-life, and that nonextractable residues can be solubilized, we propose that nonextractable residues could be used as a selective biomarker for assessing TNT contamination., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Nano-sized aluminum is currently being used by the military and commercial industries in many applications including coatings, thermites, and propellants. Due to the potential for wide dispersal in soil systems, we chose to investigate the fate and effects of nano-sized aluminum oxide (Al2O3), the oxidized form of nano aluminum, in a terrestrial organism. The toxicity and bioaccumulation potential of micron-sized (50-200 microm, nominal) and nano-sized (11 nm, nominal) Al2O3 was comparatively assessed through acute and subchronic bioassays using the terrestrial earthworm, Eisenia fetida. Subchronic (28-d) studies were performed exposing E. fetida to nano- and micron-sized Al2O3-spiked soils to assess the effects of long-term exposure. No mortality occurred in subchronic exposures, although reproduction decreased at >or=3,000 mg/kg nano-sized Al2O3 treatments, with higher aluminum body burdens observed at 100 and 300 mg/kg; no reproductive effects were observed in the micron-sized Al2O3 treatments. In addition to toxicity and bioaccumulation bioassays, an acute (48-h) behavioral bioassay was conducted utilizing a soil avoidance wheel in which E. fetida were given a choice of habitat between control, nano-, or micron-sized Al2O3 amended soils. In the soil avoidance bioassays, E. fetida exhibited avoidance behavior toward the highest concentrations of micron- and nano-sized Al2O3 (>5,000 mg/kg) relative to control soils. Results of the present study indicate that nano-sized Al2O3 may impact reproduction and behavior of E. fetida, although at high levels unlikely to be found in the environment., (Copyright (c) 2010 SETAC.)

The geochemistry of tungsten has recently gained attention in the scientific and regulatory communities. Tungsten has a complex geochemistry, existing in many environmental matrices as the soluble and mobile tungstate anion, as well as a series of ill-defined polymeric species. Previous work has shown that soluble tungsten leached from a metallic tungsten-spiked Grenada Loring soil will reach an equilibrium concentration >150 mgL(-1), and the concentration is greatly influenced by co-occurring analytes in the matrix, such as calcium and phosphate. In the present work, the mobility of tungsten compounds was investigated in a model soil with a range of aqueous leach solutions using column experiments. The relative column leachate concentrations measured followed trends from previously reported tungstate and polytungstate partition coefficients determined in the model soil under identical aqueous matrix conditions. Neutral to alkaline conditions produced maximum effluent tungsten concentrations >40 mgL(-1), whereas acid leach eluents produced concentrations in the <1-3 mgL(-1) range. The change in leached tungsten speciation over time was also measured as monomeric and polymeric tungsten species have different sorptive behaviors.

The biogeochemistry of tungsten and its effects on mobility have recently gained attention due to the existence of human cancer clusters, such as in Fallon, NV. Tungsten exists in many environmental matrices as the soluble and mobile tungstate anion. However, tungsten can polymerize with itself and other anions, creating poly- and heteropoly-tungstates with variable geochemical and toxicological properties. In the present work, geochemical parameters are determined for tungstate species in a model soil that describe the potential for tungsten mobility. Soluble tungsten leached from a metallic tungsten-spiked soil after six to twelve months aging reached an equilibrium concentration >150 mg/L within 4 h of extraction with deionized water. Partition coefficients determined for various tungstate and polytungstate compounds in the model soil suggest a dynamic system in which speciation changes over time affect tungsten geochemical behavior. Partition coefficients for tungstate and some poly-species have been observed to increase by a factor of 3 to 6 over a four month period, indicating decreased mobility with soil aging.

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.

