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Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCOgene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1bgene cluster knockout and human SLCO1B1and SLCO1B3gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [Silybum marianum]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC0–24honly (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC50values for the relevant OATPs/Oatps. Silymarin increased the Cmaxof pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter (SLCO)genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathologic and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1and SLCO1B3.Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multifactorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55-fold from the diet alone and the 1.88-fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multifactorial pharmacokinetic interactions.SIGNIFICANCE STATEMENTAdvanced stages of NAFLD cause decreased hepatic OATP1B abundance and increase systemic exposure to OATP substrates in human patients. The humanized OATP1B mouse strain may provide a clinically relevant model to recapitulate these observations and predict pharmacokinetic interactions in NAFLD. This research characterized three diet-induced and one drug-induced NAFLD model in a humanized OATP1B mouse model. Additionally, a multifactorial pharmacokinetic interaction was observed between silymarin and NAFLD.

Les traitements par inhibiteurs des points de contrôle ont révolutionné la prise en charge de nombreux cancers dont le mélanome. En favorisant la réponse immunitaire antitumorale, ces molécules sont pourvoyeuses d’effets indésirables auto-immuns. Nous rapportons un cas exceptionnel de fasciite à éosinophiles immuno-induite.

Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin Cmaxand area under the blood concentration versus time curve (AUC) by 27% and 23%, respectively, but half-life and renal clearance were unchanged. These observations suggested goldenseal altered processes involved in metformin absorption. The underlying mechanism(s) remain(s) unknown. One mechanism for the decreased metformin systemic exposure is inhibition by goldenseal of intestinal uptake transporters involved in metformin absorption. Goldenseal extract and three goldenseal alkaloids (berberine, (–)-β-hydrastine, hydrastinine) were tested as inhibitors of organic cation transporter (OCT) 3, plasma membrane monoamine transporter (PMAT), and thiamine transporter (THTR) 2 using human embryonic kidney 293 cells overexpressing each transporter. The goldenseal extract, normalized to berberine content, was the strongest inhibitor of each transporter (IC50: 4.9, 13.1, and 5.8 μM for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice compared the effects of berberine, (–)-β-hydrastine, goldenseal extract, and imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract and imatinib significantly decreased metformin Cmaxby 31% and 25%, respectively, and had no effect on half-life. Berberine and (–)-β-hydrastine had no effect on metformin pharmacokinetics, indicating neither alkaloid alone precipitated the interaction in vivo. A follow-up murine study involving intravenous metformin and oral inhibitors examined the contributions of basolateral enteric/hepatic uptake transporters to the goldenseal–metformin interaction. Goldenseal extract and imatinib had no effect on metformin AUC and half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake transporters. Results may have implications for patients taking goldenseal with drugs that are substrates for OCT3 and THTR2.SIGNIFICANCE STATEMENTGoldenseal is used to self-treat respiratory infections and digestive disorders. We investigated potential mechanisms for the clinical pharmacokinetic interaction observed between goldenseal and metformin, specifically inhibition by goldenseal of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters in vitroand decreased metformin systemic exposure in mice. These data may have broader implications for patients co-consuming goldenseal with other drugs that are substrates for these transporters.

La tomosíntesis digital ha mostrado beneficio en la evaluación del daño articular. El objetivo del estudio es describir los hallazgos frecuentes a través de la tomosíntesis digital en cuatro patologías reumatológicas y comparar su utilidad con otras técnicas de imagen.

Transthoracic echocardiography (TTE) is widely used as a pre-operative screening tool. It can provide extensive information about cardiac function and underlying pathology, which could influence decisions regarding surgery. This patient was referred for TTE as part of pre-op screening, as he had a biological prosthetic aortic valve. This was a rare case where misleading TTE measurements inadvertently led to the patient being referred for transcatheter aortic valve implantation (TAVI), which delayed non-cardiac surgery.Echocardiographers and referrers should be familiar with physiological and haemodynamic conditions that can affect measurements.Echocardiographic results should be interpreted in wider clinical context, particularly when it changes management.Lack of clinical information on the referral form limits echocardiographer’s ability to interpret results in clinical context.Referring non-cardiologists may not be aware of haemodynamic factors that could affect echocardiographic measurements.

Geological surveys have long filled the role of providing Earth system science data and knowledge. These functions are increasingly complicated by accelerating environmental and societal change. Here we describe the US Geological Survey (USGS) response to these evolving conditions. Underpinning the USGS approach is the recognition that many of the issues facing the USA and the world involve interaction among geological, hydrological and biological processes, and how these interactions in turn affect society. Therefore, a goal of USGS planning is fostering interdisciplinary science. This focus is occurring in part through implementation of the recommendations of strategic planning teams. The USGS has also put in place groups building a broad information technology infrastructure as well as identifying and disseminating new Earth science research tools. In addition, the USGS has established an analysis and synthesis centre that brings together groups of scientists who address interdisciplinary Earth system science issues. The goal is for these building blocks to evolve towards a comprehensive USGS data and knowledge platform – EarthMAP (Earth Monitoring, Assessment, and Projection). We also recognize that the modern geological survey must be a member of a community of geological surveys contributing data to a global database of three-dimensional biogeophysical observations and interpretations.

