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[Image: see text] Biotransformation has a huge impact on the efficacy and safety of drugs. Ultimately the effects of metabolism can be the lynchpin in the discovery and development cycle of a new drug. This article discusses the impact and application of biotransformation of drugs by mammalian systems, microorganisms, and recombinant enzymes, covering active and reactive metabolites, the impact of the gut microbiome on metabolism, and how insights gained from biotransformation studies can influence drug design from the combined perspectives of a CRO specializing in a range of biotransformation techniques and pharma biotransformation scientists. We include a commentary on how biology-driven approaches can complement medicinal chemistry strategies in drug optimization and the in vitro and surrogate systems available to explore and exploit biotransformation.

The synthesis, identification, and testing of drug metabolites are key in meeting regulatory guidelines. This chapter provides an overview of the methods available for generating metabolites through various means, using both chemical and biological approaches. Case studies are presented to illustrate the opportunities and challenges in producing metabolites by each method. We also address considerations needed in the purification and structure elucidation of metabolites using NMR spectroscopy, especially relevant now that the increased sensitivity of modern NMR instrumentation makes the definitive identification of metabolites possible with only low microgram quantities of purified metabolite material.

Metabolite identification is an integral part of both preclinical and clinical drug discovery and development. Synthesis of drug metabolites is often required to support definitive identification, preclinical safety studies and clinical trials. Here we describe the use of microbial biotransformation as a tool to produce drug metabolites, complementing traditional chemical synthesis and other biosynthetic methods such as hepatocytes, liver microsomes and recombinant human drug metabolizing enzymes. A workflow is discussed whereby microbial strains are initially screened for their ability to form the putative metabolites of interest, followed by a scale-up to afford quantities sufficient to perform definitive identification and further studies. Examples of the microbial synthesis of several difficult-to-synthesize hydroxylated metabolites and three difficult-to-synthesize glucuronidated metabolites are described, and the use of microbial biotransformation in drug discovery and development is discussed.

Efficient enrollment management offices routinely calculate the return on the investment made in recruitment, yield and retention activities. Offices track cost per applicant, cost per enrollee, net tuition revenue, etc. There are national benchmarks for such performance data. For example, the median cost to recruit a student is $2,433 for private colleges and $457 for public colleges, according to research published by Ruffalo Noel Levitz (see https://www.noellevitz.com/papers-research-higher-education/2013/2013-cost-of-recruiting-an-undergraduate-student-report).

An extract of a culture of the fungus Galiella rufa yielded several new derivatives of pregaliellalactone (1) that were characterised by NMR and MS experiments. The tetraene 4 has been reported previously, but was in this investigation isolated in sufficient amounts for the determination of the configuration of the C-4/C-5 double bond which is Z, not E. The possibility that any of the new compounds are involved in the biosynthesis of 1 is discussed. (C) 2015 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.

NATO troops are leaving Afghanistan in 2014, a quarter of a century after Soviet troops ended their occupation. How comparable are the two retreats, and will Afghans suffer fighting and destruction similar to what happened when foreign troops last left? Mikhail Gorbachev, who took the withdrawal decision in 1985, felt the war had become an expensive stalemate. The USSR opted to base its exit strategy on diplomacy and the idea that the Afghan government should pursue peace talks with its armed opponents. This emphasis on negotiations differs from Obama's policy, which remains predominantly military and rejects compromise with the Taliban. Obama and NATO claim progress on the battlefield and argue that combat duties can safely be “transitioned” to newly trained Afghans. But most Afghans are gloomy. Although they do not expect Kabul to fall to the Taliban, they believe that the insurgents will capture large parts of southern Afghanistan. Many also fear that ethnic tensions will grow throughout the country, p...

Microbes monitor their population density through a mechanism termed quorum sensing. It is believed that quorum-sensing molecules diffuse from the microbial cells and circulate in the surrounding environment as a function of cell density. When these molecules reach a threshold concentration, the gene expression of the entire population is altered in a coordinated manner. This work provides evidence that Aspergillus nidulans produces at least one small diffusible molecule during its growth cycle which accumulates at high cell density and alters the organism's behaviour. When added to low-density cell cultures, ethyl acetate extracts from stationary phase culture supernatants of A. nidulans resulted in the abolition of the lag phase, induced an earlier deceleration phase with 16.3 % decrease in the final cell dry weight and resulted in a 37.8 % increase in the expression of ipnA::lacZ reporter gene construct, which was used as a marker for penicillin production compared to non-treated controls. The bioactive molecule present in the stationary phase extract was purified to homogeneity and was identified by liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy to be γ-heptalactone. This study provides the first evidence that A. nidulans produces γ-heptalactone at a high cell density and it can alter the organism's behaviour at a low cell density. γ-Heptalactone hence acts as a quorum-sensing molecule in the producing strain.