As part of an investigation determining the trophically available fraction of metals in a model terrestrial food web, i.e., invertebrate prey to Western fence lizards (Sceloporus occidentalis), we evaluated the ability of several invertebrate prey to bioaccumulate lead and to form metals-rich granules, which are hypothesized to be non-available to predators. Crickets (Acheta domestica), tenebroid beetle larvae (Tenebrio molitor), and isopods (Porcellio scaber) were selected as model prey organisms. Lack of standard exposure methodologies for these species has presented a barrier to trophic transfer evaluations, as each species has particular requirements that create challenges for designing exposure conditions. We were able to devise exposure conditions for all three species that allow long-term exposure studies. All prey organisms accumulated lead from contaminated food, and for all species the majority of the accumulated Pb was associated with the exoskeleton (>50%), with metals-rich granules accounting for most of the remaining accumulated lead.

A concise synthesis of the beta-amyloid(1-42 )aggregation inhibitor (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene [(-)-2] has been developed. The key step is a regio- and diastereoselective hydroboration-amination sequence to convert alkene into amine. Enantiomeric resolution was achieved by recrystallization of amine as the dibenzoyl-D-tartaric acid salt. Hydroquinone is a potent inhibitor of the fibrillar aggregation of beta-amyloid as determined in two different assay systems.

Alpha2-adrenergic receptor agonists are analgesic agents, and the alpha2-adrenergic agonist clonidine has been used in clinical studies for regional analgesia after intrathecal administration. We review here recent developments concerning the structure activity relationships of a new class of potent alpha2-adrenergic agonists and their use as analgesic agents. The effect of structure upon cardiovascular side-effects is also monitored, such as the prolongation of the QT portion of the cardiac action potential.

A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.

A series of 4-diarylaminotropanes has been prepared. Both endo and exo diastereomeric forms bound to the delta opioid receptor but the endo isomers were more potent and selective versus the mu opioid receptor than the exo isomers. The most potent delta opioid agonist (14) exhibited a delta opioid Ki of 0.2 nM and was 860-fold selective over mu.

A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53 displayed alpha(2) receptor binding in the 10-20 nM range and also had significant antinociceptive activity in the mouse abdominal irritant test (MAIT).

Objective: To compare the efficacy and safety of controlled release oxycodone given every 12 h around the clock with immediate release oxycodone-acetaminophen (APAP) given 4 times daily for osteoarthritis (OA) pain., Methods: Adults (n=167) with moderate to severe OA pain despite regular use of nonsteroidal antiinflammatory drugs (NSAID) entered open label titration for 30 days with immediate release oxycodone qid; 107 qualified for randomization to double blind, parallel group treatment for 30 days with placebo, controlled release oxycodone, or immediate release oxycodone-APAP., Results: Following titration with immediate release oxycodone, mean (SE) pain intensity (0, none to 3, severe) decreased from 2.44 (0.04) to 1.38 (0.05) (p=0.0001), and quality of sleep (1, very poor; 5, excellent) improved from 2.58 (0.08) to 3.57 (0.07) (p=0.0001). Mean dose was about 40 mg/day. Pain intensity and quality of sleep were significantly improved in both active groups compared with the placebo group (p< or =0.05) during the double blind trial. Pain intensity and sleep scores were comparable in both active groups during double blind treatment. Nausea (p=0.03) and dry mouth (p=0.09) were less common with controlled release oxycodone than immediate release oxycodone-APAP., Conclusion: Controlled release oxycodone q12h and immediate release oxycodone-APAP qid, added to NSAID, were superior to placebo for reducing OA pain and improving quality of sleep. The active treatments provided comparable pain control and sleep quality. Controlled release oxycodone was associated with a lower incidence of some side effects.