The majority of physicians are surfeited to the point of illness by the reading of journals. Cited and translated by D A Kronick in A history of scientific and technical [...]

General impressions are never to be trusted. Unfortunately when they are of long standing they become fixed rules of life, and assume a prescriptive right not to be questioned. Consequently [...]

EDITOR--The otherwise excellent special issue on medicine and international law (14 August) did not describe, deplore, or explain that doctors have committed genocide, are still doing so, and may well [...]

In the A. and B. v. Norway case decided by the European Court of Human Rights (ECtHR) on 15 November 2016 (24130/11 and 29758/11), the principle of ne bis in idem suffered a significant blow. Via the Luca Menci (C-524/15), Garlsson Real Estate (C-537/16) and Di Puma (C-596/16 and C-597/16) cases, the European Court of Justice (ECJ) was confronted with a challenging decision: either stay with the path set out by the ECJ on 26 February 2013 in the Åkerberg Fransson case (C-617/10) or follow the ECtHR and thereby strike a knockout blow to the right that is guaranteed by the principle of ne bis in idem. In its judgments of 20 March 2018, the ECJ came up with a surprising solution. [ABSTRACT FROM AUTHOR]

In European Court of Human Rights (ECtHR) 15 November 2016, No. 24130/11 and 29758/11, (A. and B. v. Norway) the Jussila-doctrine was repeated once again. The ECtHR seems to have taken the next step in the discussion whether the criminal-head guarantees of Article 6 ECHR and other fundamental rights of the Convention should not apply in the same manner concerning tax fines as they do with 'hard core criminal law'. However, as shown in ECJ 26 February 2013, C-617/10 (Åkerberg Fransson), the European Court of Justice (ECJ) is currently on a different path. In case C-524/15 Advocate General Campos Sánchez-Bordona has advised the ECJ to stay on its present course and not to follow the ECtHR. In this article the authors discuss the different approaches of the ECtHR and the ECJ. [ABSTRACT FROM AUTHOR]

Abstract ID 23219

Meeting ProgrammeDr Nigel Botting [University of St Andrews, UK] – Isotopic Labelling of Lignan Phytoestrogens.Prof. Frédéric Dollé [CEA PET Centre, Orsay, France] – Fluorine‐18 Chemistry: A Selection of Recent Advances.Prof. Peter Scott [University of Warwick, UK] – Creating Chiral Metal Centres.Mr Laurent Brichard [WBIC, University of Cambridge, UK] – A Simple Device for the Radiosynthesis of [Carbonyl‐11C]amides, Esters and Ketones using Carbon‐11 Monoxide.Dr Michael Hickey [AstraZeneca Charnwood, UK] – Tritium‐labelling via an Iridium‐based Solid‐phase Catalyst.Prof. Wolfgang Steglich [Ludwig‐Maximilians University, Germany] – Meroterpenoids from Mushrooms, A Colourful Group of Natural Products.Dr Joe Schofield [Sanofi‐Aventis, France] – Radio‐ and Stable‐isotope Labelling of SSR591813 – A Nicotinic Partial Agonist.Dr Nikolai Kuhnert [University of Surrey, UK] – Chiral Recognition in Ion Trap Mass Spectrometry using Isotopically Labelled Trianglamine Macrocycles.Dr Paul Watts [University of Hull, UK] – The Application of Micro Reactors for Radiochemical Synthesis.Dr Tony Gee [GlaxoSmithKline, UK] – PET in Drug Discovery and Development.Dr Alan Wadsworth [GlaxoSmithKline, UK] – Stable Isotopic Labelling of Heterocyclic Compounds

Climate change and anthropogenic nitrogen deposition are both important ecological threats. Evaluating their cumulative effects provides a more holistic view of ecosystem vulnerability to human activities, which would better inform policy decisions aimed to protect the sustainability of ecosystems. Our knowledge of the cumulative effects of these stressors is growing, but we lack an integrated understanding. In this Review, we describe how climate change alters key processes in terrestrial and freshwater ecosystems related to nitrogen cycling and availability, and the response of ecosystems to nitrogen addition in terms of carbon cycling, acidification and biodiversity.

Faire un état des lieux de la fréquence des principales complications de la grossesse chez le personnel du CHU de Bordeaux et les comparer aux données de la population générale (enquête périnatale).

Objective To summarise comparisons of randomised clinical trials and non-randomised clinical trials, trials with adequately concealed random allocation versus inadequately concealed random allocation, and high quality trials versus low quality trials where the effect of randomisation could not be separated from the effects of other methodological manoeuvres. Design Systematic review. Selection criteria Cohorts or meta-analyses of clinical trials that included an empirical assessment of the relation between randomisation and estimates of effect. Data sources Cochrane Review Methodology Database, Medline, SciSearch, bibliographies, hand searching of journals, personal communication with methodologists, and the reference lists of relevant articles. Main outcome measures Relation between randomisation and estimates of effect. Results Eleven studies that compared randomised controlled trials with non-randomised controlled trials (eight for evaluations of the same intervention and three across different interventions), two studies that compared trials with adequately concealed random allocation and inadequately concealed random allocation, and five studies that assessed the relation between quality scores and estimates of treatment effects, were identified. Failure to use random allocation and concealment of allocation were associated with relative increases in estimates of effects of 150% or more, relative decreases of up to 90%, inversion of the estimated effect and, in some cases, no difference. On average, failure to use randomisation or adequate concealment of allocation resulted in larger estimates of effect due to a poorer prognosis in non-randomly selected control groups compared with randomly selected control groups. Conclusions Failure to use adequately concealed random allocation can distort the apparent effects of care in either direction, causing the effects to seem either larger or smaller than they really are. The size of these distortions can be as large as or larger than the size of the effects that are to be detected., When I became a clinical student in 1952 medical wards had many patients with incurable chronic rheumatic heart disease. Mitral valv(ul)otomy had just started, and at the Central Middlesex Hospital [...]

