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Slow strain rate tensile testing was conducted on electrodeposited copper, which is a candidate coating material for used nuclear fuel containers. Embrittlement was observed in electrodeposited copper containing 26.4 ± 1.0 ppm hydrogen, with a strain rate sensitivity such that the embrittlement was exacerbated at lower strain rate (5 × 10−7 s−1). Tensile tests conducted at 100° and 200 °C also intensified embrittlement when compared with tests conducted at room temperature. In contrast, electrodeposited copper containing only 5.25 ± 0.97 ppm hydrogen exhibited ductile behavior at all tested strain rates and temperatures. These findings suggest that a previously unexplained slow strain rate hydrogen embrittlement can operate in electrodeposited copper provided that the hydrogen concentration is sufficiently high. Further analyses revealed that the deformation of embrittled copper is achieved by the formation of internal microcracks which coalesce at the point of failure. [ABSTRACT FROM AUTHOR]

Background: Substance use-related emergency department (ED) visits have increased substantially in North America. Screening for substance use in EDs is recommended; best approaches are unclear. This systematic review synthesizes evidence on diagnostic accuracy of ED screening tools to detect harmful substance use. Methods: We included derivation or validation studies, with or without comparator, that included adult (≥ 18 years) ED patients and evaluated screening tools to identify general or specific substance use disorders or harmful use. Our search strategy combined concepts Emergency Department AND Screening AND Substance Use. Trained reviewers assessed title/abstracts and full-text articles for inclusion, extracted data, and assessed risk of bias (QUADAS-2) independently and in duplicate. Reviewers resolved disagreements by discussion. Primary investigators adjudicated if necessary. Heterogeneity precluded meta-analysis. We descriptively summarized results. Results: Our search strategy yielded 2696 studies; we included 33. Twenty-one (64%) evaluated a North American population. Fourteen (42%) applied screening among general ED patients. Screening tools were administered by research staff (n = 21), self-administered by patients (n = 10), or non-research healthcare providers (n = 1). Most studies evaluated alcohol use screens (n = 26), most commonly the Alcohol Use Disorders Identification Test (AUDIT; n = 14), Cut down/Annoyed/Guilty/Eye-opener (CAGE; n = 13), and Rapid Alcohol Problems Screen (RAPS/RAPS4/RAPS4-QF; n = 12). Four studies assessing six tools and screening thresholds for alcohol abuse/dependence in North American patients (AUDIT ≥ 8; CAGE ≥ 2; Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV-2] ≥ 1; RAPS ≥ 1; National Institute on Alcohol Abuse and Alcoholism [NIAAA]; Tolerance/Worry/Eye-opener/Amnesia/K-Cut down [TWEAK] ≥ 3) reported both sensitivities and specificities ≥ 83%. Two studies evaluating a single alcohol screening question (SASQ) (When was the last time you had more than X drinks in 1 day?, X = 4 for women; X = 5 for men) reported sensitivities 82–85% and specificities 70–77%. Five evaluated screening tools for general substance abuse/dependence (Relax/Alone/Friends/Family/Trouble [RAFFT] ≥ 3, Drug Abuse Screening Test [DAST] ≥ 4, single drug screening question, Alcohol, Smoking and Substance Involvement Screening Test [ASSIST] ≥ 42/18), reporting sensitivities 64%-90% and specificities 61%-100%. Studies' risk of bias were mostly high or uncertain. Conclusions: Six screening tools demonstrated both sensitivities and specificities ≥ 83% for detecting alcohol abuse/dependence in EDs. Tools with the highest sensitivities (AUDIT ≥ 8; RAPS ≥ 1) and that prioritize simplicity and efficiency (SASQ) should be prioritized. [ABSTRACT FROM AUTHOR]

