Class Type Separation of the Polar and Apolar Components of Petroleum.

Identification of the heteroatom (nitrogen, sulfur, and oxygen)-containing compounds of petroleum is of key importance when considering industrial and environmental issues associated with crude oil production. The more commonly performed methods of crude oil fractionation are often insufficient in the extent to which they separate oils, not allowing defined "molecular" fractions to be obtained. Methods capable of performing a class type separation are uncommon and are often extensive and resource and time intensive. Here we report a method for the separation of crude oils into discrete compound classes. The method utilizes both ion exchange and normal phase chromatography to generate fractions of saturated hydrocarbons, aromatic hydrocarbons, basic compounds, naphthenic acids, and other oxygen-containing species, carbazoles, sulfones, and thiophenes from small crude oil samples (∼0.5 g). Assessment of method selectivity with a suite of model compounds has shown the fractions to be well-defined, with classes of model compounds isolated within discrete fractions. Application of the method to five crude oils of varying API gravity (12.1-38.3°) demonstrates a potential for wide-ranging use. Sample recoveries were high (77-98%) with simple evaporative losses correlating closely with total sample loss. Repeatability was also high, demonstrated by triplicate analyses of model compound mixtures, oils spiked with model compounds and oils alone. Separation selectivity was further demonstrated by application of the scheme to the Alaska North Slope (ANS) crude oil and analysis of fractions by comprehensive two-dimensional gas-chromatography mass-spectrometry (GC × GC/MS) and/or liquid-chromatography high-resolution accurate-mass mass-spectrometry methods (LC-HRAM-MS). Isolation of discrete fractions then allowed excellent separation (by LC and GC methods) of carbazole, dibenzothiophene, fluorenones, xanthones, and quinoline fractions. Individual parent and C1-5 alkyl homologues were easily separated (GC × GC/MS), allowing high-quality mass spectra (EI) to be obtained for the individual compounds in many cases. Analysis of fractions by GC × GC/MS also allowed a series of thioxanones to be identified.

Marking of verb tense in the English of preschool English-Mandarin bilingual children: evidence from language development profiles within subgroups on the Singapore English Action Picture Test.

BACKGROUND: The phonological and morphosyntactic structures of English and Mandarin contrast maximally and an increasing number of bilinguals speak these two languages. Speech and language therapists need to understand bilingual development for children speaking these languages in order reliably to assess and provide intervention for this population. AIMS: To examine the marking of verb tense in the English of two groups of bilingual pre-schoolers learning these languages in a multilingual setting where the main educational language is English. The main research question addressed was: are there differences in the rate and pattern of acquisition of verb-tense marking for English-language 1 children compared with Mandarin-language 1 children? METHODS & PROCEDURES: Spoken language samples in English from 481 English-Mandarin bilingual children were elicited using a 10-item action picture test and analysed for each child's use of verb tense markers: present progressive '-ing', regular past tense '-ed', third-person singular '-s', and irregular past tense and irregular past-participle forms. For 4-6 year olds the use of inflectional markers by the different language dominance groups was compared statistically using non-parametric tests. OUTCOMES & RESULTS: This study provides further evidence that bilingual language development is not the same as monolingual language development. The results show that there are very different rates and patterns of verb-tense marking in English for English-language 1 and Mandarin-language 1 children. Furthermore, they show that bilingual language development in English in Singapore is not the same as monolingual language development in English, and that there are differences in development depending on language dominance. CONCLUSIONS: Valid and reliable assessment of bilingual children's language skills needs to consider the characteristics of all languages spoken, obtaining accurate information on language use over time and accurately establishing language dominance is essential in order to make a differential diagnosis between language difference and impairment.

Word production inconsistency of Singaporean-English-speaking adolescents with Down Syndrome.