We evaluated the short-term of 0 to 90 days and the longer term, up to 12.7 years, mortality for patients undergoing primary total hip replacement (THR) in Denmark in comparison to the general population. Through the Danish Hip Arthroplasty Registry we identified all primary THRs undertaken for osteoarthritis between 1 January 1995 and 31 December 2006. Each patient (n = 44 558) was matched at the time of surgery with three people from the general population (n = 133 674). We estimated mortality rates and mortality rate ratios with 95% confidence intervals for THR patients compared with the general population. There was a one-month period of increased mortality immediately after surgery among THR patients, but overall short-term mortality (0 to 90 days) was significantly lower (mortality rate ratio 0.8; 95% confidence interval 0.7 to 0.9). However, THR surgery was associated with increased short-term mortality in subjects under 60 years old, and among THR patients without comorbidity. Long-term mortality was lower among THR patients than in controls (mortality rate ratio 0.7; 95% confidence interval 0.7 to 0.7).Overall, THR was associated with lower short- and long-term mortality among patients with osteoarthritis. Younger patients and patients without comorbidity before surgery may also experience increased mortality after THR surgery, although the absolute risk of death is small.

Scientific interest in defining the human bodys ability to limit the effects of administered drugs and xenobiotics dates from the mid-19th century when developing knowledge and techniques in the field of organic chemistry first made such studies possible. The first experimental evidence documenting the existence of cytochrome p450 (CYP) dates to the year 1955, when an enzyme system capable of oxidizing xenobiotic compounds was identified in the endoplasmic reticulum of liver homogenates. From these days on several studies analyzed the expression and function of metabolizing phase I enzymes in liver cells. Due to the unique structural features of human skin, little was known about the expression and function of CYP enzymes in this tissue and their role in uptake, metabolism and elimination of xenobiotics as well as endogenous substrates. Lasting recent years it has become clear that human skin cells express various CYP enzymes, including CYP26AI which is responsible for the metabolism of retinoic acid in skin cells. It has been also shown that CYP enzyme expression patterns are cell type and tissue specific and that in skin cells this differs significantly from its expression in other environmental interfaces such as the liver, lung and gastrointestinal tract. Therefore knowledge of skinspecific CYP expression and function is a prerequisite for pharmacological studies of the skin.

To use back-to-back diffusion-weighted imaging (DWI) and PET to obtain quantitative measures of the cerebral metabolic rate of oxygen (CMRO2) within DWI lesions, and to assess the perfusion-metabolism coupling status by measuring the cerebral blood flow and the oxygen extraction fraction within DWI lesions.

In 1980s change in meat and bone meal production technology led to the spread of BSE and massive culling of beef cattle in many countries. Adding meat and bone meal to animal feed was banned, but animal carcasses still have to be disposed of.In this work the operational parameters and efficiency of a utilisation process for raw meat wastes and emissions of CO, NOx , SO2 and VOC were studied. A 5 kWth fluidised bed combustor was used and tests were repeated in a 150 kWth (KFD-s14u) boiler, with combustion of meat wastes (biomal). With combustion, the heat generated can be recovered, the meat waste is completely burned, bone pieces mineralised and fragmented and flue gas composition is similar to that with coal alone. The potential of the technology for raw meat waste utilisation has been demonstrated on a technical scale, with waste throughput of 180 kg/h*m2 (with respect to distributor area) and factors limiting the combustion efficiency have been determined.An installation (up to 3 MW thermal) has been designed for the utilisation of 500 kg/h of raw meat waste in cocombustion with coal. The installation should fulfil the requirements with respect to waste utilisation efficiency and thermal energy production.

AbstractBackground and Aim: Telomeres are hexameric repeat sequences that flank eukaryotic chromosomes. The telomere hypothesis of cellular aging proposes that replication of normal somatic cells leads to progressive telomere shortening which induces replicative senescence. Previous studies suggest that growth plate chondrocytes have a finite proliferative capacity in vivo. We therefore hypothesized that telomere shortening in resting zone chondrocytes leads to replicative senescence. Method: To test this hypothesis we compared the telomere restriction fragment (TRF) length of Mus casteneus at 1, 4, 8, and 56 weeks of age. Results and Conclusions: We found that TRF length did not diminish measurably with age, suggesting that telomere shortening in resting zone chondrocytes is not the mechanism that limits proliferation of growth plate chondrocytes in vivo.Copyright © 2005 S. Karger AG, Basel