We recently reported on a series of pyrrole Mannich bases orally active in inhibiting the conditioned avoidance response (CAR) in rats. These compounds exhibit affinity for both D2 and 5-HT1A receptors, and some are noncataleptogenic. Such a profile suggests that they may be potential antipsychotic agents which lack the propensity for causing extrapyramidal side effects and tardive dyskinesias in humans. One of these compounds, 1-[[1-methyl-5-[[4-[2-(1-methylethoxy)phenyl]- 1-piperazinyl]methyl]-1H-pyrrol-2-yl]methyl]-2-piperidinone (RWJ 25730, 1), was chosen for further development but found to be unstable in dilute acid. In order to improve stability, we replaced the pyrrole methylene linkage to the piperazine ring with ethylene, employed ethylene and dicarbonyl as linkers between the lactam and the pyrrole ring, placed electron-withdrawing groups on the pyrrole ring, and substituted acyclic amide for lactam. In addition, we replaced the pyrrole segment with other heterocycles including thiophene, furan, isoxazole, isoxazoline, and pyridine. Generally, replacement of the N-methylpyrrole segment with thiophene, furan, isoxazoline, or pyridine afforded compounds equipotent with 1 in CAR, which were more stable in dilute acid. In the case of side chain or lactam modifications, CAR activity was significantly decreased or abolished, with the exception of 6. For the most part, the modifications to 1 resulted in the decrease or loss of D2 receptor binding. However, within this series, 5-HT1A receptor binding was greatly increased, with thiophene 40 exhibiting an IC50 of 0.07 nM. The CAR activities of pyrroles 6 and 12, thiophene 40, furans 44-47, isoxazolines 49 and 50, and pyridine 54 coupled with their weak or nonexistent D2 binding and strong 5-HT1A binding suggest that they may be acting via a nondopaminergic mechanism or that dopaminergic active metabolites are responsible. Pyrrole 6 and furans 44 and 47 show promise as antipsychotic agents based on their CAR activity, receptor-binding profile, and solution stability.

If Dr. Sydenham could have benefited from today's therapy, he likely would not have had to endure thirty years of "violent ... torture" that gave birth to his most elegant and classic description of acute gout. The five key points to remember in management of the gouty spectrum are: (1) Establish the diagnosis as clearly as possible or as clearly as seems necessary under the clinical circumstances (i.e. arthrocentesis with crystal analysis to establish diagnosis is not always necessary with reliable patients when septic joint seems highly unlikely). (2) Treat acute attacks with NSAIDs alone or perhaps steroids--or rarely IV colchicine under special circumstances. (3) DO NOT START ALLOPURINOL OR PROBENECID DURING AN ACUTE FLARE OF GOUT--IT MAY MAKE THE EPISODE WORSE. (4) The pattern of disease over time (frequency and severity of attacks) determines whether or not one decides to use an agent such as allopurinol, probenecid, or prophylactic colchicine chronically once a patient is over the acute attack--the mere presence of increased uric acid and a single or rare gouty attack would not usually require any other than the appropriate acute therapy. (5) The presence of visible tophi, uric acid renal calculi and destructive gouty arthritis nearly always warrant uric acid lowering therapy.

Radiopharmaceuticals have great potential in the early detection of human tumors. Three potential 99mTc-labeled platinum compounds based on cisplatin have been synthesized and tested in tumored mice. This report presents the analysis of the disposition data obtained after a single intravenous injection with an empirical, physiologically based pharmacokinetic model. The radioactivity of each radiopharmaceutical after administration was measured in blood, urine, and 15 tissues, including tumor. Parameters included in the model were tissue volumes (experimentally determined), tissue blood flows (determined from literature values), tissue:blood extraction ratios (determined by nonlinear least-squares regression with MULTI-FORTE), and clearance terms (also determined by nonlinear least-squares regression). Data were weighted by the reciprocal of the square of the observed values. Good fits to the experimental data were obtained. As expected, the compound producing the best tumor:blood profile (3) also had the highest tumor extraction ratio (6.2 versus 2.0 and 1.3 for 1 and 2, respectively). Total body clearance values for the radioactivity associated with the three compounds 1-3 were calculated to be 0.09, 0.04, and 0.016 mL/min, respectively. Analysis of data with such an empirical, physiologically based model may assist future development of suitable tumor-imaging agents.