BACKGROUND: The nature of speech disorders in individuals with Down Syndrome (DS) remains controversial despite various explanations put forth in the literature to account for the observed speech profiles. A high level of word production inconsistency in children with DS has led researchers to query whether the inconsistency continues into adolescence, and if the inconsistency stems from inconsistent phonological disorder (IPD) or childhood apraxia of speech (CAS). Of the studies that have been published, most suggest that the speech profile of individuals with DS is delayed, while a few recent studies suggest a combination of delayed and disordered patterns. However, no studies have explored the nature of word production inconsistency in this population, and the relationship between word production inconsistency, receptive vocabulary and severity of speech disorder. AIMS: To investigate in a pilot study the extent of word production inconsistency in adolescents with DS and to examine the correlations between word production inconsistency, measures of receptive vocabulary, severity of speech disorder and oromotor skills in adolescents with DS. METHODS & PROCEDURES: The participants were 32 native speakers of Singaporean-English adolescents, comprising 16 participants with DS and 16 typically developing (TD) participants. The participants completed a battery of standardized speech and language assessments, including The Diagnostic Evaluation of Articulation and Phonology (DEAP) assessment. Results from each test were correlated to determine relationships. Qualitative analyses were also carried out on all the data collected. OUTCOMES & RESULTS: In this study, seven out of 16 participants with DS scored above 40% on word production inconsistency, a diagnostic criterion for IPD. In addition, all participants with DS performed poorly on the oromotor assessment of DEAP. The overall speech profile observed did not exactly correspond with the cluster symptoms observed in children with IPD or CAS. CONCLUSIONS & IMPLICATIONS: Word production inconsistency is a noticeable feature in the speech of individuals with DS. In addition, the speech profiles of individuals with DS consist of atypical and unusual errors alongside developmental errors. Significant correlations were found between the measures investigated, suggesting that speech disorder in DS is multifactorial. The results from this study will help to improve differential diagnosis of speech disorders and individualized treatment plans in the population with DS.

A preliminary report on the English phonology of typically developing English-Mandarin bilingual preschool Singaporean children.

BACKGROUND: There are no published data on typical phonological development for Singaporean children. There is therefore the risk that children's speech in Singapore may be misdiagnosed or that clinicians may set goals erroneously. AIMS: This paper reports a preliminary study on the English phonology of typically developing 4;0-4;5-year-old Chinese Singaporean children who speak English and Mandarin. METHOD & PROCEDURES: Seventy children were recruited throughout Singapore, and speech samples were collected in English using the Phonology Assessment of the Diagnostic Evaluation of Articulation and Phonology (DEAP). The participants were divided equally into two groups: English-dominant and Mandarin-dominant. Their speech samples were compared with British English targets (BT) and Singapore English targets (ST) in terms of phonological accuracy and types of phonological processes used. OUTCOMES & RESULTS: The results showed that Singaporean children's phonological accuracy scores increased significantly when scored against ST instead of BT. When scored against ST, English-dominant children were found to perform similarly to their DEAP counterparts. However, Mandarin-dominant children had significantly less accurate consonant production in English and exhibited more interference effects from Mandarin phonology than English-dominant children. CONCLUSIONS & IMPLICATIONS: In this preliminary study, the results highlight the importance of speech and language therapists using local dialect pronunciations to be the target of speech assessments so as to provide appropriate assessment and intervention. It is also essential to account for the language background and language dominance of the children. More local normative data are needed for the typical acquisition of Singapore English in children, especially for children whose dominant language is not English.

Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women.

BACKGROUND: The endocrine-disrupting chemical bisphenol A (BPA) is widely used in food and beverage packaging. Higher urinary BPA concentrations were cross-sectionally associated with heart disease in National Health and Nutrition Examination Survey (NHANES) 2003-2004 and NHANES 2005-2006, independent of traditional risk factors. METHODS AND RESULTS: We included 758 incident coronary artery disease (CAD) cases and 861 controls followed for 10.8 years from the European Prospective Investigation of Cancer-Norfolk UK. Respondents aged 40 to 74 years and free of CAD, stroke, or diabetes mellitus provided baseline spot urine samples. Urinary BPA concentrations (median value, 1.3 ng/mL) were low. Per-SD (4.56 ng/mL) increases in urinary BPA concentration were associated with incident CAD in age-, sex-, and urinary creatinine-adjusted models (n=1919; odds ratio=1.13; 95% confidence interval, 1.02-1.24; P=0.017). With CAD risk factor adjustment (including education, occupational social class, body mass index category, systolic blood pressure, lipid concentrations, and exercise), the estimate was similar but narrowly missed 2-sided significance (n=1744; odds ratio=1.11; 95% confidence interval, 1.00-1.23; P=0.058). Sensitivity analyses with the fully adjusted model, excluding those with early CAD (<3-year follow-up), body mass index >30, or abnormal renal function or with additional adjustment for vitamin C, C-reactive protein, or alcohol consumption, all produced similar estimates, and all showed associations at P≤0.05. CONCLUSIONS: Associations between higher BPA exposure (reflected in higher urinary concentrations) and incident CAD during >10 years of follow-up showed trends similar to previously reported cross-sectional findings in the more highly exposed NHANES respondents. Further work is needed to accurately estimate the prospective exposure-response curve and to establish the underlying mechanisms.