Developments in retinal imaging technologies have enabled the quantitative evaluation of the retinal vasculature. Changes in retinal calibre and/or geometry have been reported in systemic vascular diseases, including diabetes mellitus (DM), cardiovascular disease (CVD), and more recently in neurodegenerative diseases, such as dementia. Several retinal vessel analysis softwares exist, some being disease-specific, others for a broader context. In the research setting, retinal vasculature analysis using semi-automated software has identified associations between retinal vessel calibre and geometry and the presence of or risk of DM and its chronic complications, and of CVD and dementia, including in the general population. In this article, we review and compare the most widely used semi-automated retinal vessel analysis softwares and their associations with ocular imaging findings in common systemic diseases, including DM and its chronic complications, CVD, and dementia. We also provide original data comparing retinal calibre grading in people with Type 1 DM using two softwares, with good concordance. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to develop prediction models for the individual-level impacts of cardiovascular events on UK healthcare costs. Methods: In the UK Biobank, people 40–70 years old, recruited in 2006–2010, were followed in linked primary (N = 192,983 individuals) and hospital care (N = 501,807 individuals) datasets. Regression models of annual primary and annual hospital care costs (2020 UK£) associated with individual characteristics and experiences of myocardial infarction (MI), stroke, coronary revascularization, incident diabetes mellitus and cancer, and vascular and nonvascular death are reported. Results: For both people without and with previous cardiovascular disease (CVD), primary care costs were modelled using one-part generalised linear models (GLMs) with identity link and Poisson distribution, and hospital costs with two-part models (part 1: logistic regression models the probability of incurring costs; part 2: GLM with identity link and Poisson distribution models the costs conditional on incurring any). In people without previous CVD, mean annual primary and hospital care costs were £360 and £514, respectively. The excess primary care costs were £190 and £360 following MI and stroke, respectively, whereas excess hospital costs decreased from £4340 and £5590, respectively, in the year of these events, to £190 and £410 two years later. People with previous CVD had more than twice higher annual costs, and incurred higher excess costs for cardiovascular events. Other characteristics associated with higher costs included older age, female sex, south Asian ethnicity, higher socioeconomic deprivation, smoking, lower level of physical activities, unhealthy body mass index, and comorbidities. Conclusions: These individual-level healthcare cost prediction models could inform assessments of the value of health technologies and policies to reduce cardiovascular and other disease risks and healthcare costs. An accompanying Excel calculator is available to facilitate the use of the models. [ABSTRACT FROM AUTHOR]

Thurstan Shaw's excavations at Igbo-Ukwu revealed many artifacts and technologies that remain astonishing, unique, and incompletely understood, both within Africa and more broadly, even after 50 years. Among these are the textiles recovered primarily from Igbo Isaiah, where fragments were preserved by contact with the bronze artifacts gathered in what has been interpreted as a shrine. In the 1960s, an analysis of 20 textile samples was unable to identify the plant fibers used to weave the fabric. In this article, we report the results of new fiber identifications based on the SEM study of two Igbo-Ukwu fabric samples curated by the British Museum. The combination of bast fibers from one or more species of the fig tree (Ficus genus) and leaf fibers from Raphia sp. provides evidence of a complex indigenous weaving technology that has largely disappeared from Africa. An AMS date on one of the samples provides an important new element to our understanding of the culture and chronology of Igbo-Ukwu. A final section positions the Igbo-Ukwu cloth within the known history of textiles in Africa, emphasizing sub-Saharan West Africa over the past two millennia. [ABSTRACT FROM AUTHOR]

As an introduction to several papers from the "Igbo-Ukwu at 50" symposium in September 2021, this article reviews the history of the discoveries and excavations, the early debates over chronology, and more recent research contributions that refine and expand our understanding of this unique site. These include new field investigations at Igbo Ukwu, new radiocarbon dates, textile analysis, chemical analyses of glass, and carnelian beads plus lead isotope analyses of leaded bronze and copper artifacts to identify source areas, and metallographic studies. [ABSTRACT FROM AUTHOR]