Les eaux douces agressives ont tendance à réduire la durée de vie des canalisations des réseaux de distribution d'eau potable et la corrosion engendrée est susceptible d'altérer la qualité de l'eau. Par ailleurs, la réglementation française (décret 2001-1220 du 20/12/2001) recommande que les eaux distribuées ne soient pas agressives. Pour lutter contre l'agressivité de ces eaux faiblement minéralisées, deux types de traitement peuvent être proposés : (1) l'addition d'inhibiteurs de corrosion à base de phosphates et (2) la reminéralisation. Ces deux pratiques se révèlent techniquement équivalentes à court terme pour résoudre notamment les problèmes d'eaux rouges dans les réseaux d'eau potable. Néanmoins, leur impact à long terme sur le comportement des conduites n'a jamais été étudié et nécessite de constituer des références scientifiques et techniques. C'est dans cette optique qu'une étude sur un réseau pilote a été lancée par l'un des centres recherche de Véolia Environnement afin d'observer pendant un an l'impact de quatre eaux de qualité différente : (1) une eau agressive, (2) une eau agressive reminéralisée, une eau agressive traitée avec (3) des orthophosphates et (4) des polyphosphates sur cinq types de canalisations métalliques les plus fréquemment rencontrés dans les réseaux de distribution d'eau potable publiques ou privés (acier, fonte usagée, fonte usagée raclée, fonte revêtue ciment et cuivre). L'efficacité de ces traitements a été évaluée à l'aide d'un suivi analytique comprenant notamment le suivi des ions métalliques indicateurs de la corrosion des canalisations étudiées. Les résultats tendent à montrer que la reminéralisation est le traitement le plus efficace pour réduire l'agressivité et la corrosivité des eaux faiblement minéralisées avec un respect constant des critères de potabilité et une garantie de la pérennité des canalisations dans les réseaux de distribution.

To investigate whether the combination of fluoro-2-deoxy-d-glucose (FDG) PET measures with the APOEgenotype would improve prediction of the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).

To determine whether psychosocial factors, chronic diseases, and common geriatric problems are associated with poor physical function 3 years after primary total hip replacement (THR).We studied a sample of Medicare recipients in Ohio, Pennsylvania, and Colorado (n = 922) who underwent primary THR in 1995 (mean ± SD age 73.1 ± 5.6 years, 32% men). Participants completed a questionnaire regarding lifestyle factors, medical history, and quality of life ∼3 years after the surgery. Physical function was measured using the function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index. We assessed the relationship between functional outcome 3 years postsurgery and 4 predictor domains: pain or complications in the operated hip, other musculoskeletal comorbidity, medical factors (obesity, chronic medical comorbidity, rheumatoid arthritis, and such common geriatric problems as falls, poor balance, or incontinence), and psychosocial factors (mental health, regular alcohol consumption, smoking, provider role, living alone, and education).Ten percent of subjects had poor functional status. In a logistic regression model controlling for sex and age, the following factors were associated with an increased risk for poor functional status (in order of importance): pain in the back or lower extremity, severe pain in the operated hip, poor mental health, more than 1 common geriatric problem, obesity, and less than college education.Pain in the operated hip was strongly associated with poor functional status 3 years after THR. However, other factors associated with poor functional status were not related to the hip. Our results suggest that a comprehensive assessment of functional status in elderly THR patients should include assessment of common geriatric problems, mental health status, and weight.

AbstractObjectives: To test the hypothesis that children with short stature and peak stimulated GH (pGH) of 7–10 μg/l have partial GH deficiency and to test the hypothesis that short children with normal pGH but low IGF-I levels have partial GH deficiency or partial GH insensitivity. Design and Patients: Retrospective analysis of the clinical and biochemical profiles of 76 children who underwent an evaluation for short stature (height <5th percentile) that included two, sex steroid-primed GH stimulation tests. Results: Patients with pGH <7 μg/l (n = 14) differed significantly from those with pGH >7 μg/l (n = 62), having greater midparental height (MPH) SDS, a greater disparity between height SDS and MPH SDS, and lower IGF-I SDS. Patients with pGH of 7–10 μg/l (n = 12) did not have characteristics intermediate between those with pGH <7 μg/l and those with pGH ≥10 μg/l, but instead resembled those with pGH ≥10 μg/l. Patients with pGH ≥7 μg/l, but low IGF-I (<–2 SDS) (n = 5), did not show characteristics intermediate between those with pGH <7 μg/l and those with pGH ≥7 μg/l and normal IGF-I. Conclusions: These data do not support either the hypothesis that children with pGH of 7–10 μg/l have partial GH deficiency or the hypothesis that children with normal pGH but subnormal IGF-I levels have partial GH deficiency or insensitivity.Copyright © 2004 S. Karger AG, Basel