Subcutaneous nodules and cutaneous ulceration are rare accompaniments of chronic sarcoid arthritis. We report a patient with sarcoidosis who presented with the uncommon combination of chronic arthropathy, subcutaneous nodules and cutaneous ulceration who was initially diagnosed as rheumatoid arthritis (RA). Sarcoidosis should be included in the differential diagnosis of articular disorders that may mimic RA.

Jumpers with lumbar spine injuries caused by bad landings had a high incidence of chip or slice fractures, but degenerative disk disease was unrelated to jumping injuries.

Both a national cyclotron and a reactor are necessary to provide Australia with the complete range of radioisotopes. For the last 17 years, Australia has been well supplied with reactor radioisotopes by the Australian Atomic Energy Commission which provides a daily nationwide distribution service, but, to be self-sufficient, Australia also needs a national cyclotron. Many cyclotron radioisotopes are too short-lived for importation, and the demand can be met only by domestic production. Despite the availability of the necessary expertise and instrumentation, Australian patients are being denied a wide range of important clinical investigations because of the lack of suitable radioisotopes, for example, krypton-81m and iodine-123. An Australian medical cyclotron is overdue. Australia and New Zealand are the only developed countries that do not possess at least one medical cyclotron. The historical events in Australia's quest for a medical cyclotron are summarized, and the medical reasons why the writers believe that Australia should now acquire its own medical cyclotron are reviewed.

The review describes the three most commonly used methods of separating 99mTc from 99Mo, namely chromatography, sublimation and solvent extraction. General comparisons are made between the various generator systems and their respective advantages and weaknesses. The method of producing the parent radionuclide 99Mo often dictates which of the generator options is more appropriate to a particular 99mTc user. Although the use of fission-produced 99Mo is widespread, this technique is not ideal since it requires considerable capital investment and gives rise to large quantities of long-lived radioactive waste. In certain countries such resources cannot be presumed and as a result alternative methods of producing 99mTc from neutron-activation-produced 99Mo are attractive. Recent advances in generator technology indicate that neutron-activation-produced 99Mo may eventually replace the need for fission-produced 99Mo. The review mentions one method of achieving this goal.

153Sm, a radiolanthanide of half life 46.27 h, has a gamma emission of 0.103 MeV which is well suited to imaging, it is also a moderate energy beta emitter and tumour localization of various 153Sm chelates was evaluated in B16 murine melanoma to assess their endoradiotherapeutic potential. 153Sm was prepared from enriched 152Sm in the Australian Nuclear Science and Technology Organization reactor. 153Sm chelates were prepared from 153Sm-chloride and their chromatographic behaviour characterized. Tumour and organ uptake of 153Sm-chloride, 153Sm-citrate and the 153Sm chelates, DTPA, HEDTA, HIDA, BZ, PBH, PIH and NTA were measured at 1, 6, 24 and 48 h after intravenous administration to C57 black mice bearing either melanotic or amelanotic B16 melanoma of mean size 0.75 cm3. Histopathological examination of the tumours at each passaging assured comparability of the degree of melanogenesis and the absence of necrosis. 153Sm-chloride was immobile on chromatography and the rapid hepatic accumulation of both 153Sm-chloride and 153Sm-citrate was attributed to in vivo formation of a colloid. In contrast, 153Sm-DTPA, moving at the solvent front on chromatography, showed no reticuloendothelial accumulation in vivo and was rapidly excreted by the kidneys without tumour uptake. The other 153Sm chelates were of intermediate stability and all localized in both melanotic and amelanotic tumours, although to a significantly lesser degree than 67Ga-citrate. The relatively high 153Sm-HIDA activity in liver and 153Sm-NTA activity in bone impaired tumour definition, but on imaging of all the 153Sm chelates only 153Sm-DTPA failed to demonstrate the B16 melanoma and the best tumour delineation was obtained using 153Sm-HEDTA.