The 26S proteasome is a conserved multi-subunit machinery in eukaryotes. It selectively degrades ubiquitinated proteins, which in turn provides an efficient molecular mechanism to regulate numerous cellular functions and developmental processes. Here, we studied a new loss-of-function allele of RPN12a, a plant ortholog of the yeast and human structural component of the 19S proteasome RPN12. Combining a set of biochemical and molecular approaches, we confirmed that a rpn12a knock-out had exacerbated 20S and impaired 26S activities. The altered proteasomal activity led to a pleiotropic phenotype affecting both the vegetative growth and reproductive phase of the plant, including a striking repression of leaf senescence associate cell-death. Further investigation demonstrated that RPN12a is involved in the regulation of several conjugates associated with the auxin, cytokinin, ethylene and jasmonic acid homeostasis. Such enhanced aptitude of plant cells for survival in rpn12a contrasts with reports on animals, where 26S proteasome mutants generally show an accelerated cell death phenotype. A loss-of-function mutation in the RPN12a proteasome subunit in Arabidopsis thaliana shows that this protein is essential for hormonal homeostasis, thereby modulating plant's development and the progression of leaf senescence. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes. Methods: We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR. Results: In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2, p < 0.001) than the non-progressors (n = 3521). On Cox regression analysis, each ∆∆Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p < 0.001); the association remained significant after adjusting for baseline age, sex, HbA1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p = 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p < 0.001; adjusted OR 1.09 [95% CI 1.01, 1.17], p = 0.024). Conclusions/interpretation: rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes. [ABSTRACT FROM AUTHOR]

People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04–0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors. [ABSTRACT FROM AUTHOR]

The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10–20 years and > 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p < 0.0001 and in all (n = 253) participants without diabetes (CON). C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group [median lower quartile (LQ)–upper quartile (UQ)] 5.0 (2.6–28.7) versus 650.9 (401.2–732.4) pmol/L respectively, p < 0.0001 and lower in childhood versus adult-onset diabetes [median (LQ–UQ) 4.2 (2.6–12.2) pmol/L vs. 8.0 (2.3–80.5) pmol/L, p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend < 0.05). Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). As disturbed angiogenesis and endothelial dysfunction are strongly implicated in T2D and CVD, we aimed to investigate the association between a novel anti-angiogenic protein, FK506-binding protein like (FKBPL), and these diseases. Plasma FKBPL was quantified by ELISA cross-sectionally in 353 adults, consisting of 234 T2D and 119 non–diabetic subjects with/without CVD, matched for age, BMI and gender. FKBPL levels were higher in T2D (adjusted mean: 2.03 ng/ml ± 0.90 SD) vs. non-diabetic subjects (adjusted mean: 1.79 ng/ml ± 0.89 SD, p = 0.02), but only after adjustment for CVD status. In T2D, FKBPL was negatively correlated with fasting blood glucose, HbA1c and diastolic blood pressure (DBP), and positively correlated with age, known diabetes duration, waist/hip ratio, urinary albumin/creatinine ratio (ACR) and fasting C-peptide. FKBPL plasma concentrations were increased in the presence of CVD, but only in the non-diabetic group (CVD: 2.02 ng/ml ± 0.75 SD vs. no CVD: 1.68 ng/ml ± 0.79 SD, p = 0.02). In non-diabetic subjects, FKBPL was positively correlated with an established biomarker for CVD, B-type Natriuretic Peptide (BNP), and echocardiographic parameters of diastolic dysfunction. FKBPL was a determinant of CVD in the non-diabetic group in addition to age, gender, total-cholesterol and systolic blood pressure (SBP). FKBPL may be a useful anti-angiogenic biomarker in CVD in the absence of diabetes and could represent a novel CVD mechanism. [ABSTRACT FROM AUTHOR]