In vivo and in vitro liver and gill EROD activity in rainbow trout (Oncorhynchus mykiss) exposed to the beta-blocker propranolol.

The conservation of common physiological systems across vertebrate classes suggests the potential for certain pharmaceuticals, which have been detected in surface waters, to produce biological effects in nontarget vertebrates such as fish. However, previous studies assessing the effects of such compounds in fish have not taken into account the potential for metabolism and elimination. This study aimed to assess if propranolol, a ß-adrenergic receptor antagonist or ß-blocker, could modulate EROD activity (indicative of CYP1A activity) in rainbow trout (Oncorhynchus mykiss) gills and liver. For this, an in vivo time course exposure with 1 mg/L was conducted. Additionally, using measured in vivo plasma concentrations, an in vitro exposure at human therapeutic levels was undertaken. This allowed comparison of in vitro and in vivo rates of EROD activity, thus investigating the applicability of cell preparations as surrogates for whole animal enzyme activity analysis. In vitro exposure of suspended liver and gill cells at concentrations similar to in vivo levels resulted in EROD activity in both tissues, but with significantly higher rates (up to six times in vivo levels). These results show that propranolol exposure elevated EROD activity in the liver and gill of rainbow trout, and that this is demonstrable both in vivo (albeit nonsignificantly in the liver) and in vitro, thus supporting the use of the latter as a surrogate of the former. These data also provide an insight into the potential role of the gill as a site of metabolism of pharmaceuticals in trout, suggesting that propranolol (and feasibly other pharmaceuticals) may undergo "first pass" metabolism in this organ.

Measurement of respirable superabsorbent polyacrylate (SAP) dust by ethanol derivatization using gas chromatography-mass spectrometry (GC-MS) detection.

Superabsorbent polyacrylate (SAP) is an important industrial chemical manufactured primarily as sodium polyacrylate but occasionally as potassium salt. It has many applications owing to its intrinsic physical property of very high water absorption, which can be more than 100 times it own weight. SAP is commonly used in disposable diapers and feminine hygiene products and is known by a number of synonyms-sodium polyacrylate, superabsorbent polyacrylate (SAP), polyacrylate absorbent (PA), and superabsorbent material (SAM). Germany and The Netherlands have adopted a nonbinding scientific guideline value 0.05 mg/m³ (8-hr time-weighted average, TWA) as the maximum allowable workplace concentration for the respirable dust of SAP (<10 µm particle diameter). Three industry associations representing Europe, the United States, and Asia have adopted the German scientific guideline value of 0.05 mg/m³ (8-hr TWA) as a voluntary guideline. A new test method based on alcohol derivatization of the acrylate was developed and validated for the analysis of respirable superabsorbent polyacrylate dust collected on filter cassettes in the workplace environment. This method is an alternative to the commonly used sodium-based method, which is limited owing to potential interference by other sources of sodium from the workplace and laboratory environments. The alcohol derivatization method effectively eliminates sodium interference from several classes of sodium compounds, as shown by their purposeful introduction at two and six times the equivalent amount of SAP present in reference samples. The accuracy of the method, as determined by comparison with sodium analysis of known reference samples, was greater than 80% over the study range of 5-50 µg of SAP dust. The lower reporting limit of the method is 3.0 µg of SAP per sample, which is equivalent to 3 (µg/m³) for an 8-hr sampling period at the recommended flow rate of 2.2 L/min.

Mortality in hip fractures: Stratifying the risk of operative delay and quantifying the benefit of early mobilisation.

