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Coupling reactions of feedstock alkenes are promising, but few of these reactions are practiced industrially. Even though recent advances in the synthetic methodology have led to excellent regio- and enantioselectivies in the dimerization reactions between 1,3-dienes and acrylates, the efficiency as measured by the turnover numbers (TON) in the catalyst has remained modest. Through a combination of reaction progress kinetic analysis (RPKA) of a prototypical dimerization reaction, characterization of isolated low-valent cobalt catalyst precursors involved, several important details of the mechanism of this reaction have emerged. (i) The prototypical reaction has an induction period that requires at least two hours of stir time to generate the competent catalyst. (ii) Reduction of a Co(II) complex to a Co(I) complex, and subsequent generation of a cationic [Co(I)]+ species are responsible for this delay. (iii) Through RPKA using in situ IR spectroscopy, same excess experiments reveal inhibition by the product towards the end of the reaction and no catalyst deactivation is observed as long as diene is present in the medium. The low TON observed is most likely the result of the inherent instability of the putative cationic Co(I)-species that catalyzes the reaction. (iv) Different excess experiments suggest that the reaction is first order in the diene and zero order in the acrylate. (v) Catalyst loading experiments show that the catalyst is first order. The orders in the various regents were further confirmed by Variable Time Normalization Analysis (VTNA). (vi) A mechanism based on oxidative dimerization [via Co(I)/Co(III)-cycle] is proposed. Based on the results of this study, it is possible to increase the TON by a factor of 10 by conducting the reaction at an increased concentration of the starting materials, especially, the diene, which seems to stabilize the catalytic species.

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The WAA apheresis registry was established in 2003 and an increasing number of centers have since then included their experience and data of their procedures. The registry now contains data of more than 74,000 apheresis procedures in more than 10,000 patients. This report shows that the indications for apheresis procedures are changing towards more oncological diagnoses and stem cell collections from patients and donors and less therapeutic apheresis procedures. In centers that continue to register, the total extent of apheresis procedures and patients treated have expanded during the latest years.

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Paediatric obesity rates remain high despite extensive efforts to prevent and treat obesity in children. We investigated the quality of the methodology and reporting within systematic reviews (SRs) underpinning paediatric content in US clinical practice guidelines (CPGs). In June 2016 we searched guideline clearinghouses and professional organization websites for guidelines published by national or professional organizations in the United States from January 2007 onwards. In our primary, a priori analysis, we used PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) instruments to score SRs and meta-analyses that included paediatric populations and were cited by included CPGs. In a secondary, post hoc analysis, we determined the extent to which US CPGs use available, relevant SRs and meta-analyses compared with non-US CPGs. Eight US-based CPGs with 27 references to 22 unique SRs were found. AMSTAR and PRISMA scores were low overall, with only three SRs having 'high' methodological quality. Items dealing with bias assessments and search strategies had especially low scores. US CPGs were also older on average and cited fewer SRs than their international counterparts. Low quality scores and dated guidelines should be a cause for concern among practicing clinicians and a call to action for future guideline developers, publishers and research institutions.

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Apheresis with different procedures and devices are used for a variety of indications that may have different adverse events (AEs). The aim of this study was to clarify the extent and possible reasons of various side effects based on data from a multinational registry. The WAA-apheresis registry data focus on adverse events in a total of 50846 procedures in 7142 patients (42% women). AEs were graded as mild, moderate (need for medication), severe (interruption due to the AE) or death (due to AE). More AEs occurred during the first procedures versus subsequent (8.4 and 5.5%, respectively). AEs were mild in 2.4% (due to access 54%, device 7%, hypotension 15%, tingling 8%), moderate in 3% (tingling 58%, urticaria 15%, hypotension 10%, nausea 3%), and severe in 0.4% of procedures (syncope/hypotension 32%, urticaria 17%, chills/fever 8%, arrhythmia/asystole 4.5%, nausea/vomiting 4%). Hypotension was most common if albumin was used as the replacement fluid, and urticaria when plasma was used. Arrhythmia occurred to similar extents when using plasma or albumin as replacement. In 64% of procedures with bronchospasm, plasma was part of the replacement fluid used. Severe AEs are rare. Although most reactions are mild and moderate, several side effects may be critical for the patient. We present side effects in relation to the procedures and suggest that safety is increased by regular vital sign measurements, cardiac monitoring and by having emergency equipment nearby.