People with diabetes mellitus have shorter telomeres compared with non-diabetic subjects. The aim of this study was to investigate an in-vitro model of telomere shortening under diabetes metabolic conditions. The mechanisms of the accelerated telomere length attrition and the potential telomere protective action of fenofibrate with related cellular mechanisms were also examined. Human dermal fibroblasts were passaged and cultured in normal (5.5 mM) or high (25 mM) D-glucose, across 7 days with hydrogen peroxide (H2O2), glucosamine (GA), or glycated albumin (AGEs-BSA). Relative telomere length (RTL) was determined by qPCR. The expression of shelterin complex members which regulate telomere stability were measured by qRT-PCR and Western immunoblot. Culture in high glucose decreased RTL compared with normal glucose: H2O2 and GA lowered the RTL after 7 days (each P < 0.05 vs untreated control), whereas AGEs-BSA had no effect compared with control-BSA. At day 7 the mRNA levels of most shelterin complex members, were induced by H2O2 and to a lesser extent by GA. Trf1 and Trf2 protein were induced by H2O2. Co-treatment with fenofibrate (100 μM) significantly attenuated the reduction in RTL caused by H2O2 and GA and prevented Trf induction by H2O2. However knockdown of Trf1 and Trf2 expression using specific siRNA did not prevent H2O2 effects to lower RTL, thus implicating factors other than these Trfs alone in the fenofibrate protection against the H2O2 induction of RTL lowering. These in vitro findings demonstrate that diabetic conditions can induce telomere shortening and that fenofibrate has protective effects on telomere attrition, through as yet undefined mechanisms. [ABSTRACT FROM AUTHOR]

Background: Obesity is public health problem of epidemic proportions. Esophageal dysmotility including achalasia is more commonly seen in an obese population. Standard therapy for achalasia can be complicated by hepatomegaly and a post-surgical anatomy in a pre- and post-bariatric population. Peroral endoscopic myotomy (POEM) has not been adequately studied in this population. Methods: A retrospective review of a prospectively collected database was completed. Patients who had undergone a Roux-en-y gastric bypass (RYGB) prior to or following a POEM were enrolled. Patient demographics, operative information and post-operative course data was collected. Results: Six patients underwent POEM prior to or after RYGB. There were no peri-operative complications with an average length of stay of 1.2 days. Five patients experienced a clinical success with excellent symptom resolution. The one failure was in the setting of type III achalasia, but did have objective evidence of lower esophageal sphincter (LES) relaxation post-operatively. Conclusion: POEM in the setting of bariatric surgery is safe and feasible. The potential increase in GERD following POEM is obviated by RYGB anatomy. In an obese individual, a staged POEM prior to or following a RYGB is an appropriate treatment algorithm for obese and achalasia. [ABSTRACT FROM AUTHOR]

This paper presents the development work undertaken to tailor Cu powder size specifications to produce dense cold spray Cu coatings featuring strong adherence on steel substrates. Through review of historical data generated in the course of the development of Cu coatings for corrosion protection of Used (Nuclear) Fuel Containers, it was found that particle size distribution was particularly critical to meet application adhesion requirements of 60 MPa and prevent nozzle clogging during application; D01 and D90 were fixed at 5 and 60 µm, respectively. The effect of powder size on coating microstructure and adhesion was further investigated with four Cu powder lots presenting different granulometries. The four lots were analyzed for composition, hardness, microstructure and morphology. Their in-flight particle velocities were measured using a coldspraymeter and the impact temperatures and velocities were simulated. Using fixed spraying conditions consisting of a He bond coat and a nitrogen buildup step, 3-4-mm-thick coatings were produced and tested for bond strength. Coating cross sections and fracture surfaces of selected coatings were examined. These trials confirmed that although the various powder sizes tested produced dense and sound coatings, tight control of particle size distributions was required to achieve optimal impact velocities that ensure deformation of the steel and good coating adhesion. [ABSTRACT FROM AUTHOR]

Background: Per oral endoscopic myotomy (POEM) has gained increasing popularity for treating achalasia. A multidisciplinary approach may allow safe and early adoption of POEM into clinical practice.Materials and Methods: We performed a retrospective review of our initial POEM cases. All procedures were performed by a team of interventional gastroenterologist and thoracic surgeon. We analyzed demographics, comorbidities, achalasia subtypes, length of hospital stay, duration of surgery, morbidity, mortality, length of myotomy, preoperative and postoperative Eckardt scores.Results: Thirty-one consecutive patients underwent POEM during the 24-month period from January 2014 to December 2015. Eighteen patients (58%) had prior non-operative interventions. Average duration of follow-up was 9.6 months. Seventeen patients (66.8%) had follow-up of 12 months and longer. Average preoperative Eckardt score was 6.3 (3-10), median 6. Average postoperative Eckardt score was 1.4 (0-8), median 1, in 1 month and an average 2.2, median 1, in 1 year. Patients with type III achalasia were most refractory to treatment, while patients with type II had the best results. Average LOS was 1.3 days (1-5), median 1 day. Average DOS was 106 min (60-148), median 106. Average LOM was 13 cm (10-15), with median of 13 cm. We had one 30-day mortality secondary to coronary artery disease. Four patients had prior Heller myotomies and underwent a posterior myotomy during POEM, with outcomes similar to patients with no prior myotomy.Conclusions: We demonstrated safety and efficiency of a multispecialty approach for achalasia with POEM with a low rate of complications. [ABSTRACT FROM AUTHOR]