INTRODUCTION: Early mortality following hip fracture surgery remains a significant issue with a much studied, multifactorial aetiology. This study designed to test the variables affecting 30 day mortality in a socially deprived cohort against national models, and secondarily aimed to uncover and quantify new risk factors. METHODS: This was a single centre retrospective study based on National Hip Fracture Database (NHFD) data for 3176 hip fracture patients from 1st May 2008 to December 31st 2017. Data was condensed into a single anonymised workbook and logistic regression used to analyse associations with 30 day mortality. Firstly, the 6 casemix variables used by the NHFD were modelled. Secondarily, a new optimised model based on our data was created. RESULTS: Gross mortality was 11.1% since May 2008 (344/3074). There were 1978 patients in our cohort with sufficient data to run the NHFD casemix model. Overall, this proved fair with a similar area under ROC curve to nationally (0.75 vs. 0.76), although the Odds Ratios (OR) of individual variables differed. The optimised casemix model suggested two powerful prognostic indicators for 30 day mortality, namely delay to theatre for clinical reasons (OR =3.98, p-value=0.02) and whether the patient was mobilised day one post op (OR=0.21, p-value=0.00). Delay to theatre for non clinical reasons conveyed only a marginal and statistically insignificant increase in risk (OR=1.15, p-value=0.77). CONCLUSION: This study has confirmed the NHFD casemix adjusted model is a fair barometer for units treating a socially deprived cohort. It also has shown a clear differentiation between risk conveyed by delay to theatre for clinical reasons and suggests delay for non-clinical reasons, although clearly not desired, may not have a significant effect on death rate. Finally, it both amplifies and prompts further investigation into the potential benefit of early mobilisation.

A comparison of oral narratives in children with specific language and non-specific language impairment.

This research investigated whether children with specific language impairment (SLI) and non-specific language impairment (NLI) could be differentiated by their oral narrative characteristics. Oral narrative samples were collected from 69 children and comparisons were made among four groups of participants. The two language impairment groups (SLI and NLI), aged 4;11-6;03, were matched for age and their linguistics skills. Their oral narratives were compared between these diagnostic groups and with age-matched and language-matched control groups. Measures of narrative structure, cohesion, and information did not significantly differentiate the SLI and NLI groups, suggesting that the influence of their similar linguistic skills on oral narrative measures was stronger than the influence of their differing non-verbal cognition. The SLI group produced significantly more complex and informative oral narratives than the language-matched group, while the NLI group differed from the language-matched group on fewer measures. Interactions among linguistic, cognitive, maturational, and task factors are discussed.

Cold spells in the Nordic Seas during the early Eocene Greenhouse.

The early Eocene (c. 56 - 48 million years ago) experienced some of the highest global temperatures in Earth's history since the Mesozoic, with no polar ice. Reports of contradictory ice-rafted erratics and cold water glendonites in the higher latitudes have been largely dismissed due to ambiguity of the significance of these purported cold-climate indicators. Here we apply clumped isotope paleothermometry to a traditionally qualitative abiotic proxy, glendonite calcite, to generate quantitative temperature estimates for northern mid-latitude bottom waters. Our data show that the glendonites of the Danish Basin formed in waters below 5 °C, at water depths of <300 m. Such near-freezing temperatures have not previously been reconstructed from proxy data for anywhere on the early Eocene Earth, and these data therefore suggest that regionalised cool episodes punctuated the background warmth of the early Eocene, likely linked to eruptive phases of the North Atlantic Igneous Province.

Eslicarbazepine acetate.

Eslicarbazepine acetate, a prodrug of eslicarbazepine (S-licarbazepine), is a novel, voltage-gated sodium channel antagonist under development for the adjunctive treatment of adult patients experiencing treatment-refractory partial-onset seizures. * In phase III trials, eslicarbazepine acetate 800 and 1200 mg once daily significantly reduced seizure frequency compared with placebo over 12 weeks of maintenance treatment in adults experiencing partial-onset seizures who were taking 1-3 concomitant antiepileptic drugs. * During long-term, open-label treatment for up to 1 year, eslicarbazepine acetate at a median dosage of 800 mg once daily produced sustained reductions from baseline in seizure frequency. * Long-term treatment with eslicarbazepine acetate significantly improved from baseline health-related quality of life as assessed by the Quality-of-Life in Epilepsy Inventory-31 instrument. Similarly, eslicarbazepine acetate significantly reduced depressive symptoms assessed by the Montgomery-Asberg Depression Rating Scale. * Eslicarbazepine acetate was generally well tolerated in clinical trials. The majority of treatment-emergent adverse events were of mild to moderate severity and most occurred early in treatment.