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This study documented the use of chemicals and biological products in marine and brackish water shrimp farming in Thailand, the world's top producer of farmed shrimp. Interviews were conducted with 76 shrimp farmers in three major shrimp producing regions, the eastern Gulf coast, the southern Gulf coast and the Andaman coast area. Farmers in the study used on average 13 different chemicals and biological products. The most commonly used products were soil and water treatment products, pesticides and disinfectants. Farmers in the southern Gulf coast area used a larger number of products than farmers in the other two areas. In the study, the use of more than 290 different chemicals and biological products was documented. Many of the pesticides, disinfectants and antibiotics used by the farmers could have negative effects on the cultured shrimps, cause a risk for food safety, occupational health, and/or have negative effects on adjacent ecosystems. Manufacturers and retailers of the products often neglected to provide farmers with necessary information regarding active ingredient and relevant instructions for safe and efficient use.

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In the present experiment, we evaluated the effects on plumage condition and health of feeding a mash or a crumbled diet to two hybrids of laying hens in an aviary system. The two diets had the same composition and calculated nutrient content. A total of 3,204 birds was studied from 20 to 80 wk of age. Two hybrids, Lohmann Selected Leghorn and SLU-1329 (two line crosses of Leghorn and Rhode Island Red), were housed in six pens each of an aviary system with groups of 269 and 265 birds, respectively. There were three replicates per treatment (diet x hybrid). Diet generally had little effect on plumage condition, health, and tonic immobility. However, birds fed the crumbled diet had significantly fewer problems with bumble foot than those fed the mash diet. Hybrids reacted differently in most traits studied; SLU-1329 had better health scores but more problems with cannibalism and salpingitis than Lohmann Selected Leghorns, whereas the reverse was found in the proportion of cases with coccidiosis. The hybrid differences found underline the importance of genotype.

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Effects of feeding a crumbled diet compared with a mash diet on laying performance and egg quality of two hybrids of laying hens, a total of 3,204 birds, kept in an aviary system from 20 to 80 wk of age, were investigated. The two diets had the same composition and calculated nutrient content. Two hybrids, Lohmann Selected Leghorn (LSL) and SLU-1329 (a two-line cross of Leghorn x Rhode Island Red), were housed in six pens each of an aviary system with groups of 269 and 265 birds, respectively. There was a total of three replicates per treatment (diet x hybrid). Birds fed the mash diet compared with those fed the crumbled diet had a significantly higher proportion of misplaced eggs, inferior feed conversion ratio (FCR), and higher energy consumption per kilogram egg mass produced (collectable misplaced eggs included). The latter birds had higher body and egg weight, suggesting a higher nutritive value for the crumbled diet. Higher egg mass production and a more intensive yolk color were also found for the birds fed the crumbled diet compared with the mash diet. Hybrid affected production and egg quality traits the most. The LSL also showed significantly higher excreta DM compared with SLU-1329. Interactions between diets and hybrids were found regarding the proportion of misplaced eggs, dirty eggs, egg weight, and FCR. Some of the interactions may indicate other genetic and nutritional factors affecting bird performance in aviary systems more than is normally seen in cages.