Carbon steel is widely considered as a candidate material for the construction of spent fuel and high-level waste disposal canisters. In order to investigate corrosion processes representative of the long term evolution of deep geological repositories, two in situ experiments are being conducted in the Mont-Terri rock laboratory. The iron corrosion (IC) experiment, aims to measure the evolution of the instantaneous corrosion rate of carbon steel in contact with Opalinus Clay as a function of time, by using electrochemical impedance spectroscopy measurements. The Iron Corrosion in Bentonite (IC-A) experiment intends to determine the evolution of the average corrosion rate of carbon steel in contact with bentonite of different densities, by using gravimetric and surface analysis measurements, post exposure. Both experiments investigate the effect of microbial activity on corrosion. In the IC experiment, carbon steel showed a gradual decrease of the corrosion rate over a period of 7 years, which is consistent with the ongoing formation of protective corrosion products. Corrosion product layers composed of magnetite, mackinawite, hydroxychloride and siderite with some traces of oxidising species such as goethite were identified on the steel surface. Microbial investigations revealed thermophilic bacteria (sulphate and thiosulphate reducing bacteria) at the metal surface in low concentrations. In the IC-A experiment, carbon steel samples in direct contact with bentonite exhibited corrosion rates in the range of 2 µm/year after 20 months of exposure, in agreement with measurements in absence of microbes. Microstructural and chemical characterisation of the samples identified a complex corrosion product consisting mainly of magnetite. Microbial investigations confirmed the limited viability of microbes in highly compacted bentonite. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Baseline circulating fibroblast growth factor 21 (FGF21) levels can predict total cardiovascular disease events in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. This paper describes the relationship of baseline FGF21 levels and new on-study microvascular disease in patients with type 2 diabetes from the FIELD study. Methods: Baseline FGF21 levels were measured in plasma by enzyme-linked immunosorbent assay in 9697 study participants. Total microvascular disease was defined as the presence of any nephropathy, retinopathy, neuropathy and/or microvascular amputation. The relationship between FGF21 levels and microvascular disease was assessed by multivariable logistic regression. Results: Higher baseline FGF21 levels were found in patients with baseline total microvascular disease ( p < 0.001). The association remained significant after adjusting for potential confounding factors (OR [95% CI] 1.13 [1.08, 1.19] per SD increase in log-transformed FGF21 levels, p < 0.001). Of 6465 patients without baseline total microvascular disease, 1517 developed new on-study total microvascular disease over 5 years of follow-up. Higher baseline FGF21 levels were associated with a higher risk of new on-study total microvascular disease after adjusting for potential confounding factors (OR [95% CI] 1.09 [1.02, 1.16] per SD increase in log-transformed FGF21 levels, p = 0.01). Addition of FGF21 levels in a model of new on-study total microvascular disease with established risk factors significantly, but modestly, increased the integrated discrimination improvement and the net reclassification improvement (both p < 0.01). Conclusions/interpretation: Higher baseline FGF21 levels are seen in patients with type 2 diabetes and established microvascular disease, and predict the future development of new microvascular disease. [ABSTRACT FROM AUTHOR]