Duloxetine: a review of its use in the treatment of generalized anxiety disorder.

Duloxetine (Cymbalta(R)) is a potent serotonin and noradrenaline (norepinephrine) reuptake inhibitor (SNRI) in the CNS. It is indicated for the treatment of generalized anxiety disorder (GAD) as well as other indications. In patients with GAD of at least moderate severity, oral duloxetine 60-120 mg once daily was effective with regard to improvement from baseline in assessments of anxiety and functional impairment, and numerous other clinical endpoints. Longer-term duloxetine 60-120 mg once daily also demonstrated efficacy in preventing or delaying relapse in responders among patients with GAD. In addition, duloxetine was generally well tolerated, with most adverse events being of mild to moderate severity in patients with GAD in short- and longer-term trials. Additional comparative and pharmacoeconomic studies are required to position duloxetine among other selective serotonin reuptake inhibitors and SNRIs. However, available clinical data, and current treatment guidelines, indicate that duloxetine is an effective first-line treatment option for the management of GAD. Duloxetine is a potent and selective inhibitor of serotonin and noradrenaline transporters, and a weak inhibitor of dopamine transporters. It has a low affinity for neuronal receptors, such as alpha(1)- and alpha(2)-adrenergic, dopamine D(2), histamine H(1), muscarinic, opioid and serotonin receptors, as well as ion channel binding sites and other neurotransmitter transporters, such as choline and GABA transporters. It does not inhibit monoamine oxidase types A or B. The pharmacokinetics of duloxetine in healthy volunteers were dose proportional over the range of 40-120 mg once daily. Steady state was typically reached by day 3 of administration. Duloxetine may be administered without regard to food or time of day. Duloxetine is highly protein bound and is widely distributed throughout tissues. It is rapidly and extensively metabolized in the liver by cytochrome P450 (CYP) 1A2 and 2D6, and its numerous metabolites, which are inactive, are mainly excreted in the urine. The mean elimination half-life of duloxetine is approximately 12 hours. Duloxetine is a substrate for CYP1A2 and CYP2D6 and a moderate inhibitor of CYP2D6. Concomitant use of duloxetine and potent CYP1A2 inhibitors should be avoided and duloxetine should be used with caution in patients receiving drugs that are extensively metabolized by CYP2D6, particularly those with a narrow therapeutic index. Duloxetine was effective in the short-term treatment of patients with primary GAD of at least moderate severity. In four randomized, double-blind, placebo-controlled, multicentre, phase III trials, duloxetine 60-120 mg once daily for 9 or 10 weeks was significantly more effective than placebo with regard to the primary endpoint of mean change in Hamilton Anxiety Rating Scale (HAM-A) total score from baseline to study endpoint. In addition, all other endpoints were generally improved from baseline to a greater extent with duloxetine 60-120 mg once daily than with placebo. Duloxetine also improved patient role functioning (assessed using Sheehan Disability Scale global impairment functioning scores), health-related quality of life and patient well-being compared with placebo. Duloxetine was effective in patients with GAD who were aged >/=65 years. Pooled results of data from the two short-term efficacy trials that also included an active comparator arm showed that the mean change in HAM-A scores with duloxetine relative to placebo were of the same magnitude as those with venlafaxine extended release versus placebo. Duloxetine 60-120 mg once daily was also more effective than placebo in preventing or delaying relapse in responders to duloxetine in a longer-term study. In this study, patients with GAD received duloxetine during a 26-week, open-label, acute treatment phase and responders were then randomized to continue on duloxetine or receive placebo during a 26-week, double-blind, continuation phase. Time to relapse was significantly longer in duloxetine recipients than in placebo recipients. In addition, significantly fewer duloxetine recipients than placebo recipients relapsed during the double-blind phase of the trial and more duloxetine recipients achieved remission. Short- (9-10 weeks) and longer-term (52 weeks) treatment with duloxetine 60-120 mg once daily was generally well tolerated in patients with GAD, with the majority of adverse events being of mild to moderate severity. Nausea, dry mouth, headache, constipation, dizziness and fatigue were among the most common treatment-emergent adverse events. The adverse event profile of duloxetine did not differ with dose or treatment duration. Significantly more patients receiving short-term duloxetine than placebo discontinued treatment because of an adverse event, with nausea being the only event that resulted in significantly more treatment discontinuations in duloxetine recipients than in placebo recipients. Serious adverse events were uncommon with both short- and longer-term duloxetine treatment. Two episodes of attempted suicide and one episode of completed suicide occurred in duloxetine recipients during the 24-week open-label phase of a longer-term trial. No deaths or suicides were reported in any of the short-term trials. Discontinuation-emergent adverse events, most commonly nausea and dizziness, occurred in up to one-third of duloxetine recipients in the short-term trials.