There have been many recent advances in techniques for prenatal diagnosis. The direct diagnostic procedures of amniocentesis and chorionic villus sampling, which involve analysis of foetal material, are described and indications of their risks and reliability are given. Other direct procedures are briefly mentioned. Indirect biochemical analyses that identify groups at increased risk are also considered and their individual reported relationships with Down's syndrome are discussed. Technical problems and reported acceptability of maternal serum alpha fetoprotein screening are briefly mentioned. Studies reporting the potential of ultrasonography in the prenatal detection of Down's syndrome are reviewed. Other indications of increased risk are briefly mentioned.

The Guardian's Senior Foreign Correspondent and in-house columnist on international affairs analyses the possibilities and problems facing the incoming Obama administration in Iraq and the wider Middle East region. Jonathan Steele argues that the Bush administration was defeated in Iraq on a number of fronts and that US influence has declined across the region. He explains how the gains made in establishing order have been largely a result of the actions taken by Iraqi actors in reasserting Iraqi sovereignty both against the US and Al-Qaeda. Despite the debacle of US intervention, Steele argues that Barack Obama has a platform of opportunity to address the problems of the Middle East through the exercise of US ‘soft power’ rather than military might.

Forensic services in Scotland are evolving, based on similar developments previously in England and Wales. The Orchard Clinic in Edinburgh is the first medium secure unit to open in Scotland. This paper aims to describe the patients admitted to the unit in the first five years of its operation, to consider antecedents to their admission, patient characteristics and progress through the system. With the development of a new service it is important to benchmark against established services and, therefore, a comparison is made with earlier studies of forensic populations in Scotland and elsewhere in the UK.

Assessment of risk of violence is essential in the management of patients with schizophrenia admitted to secure hospitals. The present study was conducted to test the validity of actuarial measures and psychotic symptoms in the prediction of further violence and offending in this group. The H-10 scale of the HCR-20, Violence Risk Appraisal Guide and Psychopathy Checklist-Revised were scored retrospectively. Symptom severity was rated at interview and persistence from notes. Outcome was measured using criminal records and recorded incidents of aggression over an 8-10 year period. Seventy-six percent of patients were involved in more than 1800 incidents defined as physical contact with a victim or damage to property, and 28% in a serious incident defined as injury to a victim requiring hospital treatment, a contact sexual incident or fire setting. Fifteen percent of patients were convicted of any offense and 5% of a violent offense. The risk scales had moderate to high predictive accuracy for offenses and v...

SummaryDaptomycin is a lipopeptide antibiotic produced by a nonribosomal peptide synthetase (NRPS) in Streptomyces roseosporus. The holoenzyme is composed of three subunits, encoded by the dptA, dptBC, and dptD genes, each responsible for incorporating particular amino acids into the peptide. We introduced expression plasmids carrying dptD or NRPS genes encoding subunits from two related lipopeptide biosynthetic pathways into a daptomycin nonproducing strain of S. roseosporus harboring a deletion of dptD. All constructs successfully complemented the deletion in trans, generating three peptide cores related to daptomycin. When these were coupled with incomplete methylation of 1 amino acid and natural variation in the lipid side chain, 18 lipopeptides were generated. Substantial amounts of nine of these compounds were readily obtained by fermentation, and all displayed antibacterial activity against gram-positive pathogens.

Lakhdar Brahimi, a former Algerian foreign minister with long experience in the U.N. system, who was asked by Kofi Annan in 2000 to prepare a report on reforming peacekeeping, has called these "peace-building" tasks. In the case of East Timor, the Security Council devised a unique mandate. For the first time in history, it took total control of a country, with all executive, legislative, judicial, and even military power vested in its appointed administrator, who ran everything from the power stations and fire departments to radio, television, and a U.N. newspaper. So when Kofi Annan watched the blue U.N. flag come down over Dili, East Timor's capital, at midnight this past May 19, the tropical air hung heavy with colonial antecedents. The secretary general was not just a VIP at someone else's independence party. He was an imperial sovereign handing over the reins of power. The mission he closed was the shortest, least bloody, most benevolent, and possibly most successful colonization since the Middle Ages. But, in carrying out its mandate, UNTAET made mistakes from which future U.N. missions would do well to learn. Untaet's very name United Nations Transitional Administration in East Timor conceded that this was no proud empire on which the sun would never set. U.N. Resolution 1272 of October 25, 1999, which authorized the mission, did not mention an exit date, but U.N. members foresaw a timeframe of two, perhaps three, years. In early September 1999, Indonesia had agreed to withdraw from East Timor and allow an Australian-led peace force to enter the territory to guarantee security. Untaet was to take over command from the Australians and create a civil administration to