Scaling problems have been intensively investigated using carbonically pure water (i.e. synthetic water containing only calcium and carbonates ions) or natural water which only contain few particle suspensions. Nervertheless, industrial water can contain a lot of materials in suspension, especially when the water is taken from rivers. Thus, the objective of the present study is to characterise the interactions between clays in suspension and scaling phenomenon.In order to estimate the effect of clays in suspension, we first performed Rapid Controlled Precipitation assays (RCP). This method can evaluate the effect of an addition of clay in suspension on the CaCO3nucleation-growth kinetics in calcifying water. In this way we found that, whichever clay used, process kinetics always slowed down.Secondly, gravimetric scaling experiments on polyethylene were achieved. Now, results are much more contrasting. It appears that some clay like smectite leads to a high slowdown of scaling. In addition, calcium carbonate weakly deposits while clay deposits a littie. With other clay like kaolinite or granitic clay, the deposit consists of CaCO3with clay.Finally, some clay does not deposit on polyethylene at all and has almost no inhibition effect on scaling (case of a natural clay)We noticed that the antiscaling effect of clays is maximum if the clay displays the maximum quantity of suspended materials as well as a highly negative potential ζ.We should précise that if the nucleation-growth phenomenon is slowed down by clay suspensions, the deposit quantity obtained is not always minimised. This is due to the fact that some clays can also deposit themselves.

Recently treatment strategies in advanced malignant melanoma have significantly changed. Due to high response rates (e.g. more than 50% for the Dartmouth-regimen), combination chemotherapy has been the standard therapy in several oncological and dermatooncological centers in the USA and Europe. For the last three years different prospective randomized phase III trials failed to achieve similar results. There was no benefit in overall survival and in response duration in comparison to single agent chemotherapy. Currently, randomized clinical trials seem to be the best approach for the clinical treatment of metastatic melanoma. In this review several novel strategies against malignant melanoma are discussed with focus on the role of single agent chemotherapy and biochemotherapy.

Patients with mild cognitive impairment (MCI) were assessed, and a metabolic profile associated with conversion to AD at 18-month follow-up was sought. As compared with nonconverters (n 10), converters (n 7) had lower fluorodeoxyglucose uptake in the right temporoparietal cortex (p0.02, corrected for cluster size), without individual overlap. Awaiting replication in an independent sample, these findings suggest that among patients with MCI, fluorodeoxyglucose PET may accurately identify rapid converters.

Estrogen regulates skeletal growth and promotes epiphyseal fusion. To explore the mechanisms underlying these effects we investigated the expression of estrogen receptor-alpha (ERalpha) and -beta (ERbeta) in rat and rabbit growth plates during postnatal development, using immunohistochemistry. Immunoreactivity for ERalpha and ERbeta was observed in resting zone and proliferative zone chondrocytes at all ages studied for both rat (7, 14, 28 and 70 days of age) and rabbit (1, 7, 28 and 120 days of age). In the rat distal humerus and the rabbit proximal tibia, expression of both receptors in the hypertrophic zone was minimal at early ages, increasing only at the last time point prior to epiphyseal fusion. Expression was rarely seen in the hypertrophic zone of the rat proximal tibia, a growth plate that does not fuse until late in life. Therefore, we conclude that ERalpha and ERbeta are both expressed in the mammalian growth plate. The temporal and anatomical pattern suggests that ER expression in the hypertrophic zone in particular may play a role in epiphyseal fusion.

OBJECTIVES: Hippocampal atrophy and hypometabolism in the posterior association neocortex are two well known features of Alzheimer's disease. A correlation between these two features was reported twice previously, suggesting intriguing relations. This question has been reassessed, this time controlling for severity of dementia as well as assessing each side of the brain separately and using a voxel based image analysis in addition to the previously employed regions of interest (ROIs). PATIENTS AND METHODS: Eleven patients were studied with probable Alzheimer's disease and mild to moderate dementia in whom both volume MRI and PET assessed cerebral glucose consumption (CMRGlc) were available. Hypothesis driven correlations between hippocampal width (an index of atrophy) and CMRGlc were performed for two posterior association regions, the superior temporal and the inferior parietal (angular gyrus) cortices, using ROIs set separately for each hemisphere. To confirm significant correlations from the ROIs approach, if any, and to assess their specificity for the posterior association neocortex, CMRGlc image voxel based analysis of correlations with hippocampal width was then carried out. RESULTS: There was a significant correlation, in the positive--neurobiologically expected--direction, between right hippocampal width and right angular gyrus metabolism (p< 0.01, Spearman), which remained significant with Kendall partial correlation controlling for dementia severity (estimated by mini mental state scores). Statistical non-parametric mapping (SnPM) confirmed this correlation (p< 0.025), and showed a single additional correlation in the right middle temporal gyrus (p<0.005), which is also part of the posterior association cortex. CONCLUSION: The findings with both ROIs and voxel based mapping replicate earlier reports of a relation between hippocampal atrophy and ipsilateral association cortex hypometabolism in Alzheimer's disease, and for the first time document that this relation is both region specific and independent of the dementing process itself. Why the correlation was significant only for the right hemisphere is unclear but may be related to the limited sample. Hippocampal-neocortical disconnection due to early and severe medial temporal lobe pathology may at least partly explain the posterior association cortex hypometabolism found in Alzheimer's disease.