Adalimumab: in plaque psoriasis.

Adalimumab is a recombinant, human, IgG1 monoclonal antibody specific for tumor necrosis factor. The clinical efficacy and safety of adalimumab (40 mg administered subcutaneously every other week) in patients with moderate-to-severe chronic plaque psoriasis have been demonstrated in several randomized, double-blind clinical trials, including the pivotal trials REVEAL (n = 1212) and CHAMPION (n = 271). Based on these trials, adalimumab was significantly more effective than placebo and methotrexate at relieving the signs and symptoms of psoriasis after 16 weeks of treatment, as assessed by the percentage of patients achieving a 75% improvement from baseline in Psoriasis Area and Severity Index. Based on open-label extension studies of up to 2 years' duration, the efficacy of adalimumab was sustained over the long term. Of patients who had responded to 33 weeks of treatment with adalimumab in REVEAL, patients randomized to remain on adalimumab for an additional 19 weeks of treatment were significantly less likely to experience loss of an adequate response than patients who were transferred to placebo. Compared with placebo or methotrexate, adalimumab was associated with significantly greater improvements in dermatology-specific and general measures of health-related quality of life in patients with plaque psoriasis. Adalimumab was generally well tolerated in trials in patients with plaque psoriasis, and the adverse-event profile was similar to that associated with its use in rheumatoid arthritis.

Rotavirus vaccine RIX4414 (Rotarix): a review of its use in the prevention of rotavirus gastroenteritis.

Rotavirus vaccine RIX4414 is an oral vaccine composed of a monovalent, live, attenuated, human rotavirus strain of G1P[8] type. RIX4414 vaccination in infants aged 6-17 weeks at enrolment provided protection against rotavirus gastroenteritis (RVGE) of any severity and high-level protection against severe RVGE requiring hospitalization in large, randomized clinical trials conducted in a wide range of geographic regions. Protective efficacy was evident over the period (2 months) between the first and second doses of vaccine, and the protection afforded by the full two-dose course was sustained for at least 2 years, the limit to which efficacy was assessed. RIX4414 displayed protective efficacy against the common rotavirus G, P[8] types (G1P[8], G3P[8], G4P[8], and G9P[8]) and the fully heterotypic G2P[4] type. RIX4414 did not interfere with other common childhood injectable immunizations when administered concomitantly, suggesting that it should be possible to integrate the vaccine into most routine childhood vaccination schedules, including those still using oral poliovirus vaccine. RIX4414 was generally well tolerated and there was no evidence of an increased risk of intussusception. Although dependent on many factors, including prevalent infecting strains, efficacy rates, and vaccine costs, pharmacoeconomic analyses suggest that mass immunization with RIX4414 would be cost effective in many countries, especially when assessed from the societal perspective. Therefore, rotavirus vaccine RIX4414 offers a highly effective control strategy for reducing the burden of RVGE in infants.

Establishing a link between composition and toxicity of offshore produced waters using comprehensive analysis techniques - A way forward for discharge monitoring?