Government failure is a much bigger problem than its contemporary treatment implies. Setting aside natural disasters, most of the great catastrophes of human history have been government failures of one sort or another. We argue that many so-called market failures are government failures because government defines the institutions in which markets succeed or fail. The concept of government failure has been trapped in the cocoon of the theory of perfect markets. Narrowly defined deviations from market perfection have been designated market failures, for which government corrections may or may not really be a solution. Government failure in the contemporary context means failing to resolve a classic market failure. We propose an alternative approach for evaluating whether government fails: the Pareto standard. If an available Pareto improvement is not chosen, or is not implemented, that is a government failure. We organize government failure into two types: substantive and procedural. Substantive failures include the inability or unwillingness to maintain order, to maintain sound fiscal and monetary policies, and to reduce risks of transaction costs, which we classify as corruption, agency and rent-seeking. Procedural failures are inadequacies of available social choice mechanisms, causing collective decisions to be arbitrary, capricious, or manipuated. We conclude with some reflections on human rationality and the implications of behavioral economics. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Circulating fibroblast growth factor 21 (FGF21) levels are often elevated in obesity, dyslipidaemia, insulin resistance and type 2 diabetes. This study investigated the relationship of plasma FGF21 levels with cardiovascular events in patients with type 2 diabetes. Methods: Plasma FGF21 levels were measured by ELISA at baseline in 9,697 individuals with type 2 diabetes participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. We assessed the association of FGF21 levels with the incidence of different cardiovascular outcomes over 5 years. The primary outcome was total cardiovascular disease (CVD) events and the secondary outcomes were the four individual components: coronary heart disease events, total stroke, CVD mortality and coronary and carotid revascularisation. The tertiary outcome was hospitalisation for angina pectoris. Results: Higher baseline FGF21 levels were associated with higher risks of all cardiovascular outcome events after adjusting for the study treatment allocation (all p < 0.01). The associations remained significant for total CVD events and for coronary and carotid revascularisation after further adjusting for confounding factors, with the HR (95% CI) being 1.28 (1.10, 1.50) and 1.26 (1.01, 1.56), respectively, for the highest tertile compared with the lowest tertile (overall effect p = 0.002 and 0.007, respectively). The addition of FGF21 levels to a model including established CVD risk factors predicting total CVD events led to a non-significant increase in the C-statistic but there was a significant improvement in integrated discrimination and net reclassification. Conclusions/interpretation: Higher baseline plasma FGF21 levels were associated with higher risk of cardiovascular events in patients with type 2 diabetes. Trial registration: ISRCTN64783481 [ABSTRACT FROM AUTHOR]

Aims/hypothesis: In the double-blind placebo-controlled Fenofibrate Intervention and Event Lowering in Diabetes trial ( n = 9,795), fenofibrate reduced major cardiovascular events in type 2 diabetes. Sex-related differences in fenofibrate response could be clinically relevant and were pre-specified analyses. Methods: Women ( n = 3,657) and men ( n = 6,138) with type 2 diabetes not using statins were assigned fenofibrate (200 mg/day) or placebo for 5 years. Effects on lipoproteins and total cardiovascular events were evaluated by sex. Results: Baseline total, LDL-, HDL- and non-HDL cholesterol and apolipoproteins A-I and B differed between sexes, and these and triacylglycerol levels improved with fenofibrate in both sexes (all p < 0.001). Fenofibrate reduced total, LDL- and non-HDL cholesterol and apolipoprotein B more in women (all p < 0.001), independent of menopausal status and statin uptake. Adjusted for covariates, fenofibrate reduced total cardiovascular outcomes (cardiovascular death, fatal and non-fatal stroke and carotid and coronary revascularisation) by 30% in women (95% CI 8%, 46%; p = 0.008) and 13% in men (95% CI −1%, 24%; p = 0.07) with no treatment-by-sex interaction ( p > 0.1). In patients with high triacylglycerol levels and low HDL-cholesterol, fenofibrate reduced total cardiovascular outcomes by 30% (95% CI −7%, 54%) in women and 24% (95% CI 2%, 42%) in men, with no treatment-by-sex interaction ( p > 0.1). Conclusions/interpretation: Fenofibrate improved the lipoprotein profile more in women than men. Cardiovascular event reductions with fenofibrate were consistently similar in women and men, both overall and among those with low HDL-cholesterol and high triacylglycerol levels. These data provide reassurance about fenofibrate efficacy in women and men. Both sexes with type 2 diabetes should be considered for fenofibrate therapy for cardioprotection. [ABSTRACT FROM AUTHOR]