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The opioid receptor binding in the human thalamic area was studied with U-69593 and naloxone as ligands for the kappa and mu receptors, respectively. The binding was inhibited by various tricyclic antidepressants including amitriptyline, nortriptyline, clomipramine and fluoxetine. The antidepressants tested had a slight selectivity for the kappa receptor type. The IC50-values for all tricyclic antidepressants tested were in the 10(-6) M concentration range. Morphine and tricyclic antidepressants are substrates of a liver microsomal uridine diphosphate glucuronyl transferase (UDPGT). The interaction of the tricyclic antidepressants with morphine glucuronidation was investigated in human liver microsomal preparations. All drugs inhibited the morphine UDPGT. In Dixon plots inhibition of the formation of morphine-3-glucuronide and morphine-6-glucuronide was non-competitive for nortriptyline, and competitive or mixed for amitriptyline and clomipramine. Lubrol PX activated the morphine-UDPGT four to five times. The degree of activation of the enzyme(s) was unaltered in presence of the inhibiting drugs. The inhibition was also observed at a tricyclic antidepressant/morphine concentration ratio close to that achieved in plasma from patients treated with these drugs.

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Metabolic interaction between naloxone and morphine has been studied in vitro in human liver microsomes. Morphine and naloxone are metabolized by an UDP-glucuronyl transferase to their 3-glucuronides. There is a very good correlation between the rates of formation of morphine-3-glucuronide and of naloxone-3-glucuronide. Naloxone seems to have a 10-fold higher affinity for the enzyme binding site than does morphine. Morphine and naloxone show bisubstrate kinetic patterns which appear very similar.

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1. Morphine uridine diphosphate glucuronyl transferase (UDP-GT) was studied in human liver microsomes. The (-)- and (+)-morphine enantiomers were used as substrates and inhibitors, such as oxazepam and various opioid congeners were employed to characterize the different glucuronidation pathways. The kinetics of the oxazepam inhibition were studied in the rat liver. 2. The overall glucuronidation of (+)-morphine was higher than that of (-)-morphine. The morphine congeners tested, potently inhibited the formation of (-)-morphine-3-glucuronide ((-)-M3G), except for normorphine and codeine. The formation of (+)-morphine-6-glucuronide [+)-M6G) was potently inhibited by only dextromethorphan and (+)-naloxone. All drugs except normorphine inhibited the formation of (+)-M3G by 18-50%. 3. The metabolism of (-)-morphine to (-)-M3G was more sensitive to oxazepam inhibition than the formation of (+)-M3G from (+)-morphine in the rat liver. 4. The glucuronidation of natural morphine is subject to in vitro interaction with oxazepam and several opiate drugs. Our study supports the theory of more than one type of UDP-GT being involved in morphine glucuronidation.

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A reversed-phase HPLC system was used to concentrate and separate components of substance P-like immunoreactivity (SP-LI) from human CSF. When CSF was injected and fractions collected, no SP-LI could be detected by radioimmunoassay (RIA) at the retention time of SP or SP-sulfoxide. Instead, SP-LI was detected in later eluting fractions. This SP-LI reacted with two different antisera raised against the C-terminal part of SP, but not with an antiserum against the N-terminal part. A compound with similar properties was also found to be present in neutral extracts of rat dorsal spinal cord. When the late-eluting compound from human CSF was treated with trypsin and rechromatographed on HPLC, an immunoreactive component eluting at the position of SP could be detected with both the C- and N-terminally directed SP antisera. These results suggest that an N-terminally extended form of SP is present in human CSF. Trypsinization also gave two other compounds with affinity for the N- but not the C-terminally directed antisera. This may indicate that N-terminal fragments of SP extended at the N-terminus or SP molecules extended at both the N- and the C-terminus (i.e., preprotachykinins) also are present in human CSF. In 32 CSF samples from depressed patients, SP-LI was determined with a C-terminally directed antiserum with and without prior HPLC separation. SP itself could not be detected, but the late-eluting form of SP-LI could be quantitated in all samples by combined HPLC-RIA. In most samples, there was a relatively good agreement between the SP-LI levels measured with and without HPLC.

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Morphine UDP-glucuronyltransferase activity was demonstrated in the brain of mice from recombinant inbred strains of the BXD series. The formation rate of morphine-3-glucuronide was about 4 fold higher in the progenitor DBA as compared to the C57BL strain.