Extracts of produced waters from five mature Norwegian Sea oil fields were examined as total organic extracts (TOEs) and after fractionation into operationally-defined 'polar' and 'apolar' fractions. The TOEs and fractions were examined by gas chromatography (GC), GC-mass spectrometry (GC-MS), two dimensional GC-MS (GC × GC-MS) and liquid chromatography with high-resolution spectrometry (LC-HRMS) techniques. Low molecular weight aromatics, phenols and other common petroleum-derived hydrocarbons were characterized and quantified in the TOEs and fractions. In addition, a range of more uncommon polar and apolar constituents, including those likely derived from production chemicals, such as trithiolane, imidazolines and quaternary amine compounds (so-called 'quats'), were tentatively identified, using GC × GC-MS and LC-HRMS. The acute toxicity of the TOEs and subfractions was investigated using early life stages of the marine copepod Acartia tonsa. Toxicity varied significantly for different PW TOEs and subfractions. For some PWs, the toxicity was attributed mainly to the 'polar' components, while that of other PWs was associated mainly with the 'apolar' components. Importantly, the observed toxicity could not be explained by the presence of the commonly reported compounds only. Although, due to the vast chemical complexity even of the sub-fractions of the PW extracts, specific compounds driving the observed toxicity could be not be elucidated in this study, the proposed approach may suggest a way forward for future revisions of monitoring regimes for PW discharges.

Diclofenac sodium injection (Dyloject): in postoperative pain.

*A new formulation of the nonselective NSAID diclofenac sodium suitable for intravenous bolus injection has been developed using hydroxypropyl beta-cyclodextrin as a solubility enhancer (HPbetaCD diclofenac). * HPbetaCD diclofenac intravenous bolus injection was shown to be bioequivalent to the existing parenteral formulation of diclofenac containing propylene glycol and benzyl alcohol as solubilizers (PG-BA diclofenac), which is relatively insoluble and requires slow intravenous infusion over 30 minutes. * Single-dose HPbetaCD diclofenac 3.75, 9.4, 18.75, 25, 37.5, 50 and 75 mg administered by intravenous bolus injection produced significantly greater responses than placebo for total pain relief (TOTPAR) over 6 hours or pain intensity at 4 hours in the treatment of moderate or severe postoperative dental pain in randomized, double-blind trials. HPbetaCD diclofenac 37.5 and 75 mg were similar in efficacy to intravenous bolus ketorolac 30 mg. * In a well controlled trial, single-dose HPbetaCD diclofenac 75 mg intravenous bolus injection was shown to be superior to PG-BA diclofenac 75 mg intravenous infusion with respect to TOTPAR over 4 hours, indicating faster onset of analgesia in the treatment of moderate or severe postoperative dental pain. Both HPbetaCD diclofenac and PG-BA diclofenac were superior to placebo. * HPbetaCD diclofenac was generally well tolerated during single-dose treatment of postoperative pain. The tolerability profile was similar to that of PG-BA diclofenac, but with a lower incidence of thrombophlebitis.

Bevacizumab: a review of its use in metastatic colorectal cancer.

Bevacizumab (Avastin) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to inhibit VEGF function in vascular endothelial cells and thereby inhibit tumour angiogenesis, upon which solid tumours depend for growth and metastasis. The addition of bevacizumab to fluoropyrimidine-based chemotherapy, with or without irinotecan or oxaliplatin, in both the first- and second-line treatment of metastatic colorectal cancer, significantly increased median progression-free survival or time to disease progression in most randomized controlled trials. Bevacizumab was generally, but not always, associated with a survival advantage; in phase III trials, the increases in median overall survival attributable to bevacizumab were 4.7 months with first-line therapy and 2.1 months with second-line therapy. In some studies, patients experienced clinical improvement without an apparent overall survival benefit. Bevacizumab had acceptable tolerability, with the majority of adverse events being generally mild and clinically manageable. However, from the UK National Health Service perspective, bevacizumab was not considered to be cost effective in combination with bolus fluorouracil/folinic acid or irinotecan/bolus fluorouracil/folinic acid. Additional pharmacoeconomic analyses from different perspectives and using clinical data for combinations with the more efficacious infusional fluorouracil/folinic acid plus oxaliplatin or irinotecan chemotherapy regimens are required. Although cost effectiveness may be a concern, the combination of bevacizumab and fluoropyrimidine-based chemotherapy has potential in the treatment of metastatic colorectal cancer.

Olmesartan medoxomil: a review of its use in the management of hypertension.