Clinical and laboratory features as well as immunogenetic markers were analyzed in 150 patients with SLE to determine if demographic factors--age at diagnosis, sex and race--influenced the expression of disease. The overall series included 103 white females, 35 black females, 10 white males and 2 black males; the mean age at diagnosis was 32.5 years. Males had a significantly older mean age at diagnosis than females (40.4 versus 31.8 years) and a significantly higher frequency of peripheral neuropathy (50% versus 18.8%). No other differences in clinical or laboratory features or HLA-DR or DQ phenotype frequencies were noted. Blacks had a significant younger mean age at diagnosis than whites (26.9 versus 33.4 years) as well as significantly higher frequencies of nephritis, hypertension, acute lupus pneumonitis, discoid rash, hyperglobulinemia and hypocomplementemia. There were no differences in autoantibody frequencies between race-specific subgroups. HLA-DR2, DRw52 and DQ1 were significantly associated with SLE in whites compared to controls; no HLA-DR or DQ associations were found with SLE in blacks. In whites, HLA-DR2 was associated with the presence of anti-Ro(SS-A) antibody while HLA-DR3 was associated with the presence of both anti-Ro(SS-A) and anti-La(SS-B) antibody. In blacks, HLA-DR2 was associated with the presence of anti-nDNA antibody. In whites, patients with late-onset SLE (age at diagnosis greater than or equal to 50 years) had significantly lower frequencies of nephritis and mesenteric vasculitis but, on the other hand, a higher frequency of secondary Sjögren syndrome than patients with age at diagnosis less than or equal to 22 years. Similar findings were noted when blacks aged 35 and above were compared to those aged 17 and below at diagnosis. In whites, the frequency of both anti-Ro(SS-A) and La(SS-B) antibodies increased with increasing age as did that of HLA-DR3; HLA-DR2, however, was more frequent in those with younger age at diagnosis. These data suggest the existence of two serologic-genetic subsets of SLE with different age at diagnosis.

Strychnine poisoning results in a predictable and treatable sequence of events involving blockade of the inhibitory neurotransmitter, extensor muscle spasms, seizures, and respiratory paralysis. These spasms may lead to hyperthermia, profound lactic acidosis, and rhabdomyolysis. Acidosis is primarily attributable to lactate, as indicated by the correlation between arterial pH and log of lactic acid concentration (r = -0.878). Interruption of the strychnine blockade is the primary therapy for strychnine poisoning. Phenobarbital in moderate doses should be the first intervention and anesthetic doses should be used if necessary. Suppression of convulsions will permit successful management of the complications of strychnine poisoning. Our patient survived, even though at one point he had a pH of 6.55, a lactate level of 32 mM/liter, a temperature of 43 degrees C, and rhabdomyolysis with an increased creatine phosphokinase level of 359,000 mU/ml (5,983 mumol/s/liter).

Eleven patients with active systemic lupus erythematosus, previously untreated, were studied to 1) determine the acute effect of corticosteroids on circulating immune complex (CIC) levels and 2) correlate the initial CIC profile with the development of organ system involvement. Using serial measurements of CIC as detected by assays for cryoglobulins and binding to C1q, Raji cells, and rheumatoid factor, we found that levels of CIC change little during the first month of high dose daily steroid therapy, but they uniformly decrease to near normal by 6 to 12 months. High levels of CIC detected by Raji cell assay early in the course of systemic lupus erythematosus and before steroid therapy appear to be predictive of the development of chronic lupus nephritis (P less than 0.005).

Potential tumor imaging radiopharmaceutical agents have been prepared by attaching a cisplatin derivative to a ligand capable of forming a stable complex with 99mTc. Three new organometallic compounds, with iminodiacetic acid as the 99mTc chelating group and 2,3-diaminopropionamide as the platinum complexing group, have been prepared and characterized. Preliminary biodistribution studies in tumor bearing mice support the utility of this approach.