Background. People sometimes object to the results of cost-effectiveness analysis when the analysis produces a ranking of options based on both cost and benefit. The authors suggest 2 new reasons for these objections: the prominence effect, in which people attend mostly to a more prominent attribute (benefit as opposed to cost), and distortion of utility judgments. Method. The authors simulated the production of a cost-effectiveness ranking list in 3 experiments using questionnaires on the World Wide Web. Subjects rated the utility of 16 health benefits using either rating scale or person trade-off elicitation methods. In some experiments, subjects were asked to rate the utility of the health benefits with attention also to the cost of achieving the benefits. In all experiments, at the end, subjects were shown a priority list based on their own utility judgments and were asked whether they wanted to move any of the health benefits up or down the list. Results. In all experiments, subjects wanted to give higher priority to treatments with higher benefit, even when they also had higher cost. They thus wanted to give less weight to high cost (which would, by itself, lead to lower ranking) and more weight to benefit than the weight implied by their own prior judgments. The desire for revision was reduced when subjects made their utility judgments after indicating whether the utility was above or below the midpoint of the scale (a manipulation previously found to reduce distortion). Conclusion. The desire to change cost-effectiveness rankings is in part a preference reversal phenomenon that occurs because people attend mainly to the benefit of health interventions as opposed to cost, when they examine the ranking. People should be wary of tinkering with priority lists by examining the lists themselves.

The Guidelines for Counselling in Infertility describe the purpose, objectives, typical issues and communication skills involved in providing psychosocial care to individuals using fertility services. The Guidelines are presented in six sections. The first section describes how infertility consultations differ from other medical consultations in obstetrics and gynaecology, whereas the second section addresses fundamental issues in counselling, such as what is counselling in infertility, who should counsel and who is likely to need counselling. Section 3 focuses on how to integrate patient-centred care and counselling into routine medical treatment and section 4 highlights some of the special situations which can provoke the need for counselling (e.g. facing the end of treatment, sexual problems). Section 5 deals exclusively with third party reproduction and the psychosocial implications of gamete donation, surrogacy and adoption for heterosexual and gay couples and single women without partners. The final section of the Guidelines is concerned with psychosocial services that can be used to supplement counselling services in fertility clinics: written psychosocial information, telephone counselling, self-help groups and professionally facilitated group work. This paper summarizes the different sections of the Guidelines and describes how to obtain the complete text of the Guidelines for Counselling in Infertility.

Some compounds used for phenotyping of cytochrome P450s are substrates of P-glycoprotein (pgp). It is likely that in these cases, the level of pgp modulates the metabolism of in vivo probes. To address this important issue, we have analyzed the effects of pgp on CYP3A4-mediated reactions in two newly established cell lines (3A4/HR/MDR(-) and 3A4/HR/MDR(+)), which express CYP3A4 in the absence and presence of pgp, respectively. In cultured cells, the presence of pgp increased the apparent K(m) for the 6beta-hydroxylase activity of CYP3A4 toward testosterone and cortisol by a factor of 1.7 and 4, respectively. These steroids are poor and good substrates of pgp, respectively, and cortisol 6beta-hydroxylase has been frequently used as an in vivo probe for CYP3A4. Interestingly, we also found that pgp modulated the inhibition of CYP3A4-mediated metabolism by several compounds in intact cells. Although quinidine inhibited testosterone 6beta-hydroxylase activity in membranes or in intact cells that expressed recombinant CYP3A4 in the absence of pgp, low concentrations of this compound increased CYP3A4 activity in intact cells that expressed pgp. These results imply that pharmacokinetic drug-drug interactions involving CYP3A4 can be influenced by pgp.

Article abstract

Although ‘intrahemispheric diaschisis’ (i.e. a hypometabolism affecting the cerebral hemisphere ipsilateral to but remote from the infarct) may classically exacerbate acute-stage neurological deficit and influence early recovery, it has been studied only rarely. Out of a series of 30 patients with first-ever middle cerebral artery (MCA) territory stroke, we analyzed the data from 19 survivors investigated by 15O positron emission tomography (PET) both in the acute (within 5–18 h of clinical onset) and subacute (approximately 3 weeks later) stage, and for whom chronic-stage CT coregistered with PET was available to assess infarct topography and size. Orgogozo’s MCA scale was used to assess neurological deficits at the time of, and recovery between, the PET studies. Oxygen consumption was obtained for both PET sessions for the whole ipsilateral hemisphere (excluding ventricles and infarct), as well as for the thalamus and the occipital and mesial-prefrontal cortex (i.e. potentially deafferented tissue outside the MCA territory). In all regions except the occipital cortex, the oxygen consumption significantly decreased between the first and the second session, without significant correlation with the concomitant changes in MCA scores. However, acute-stage mesial-prefrontal metabolism was significantly correlated with neurological recovery. Also, both the hemisphere and the mesial-prefrontal metabolism at the second session were significantly correlated with both infarct size and concomitant MCA scores, but the latter relationship became insignificant when infarct size was taken into account. This study reveals no evidence of acute intrahemispheric diaschisis after MCA territory stroke in man. However, it documents for the first time a phenomenon of delayed intrahemispheric remote hypometabolism developing while the patients clinically recover. Because the degree of this secondary phenomenon is a function of infarct size, a mechanism of degeneration of the damaged neuron terminals is likely. Finally, contrary to other reports, neurological recovery was not a function of thalamic hypometabolism, but appeared to be influenced by acute-stage mesial-frontal metabolism, perhaps because this region is part of a network that has an important compensatory role in motor recovery.