Olmesartan medoxomil (Olmetec, Benicar) is an angiotensin II type 1 (AT(1)) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system, which plays a key role in the pathogenesis of hypertension. Oral olmesartan medoxomil 10-40 mg once daily is recommended for the treatment of adult patients with hypertension. In those with inadequate BP control using monotherapy, fixed-dose olmesartan medoxomil/hydrochlorothiazide (HCTZ) [Olmetec plus, Benicar-HCT] combination therapy may be initiated. Extensive clinical evidence from several large well designed trials and the clinical practice setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olmesartan medoxomil, as monotherapy or in combination with HCTZ, in patients with hypertension, including elderly patients with isolated systolic hypertension (ISH). Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 4 hours of this period. In clinical trials, olmesartan medoxomil monotherapy provided better antihypertensive efficacy than losartan, candesartan cilexetil or irbesartan monotherapy, and was at least as effective as valsartan treatment, with a faster onset of action than other ARBs in terms of reductions from baseline in diastolic BP (DBP) and, in most instances, systolic BP (SBP). Combination therapy with olmesartan medoxomil plus HCTZ was superior to that with benazepril plus amlodipine, as effective as that with losartan plus HCTZ, noninferior to that with atenolol plus HCTZ, but less effective than that with telmisartan plus HCTZ, in individual trials. Data from ongoing clinical outcome trials are required to more fully determine the relative position of olmesartan medoxomil therapy in the management of hypertension. In the meantime, the consistent antihypertensive efficacy during the entire 24-hour dosage interval and good tolerability profile of olmesartan medoxomil, with or without HCTZ, make it a valuable option for the treatment of adult patients with hypertension, including the elderly.

Methoxy polyethylene glycol-epoetin beta: a review of its use in the management of anaemia associated with chronic kidney disease.

Methoxy polyethylene glycol-epoetin beta (Mircera) is a continuous erythropoietin receptor activator, with a long half-life (approximately 130 hours). In patients with anaemia associated with chronic kidney disease (CKD), both on and not on dialysis, who had not previously received an erythropoiesis-stimulating agent (ESA), methoxy polyethylene glycol-epoetin beta administered intravenously or subcutaneously once every 2 weeks resulted in a smooth and steady rise in haemoglobin levels. The response rates were high (up to 97.5%) in these patients at the end of the correction period; response rates with the comparator ESAs (epoetin alfa or beta, or darbepoetin alfa) were up to 96.3%. Moreover, patients with CKD on dialysis who had previously been treated with an ESA maintained stable haemoglobin levels (within +/-1 g/dL of baseline and within a range of 10-13.5 g/dL) when directly converted to methoxy polyethylene glycol-epoetin beta administered intravenously or subcutaneously once every 2 or 4 weeks. Methoxy polyethylene glycol-epoetin beta is generally well tolerated, with most adverse events being of mild to moderate severity, consistent with the co-morbidities known to occur in this patient group and those reported with other ESAs. In conclusion, in patients with anaemia associated with CKD, subcutaneous or intravenous methoxy polyethylene glycol-epoetin beta achieved a high haemoglobin response rate (ESA-naive patients) when administered once every 2 weeks and maintained stable haemoglobin levels (patients previously treated with ESAs) when administered once monthly.

Febuxostat.

*Febuxostat is an orally administered, non-purine, selective inhibitor of xanthine oxidase approved for the management of chronic hyperuricaemia in patients with gout. *In a randomized, double-blind, dose-ranging study in patients with gout and hyperuricaemia, significantly more recipients of febuxostat 40-120 mg/day than placebo had serum urate levels of < 6.0 mg/dL after 4 weeks of treatment. *Serum urate levels were reduced below 6.0 mg/dL at the last three monthly observations in a significantly greater proportion of patients with gout and hyperuricaemia receiving febuxostat 80 or 120 mg once daily than in those receiving allopurinol 300 mg once daily in a 52-week, randomized, double-blind trial (FACT). *Similarly, febuxostat 80, 120 or 240 mg once daily showed significantly greater urate-lowering efficacy than allopurinol 100 or 300 mg once daily in a 28-week, randomized, double-blind, placebo-controlled trial (APEX) in patients with gout and hyperuricaemia. *Long-term treatment with febuxostat for up to 4 years or more reduced the incidence of gout flares to (or close to) zero. *Febuxostat was generally well tolerated in clinical trials, including extension studies lasting > or = 4 years, with most treatment-related adverse events being mild to moderate in severity.