Swedish public law has incorporated a general rule of public access to documents, and to information in the wider sense, since the Freedom of the Press Act of 1766. On the Community level, the relationship between Regulation (EC) 45/2001 on data protection and Regulation (EC) 1049/2001 on public access to documents exemplifies the tension between the public's interest in scrutinising the administration carried on in its name, and the integrity of the individual. However, a similar tension exists between Sweden's Personal Data Act of 1998, implementing Directive 95/46, and the Freedom of the Press Act. A misuse model of data protection law, by seeking to concentrate on serious rather than technical infringements of privacy, might serve to ease the tension. The views expressed in this article are solely those of the author and are not attributable to any Community institution.

Aims and MethodThis paper is based on two audits carried out in 1996 and 1998 atThe State Hospital, Carstairs. Each audit looked at anti-muscarinic drug use within the hospital, in relation to approved prescribing standards issued in 1996. All patients within the hospital on anti-muscarinic drugs were identified at the timeof each audit. These prescriptions were compared with the approved prescribing standards. In the 1998 audit additional information was obtained from the case notes and the consultants, when the approved standards were not met.ResultsThe percentage of patients on regular anti-muscarinic drugs, falling outwith the prescribing standards, reduced between the two audits. However, in 1998 a small number of patients were still outwith the approved prescribing standards set in 1996.ConclusionsAn improvement in the prescribing practice of anti-muscarinics occurred following the introduction of prescribing guidelines. However, the guidelines were not fully met in the 1998 audit. This demonstrates the need for further audit and continued monitoring of anti-muscarinic prescription at the State Hospital.

The inclusion of pupils with learning difficulties within their communities depends on many complex factors, with educational placement being only one of these. Concepts of integration and segregation are not poles on a linear continuum, but even if they were, the concept of true inclusion would not appear anywhere on such a line. The factors which influence inclusion alter with time as changes and developments are made in different aspects of community provision. Such changes can be effected by simple movement or appointment of key personnel. Attitudes have a major effect on expectations and the way people with special needs are treated (Johnson and Johnson, 1986). The range of attitudes to, and expectations of pupils with, severe learning difficulties (SLD) will be clear to those involved in the field; variations can be observed within and between schools and communities as well as at different points in time. This chapter considers ways of promoting more inclusive practice through the exploitation of links between special schools and a range of mainstream or community environments.

Goodbye to glasnost, welcome back propaganda. Uncertain of the outcome of the December elections, the President reverts to the old ways

Stunned by the sudden imposition of martial law in Poland, the West reacted with astonishing naivety. Politicians and commentators asked whether General Jaruzelski was a patriot or a puppet. Should he so the assumption went be put on probation or punished? Was martial law a Polish initiative or a Soviet one? If it was the former, then it could be seen as pre-empting a Russian move, and deserved to be treated in a less critical light. Was he and this was the most optimistic of all the new theories a kind of Polish Tito? All three questions were disarming, and none more so than the vision of Jaruzelski as Tito. Could it seriously be supposed that the man presiding over martial law and locking up the leaders of Solidarity was suddenly going to become non-aligned and take Poland out of the Warsaw Pact? The reality, surely, is that the question whether Russians or Poles contrived the hardline policies which are now underway in Poland is irrelevant. If one imagines Poland back again as it was in November 1981 and then imagines what it would be like under Russian occupation, the position of Polish-administered martial law (prevailing at the time of writing in mid-January) is far closer to the latter. Poland has not gone all the way down the road of Czechoslovakia in 1968, but that is less important than the fact that the path of conciliation, and reform by consensus, and controlled pluralism has been blocked. The hopes of 1981 have been shattered. Poland has invaded itself. One should not forget that it took eight months after the invasion of Czechoslovakia for Mr Dubcek to be formally removed from power. Consolidation of the new hardline took some time, as it will do in Poland. But one should not confuse the time and false promises necessary for consolidation with illusions about the chances for compromise. In September and October 1968 people in the West were using the same arguments about future developments in