A growing body of literature suggests that physical activity may be a protective factor against hip fracture.

Since the estrogen receptor alpha (ER) is an important mediator of hormonal responses such as proliferation in estrogen-sensitive tissues, we hypothesized that polymorphisms in the ER gene could be functional and associated with endometrial cancer risk. We performed a population-based case-control study in Sweden, focusing on restriction fragment length polymorphisms for XbaI and PvuII and an upstream TA repeat polymorphism. In the main analysis, 154 cases and 205 controls who never used hormone replacement therapy took part and we calculated age-adjusted and multivariate odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression. The XbaI X allele appeared to confer a reduced risk for endometrial cancer. The multivariate OR for the XX genotype was 0.52 (95% CI 0.21-1.29) compared to the xx genotype and there were suggestions of decreasing risk with increasing number of X alleles (P for trend = 0.07). The PvuII PP genotype was also associated with a non-significantly decreased risk for endometrial cancer (multivariate OR 0.70, 95% CI 0.34-1.44) compared with the pp genotype (P for trend = 0.43). The multivariate OR for two short TA (<19 repeats) alleles versus two long alleles was 1.54 (95% CI 0. 73-3.27) and there were suggestions of increasing risk with increasing number of short alleles (P for trend = 0.26). We observed the same pattern of results in an expanded group of subjects, which included women who had used hormone replacement (in total 288 cases and 392 controls). Our data suggest that variants of the ER gene may be associated with an altered risk of endometrial cancer.

L'utilisation de canalisations anciennes non revêtues en acier ou en fonte entraîne l'augmentation de la teneur en fer de l'eau véhiculée. De même, dans les installations récentes, des émissions de fer restent possibles dans des zones dégradées où peuvent se produire des corrosions localisées.La corrosion du fer et de la fonte se fait sous la forme d'ions Fe2+. Or, dans la plupart des eaux naturelles et industrielles, les teneurs en oxygène sont suffisantes pour que ces ions Fe2+s'oxydent, avec des cinétiques variables, en ions Fe3+. Ces derniers, aux pH habituels des eaux, sont quasi insolubles. Ils précipitent donc très rapidement sous forme de FeOOH colloïdal, généralement amorphe.Ce FeOOH peut, soit rester en suspension, soit contribuer à former des produits de corrosion. Dans la pratique on a donc cohabitation d'ions Fe2+et de précipités de Fe00H.Le présent travail montre que si l'on prend soin d'introduire des ions Fe2+, de manière continue, par corrosion (lente) de fer, ces ions jouent un rôle accélérateur dans la cinétique de germination-croissance de la CaCO3.L'entartrage se trouve ainsi favorisé à cause de l'augmentation du pouvoir entartrant de l'eau.La comparaison des résultats obtenus sur une eau d'origine superficielle et sur une eau d'origine souterraine permet de conclure que l'effet du fer est beaucoup plus important dans le cas de l'eau superficielle, plus riche en matières organiques, que dans le cas de l'eau souterraine, même si, dans tous les cas, le ferIIjoue un rôle accélérateur de la précipitation de CaCO3.

Abstract:: The two types of hip fracture – cervical and trochanteric femoral fractures – are generally considered together in etiologic studies. However, women with a trochanteric fracture may be more osteoporotic than those with cervical hip fractures, and have higher post-fracture mortality. To explore differences in risk factor patterns between the two types of hip fracture we used data from a large population-based case–control study in Swedish women, 50–81 years of age. Data were collected by questionnaire, to which more than 80% of subjects responded. Of the cases included, 811 had had a cervical fracture and 483 a trochanteric fracture during the study period; these cases were compared with 3312 randomly selected controls. Height and hormonal factors appeared to affect the risk of the two types of hip fracture differently. For every 5 cm of current height, women with a cervical fracture had an adjusted odds ratio (OR) of 1.23 (95% CI 1.15–1.32) compared with an OR of 1.06 (95% CI 0.97–1.15) for women with trochanteric fractures. Later menopausal age was protective for trochanteric fractures (OR 0.95, 95% CI 0.91–0.99 per 2 years) but no such association was found for cervical fractures. Compared with never smokers, current smokers had an OR of 1.48 (95% CI 1.12–1.95) for trochanteric fractures and 1.22 (95% CI 0.98–1.52) for cervical fractures. Current hormone replacement therapy was similarly protective for both fracture types, but former use substantially reduced risk only for trochanteric fractures: OR 0.55 (95% CI 0.33–0.92) compared with 1.00 (95% CI 0.71–1.39) for cervical fractures. These risk factor patterns suggest etiologic differences between the fracture types which have to be considered when planning preventive interventions.