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A high molecular weight polypeptide (ca. 24000 Da) which contained only (Leu) enkephalin immunoreactivity, has been isolated from spinal cord. Molecular size and the presence of at least one copy of (Leu)enkephalin was established by chromatography in combination with a specific radioimmunoassay for (Leu)enkephalin.

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Opioid peptides have been purified from large pooled samples of human cerebrospinal fluid. The purification steps involved chromatography on Sephadex G-10 and electrophoresis in agarose suspension. The purified material was further characterized by HPLC and radioimmunoassay. All procedures were guided by a specific radioreceptor assay. The Sephadex G10 fractionation yielded receptor activity in two discrete fractions, Fraction I (FI) and Fraction II (FII). A second Sephadex run of FII gave a partial resolution of two components, one of which was larger (FIIA). Electrophoresis resolved these fractions into several components, most of which showed a more basic behaviour than the enkephalins. Thus, FI separated into at least 4 components and FIIB into two components while FIIA remained a single peak. These components appeared to migrate as distinct peaks and some of them also chromatographed on a HPLC-column as single components. Considering their behaviour in electrophoresis and on HPLC, two components are suggested to represent known endorphin structures. The predominant FII component (FIIA) was thus indistinguishable from Met-enkephalin-Lys6 in all chromatographic systems and one of the most basic FI components showed close similarity with dynorphin. Each of these components occurs at a higher concentration than Met- or Leu-enkephalin, dynorphin or beta-endorphin.

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The tridecapeptide NH2-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr-COOH has been purified from extracts of bovine posterior pituitary glands. This unique peptide, which has been given the name "rimorphin," is a major [Leu]enkephalin-containing peptide in all tissues examined that contain dynorphin and alpha-neo-endorphin. However, except for the initial hexapeptide sequence, it is structurally unrelated to the other two peptides.

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In a series of 90 patients with chronic pain syndromes of psychogenic and organic etiology, the concentrations of fraction I endorphins in cerebrospinal fluid were investigated. A significant circannual variation in the concentrations of endorphins was found, with the highest concentrations in January-February and the lowest concentrations in July-August. There was no corresponding seasonal variation with regard to age, sex, bodylength, possible etiology of the pain syndrome self-rated pain levels, or experimental pain measures. Circannual difference in the intensity of symptoms in chronic pain syndromes and in affective disorders have been described in the literature. The present results suggest an association between these observations, giving further support for functional importance of endorphins in chronic pain.

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Levels of endorphins were determined in CSF from alcoholics while intoxicated or after 1 day, 1 week, and 3 weeks of abstinence, respectively, and from healthy volunteers. The level of endorphins was determined by a radioreceptor assay and two fractions were analyzed. With fraction 1, there were no significant differences between the groups, but the level was negatively correlated with the blood-alcohol level. The mean level of endorphin fraction 2 during the early withdrawal phase was significantly lower than those of the other groups. With respect to clinical conditions and monoamine metabolites, fraction 2 in early withdrawal correlated significantly to duration of abuse and age. During late withdrawal, fraction 1 level correlated to depressive symptoms and, after 3 weeks of abstinence, fraction 2 correlated to MOPEG levels. This study suggests that endorphin systems are affected during alcohol intoxication and withdrawal in alcoholics.

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Endorphin levels were measured in 51 cerebrospinal fluid samples from 27 opioid-dependent or postdependent subjects. Radioreceptor assay showed the endorphin levels to be higher than those found in normal subjects. These high levels were found even while subjects were on methadone maintenance. The duration of opioid dependence was positively correlated with fraction I values. Both fractions tended to be lower during early withdrawal than late withdrawal. In naltrexone-maintained patients, radioreceptor assay showed FII to be greatly elevated, but electrophoresis and HPLC indicated that the elevations were not due to a peptide. Thus, the possibility of unextracted naltrexone metabolites remains at least a partial explanation for this apparent FII elevation.

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