Temporoparietal glucose hypometabolism, neuronal loss in the basal forebrain cholinergic structures and preferential accumulation of neurofibrillary tangles in the rhinal cortex (i.e. in the entorhinal and perirhinal cortices) are three early characteristics of Alzheimer's disease. Based on studies of the effects of neurotoxic lesions in baboons, we previously concluded that damage to the cholinergic structures plays, at best, a marginal role in the association neocortex hypometabolism of Alzheimer's disease. In the present study, we have assessed the remote metabolic effects of bilateral neurotoxic lesions of both entorhinal and perirhinal cortices. Using coronal PET coregistered with MRI, the cerebral metabolic rate for glucose (CMRglc) was measured before surgery and sequentially for 2–3 months afterward (around days 30, 45 and 80). Compared with sham-operated baboons, the lesioned animals showed a significant and long-lasting CMRglc decline in a small set of brain regions, especially in the inferior parietal, posterior temporal, posterior cingulate and associative occipital cortices, as well as in the posterior hippocampal region, all of which also exhibit glucose hypometabolism in Alzheimer's disease. Remarkably, the degree of CMRglc decline in four of these regions significantly correlated with the severity of histologically determined damage in the rhinal cortex, strongly supporting the specificity of the observed metabolic effects. There were also differences between the metabolic pattern observed in the lesioned animals and that classically reported in Alzheimer's disease; for instance, the hypometabolism we found in the stratum has not been reported in early Alzheimer's disease, although this structure can be affected in late stages of the disease and has direct anatomical connections with the rhinal cortex. Nevertheless, this study shows for the first time that the temporoparietal and hippocampal hypometabolism found in Alzheimer's disease may partly result from neuroanatomical disconnection with the rhinal cortex. This, in turn, further strengthens the hypothesis that neuronal damage and dysfunction in the rhinal cortices play a major role in the expression of Alzheimer's disease.

Experimental and observational findings suggest that calcium intake may protect against colorectal neoplasia. To investigate this hypothesis, we conducted a randomized, double-blind trial of colorectal adenoma recurrence. Nine hundred thirty patients with a recent history of colorectal adenomas were randomly given calcium carbonate (3 gm daily; 1200 mg elemental calcium) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The main analysis focused on new adenomas found after the first follow-up endoscopy, up to (and including) the second follow-up examination. Risk ratios of at least one recurrent adenoma and ratios of the average numbers of adenomas were calculated as measures of calcium effect. There was a lower risk of recurrent adenomas in subjects assigned calcium. Eight hundred thirty-two patients had two follow-up examinations and were included in the main analysis; the adjusted risk ratio of one or more adenomas was 0.81 (95 CI 0.67 to 0.99); the adjusted ratio of the average numbers of adenomas was 0.76 (95 CI 0.60 to 0.96). Among subjects who had at least one follow-up colonoscopy, the adjusted risk ratio of one or more recurrent adenomas was 0.85 (95 CI 0.74 to 0.98). The effect of calcium seemed independent of initial dietary fat and calcium intake. No toxicity was associated with supplementation. These findings indicate that calcium supplementation has a modest protective effect against colorectal adenomas, precursors of most colorectal cancers.

Abstract Objectives To assess episodic memory (especially anterograde amnesia) during the acute phase of transient global amnesia to differentiate an encoding, a storage, or a retrieval deficit. Methods In three patients, whose amnestic episode fulfilled all current criteria for transient global amnesia, a neuropsychological protocol was administered which included a word learning task derived from the Grober and Buschke's procedure. Results In one patient, the results suggested an encoding deficit, and in two others, a storage deficit. Conclusions The encoding/storage impairment concerning anterograde amnesia documented in our patients stands in clear contrast with the impairment in retrieval which must underly the retrograde amnesia that also characterises transient global amnesia. This dissociation in turn favours the idea of a functional independence among the cognitive mechanisms that subserve episodic memory.

Abstract: Hydroxyethyl starch (HES) is one of the most frequently used plasma substitutes. A variety of different HES solutions exist worldwide, which differ greatly in their pharmacological properties. HES is classified according to its manufactured or in vitro molecular weight (MW) into high MW (450–480 kDa), medium MW (200 kDa), and low MW (70 kDa) starch preparations. However, this is not sufficient, because as HES is metabolized in vivo, its MW changes, and it is the in vivo MW which is responsible for the therapeutic and adverse effects of each HES. The rate of metabolization depends mainly on the degree of hydroxyethyl substitution (ranging from 0.4 to 0.7), and the C2/C6 ratio of hydroxyethylation. A high degree of substitution and a high C2/C6 ratio lead to a slow metabolization of HES, resulting in a large in vivo MW. Slowly degradable high MW HES 450/0.7 and medium MW HES 200/0.62 have a high in vivo MW and are eliminated slowly via the kidneys. As a result, these starches have a relatively long-lasting volume effect. When infusing higher volumes ( > 1500 ml) are infused, large molecules accumulate in the plasma. This can result in bleeding complications due to decreased factor VIII/von Willebrand factor, platelet function defects, incorporation into fibrin clots, and an unfavorable effect on rheological parameters. Rapidly degradable medium MW HES 200/0.5 or low MW HES 70/0.5 are quickly split in vivo into smaller, more favorable molecule sizes, resulting in faster renal elimination, shorter volume effect, and fewer adverse effects on coagulation and rheological parameters. For historical and marketing reasons, only slowly degradable, high MW HES (480/0.7) is available in the United States. In Europe, a large variety of HES solutions are available, dominated by medium MW, easily degradable HES (200/0.5). Because of increasing international competition and the availability of newly developed starches, it is important to be aware of the pharmacological properties of HES and the advantages and disadvantages of the individual preparations.