Conifers have dominated forests for more than 200 million years and are of huge ecological and economic importance. Here we present the draft assembly of the 20-gigabase genome of Norway spruce (Picea abies), the first available for any gymnosperm. The number of well-supported genes (28,354) is similar to the >100 times smaller genome of Arabidopsis thaliana, and there is no evidence of a recent whole-genome duplication in the gymnosperm lineage. Instead, the large genome size seems to result from the slow and steady accumulation of a diverse set of long-terminal repeat transposable elements, possibly owing to the lack of an efficient elimination mechanism. Comparative sequencing of Pinus sylvestris, Abies sibirica, Juniperus communis, Taxus baccata and Gnetum gnemon reveals that the transposable element diversity is shared among extant conifers. Expression of 24-nucleotide small RNAs, previously implicated in transposable element silencing, is tissue-specific and much lower than in other plants. We further identify numerous long (>10,000 base pairs) introns, gene-like fragments, uncharacterized long non-coding RNAs and short RNAs. This opens up new genomic avenues for conifer forestry and breeding. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Bilirubin has antioxidant and anti-inflammatory activities. Previous studies demonstrated that higher bilirubin levels were associated with reduced prevalence of peripheral arterial disease (PAD). However, the relationship between bilirubin and lower-limb amputation, a consequence of PAD, is currently unknown. We hypothesised that, in patients with type 2 diabetes, bilirubin concentrations may inversely associate with lower-limb amputation. Methods: The relationship between baseline plasma total bilirubin levels and amputation events was analysed in 9,795 type 2 diabetic patients from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. The analysis plan was pre-specified. Lower-limb amputation was adjudicated blinded to treatment allocation. Relevant clinical and biochemical data were available for analyses. Amputation was a pre-specified tertiary endpoint. Results: Bilirubin concentrations were significantly inversely associated with lower-limb amputation, with a greater than threefold risk gradient across levels. Individuals with lower bilirubin concentrations had a higher risk for first amputation (HR 1.38 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.07, 1.79, p = 0.013). The same association persisted after adjustment for baseline variables, including age, height, smoking status, γ-glutamyltransferase level, HbA, trial treatment allocation (placebo vs fenofibrate), as well as previous PAD, non-PAD cardiovascular disease, amputation or diabetic skin ulcer, neuropathy, nephropathy and diabetic retinopathy (HR 1.38 per 5 μmol/l decrease in bilirubin concentration, 95% CI 1.05, 1.81, p = 0.019). Conclusions/interpretation: Our results identify a significant inverse relationship between bilirubin levels and total lower-limb amputation, driven by major amputation. Our data raise the hypothesis that bilirubin may protect against amputation in type 2 diabetes. [ABSTRACT FROM AUTHOR]

ims/hypothesis: Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods: Type 2 diabetic patients ( n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate ( n = 4,895) or placebo ( n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. Results: During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l ( p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min 1.73 m annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min 1.73 m, p = 0.065) than on placebo (6.9 ml min 1.73 m, p < 0.001), sparing 5.0 ml min 1.73 m (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia ( n = 169 vs 491 without) alone, or combined with low HDL-cholesterol ( n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) ( n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% ( p < 0.001; mean difference 14% [95% CI 9-18]; p < 0.001), with 14% less progression and 18% more albuminuria regression ( p < 0.001) than in participants on placebo. End-stage renal event frequency was similar ( n = 21 vs 26, p = 0.48). Conclusions/interpretation: Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier SA (Dijon, France; now part of Abbott Pharmaceuticals) and the National Health and Medical Research Council, Australia [ABSTRACT FROM AUTHOR]

ims/hypothesis: We investigated effects of renal function and albuminuria on cardiovascular outcomes in 9,795 low-risk patients with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Methods: Baseline and year 2 renal status were examined in relation to clinical and biochemical characteristics. Outcomes included total cardiovascular disease (CVD), cardiac and non-cardiac death over 5 years. Results: Lower estimated GFR (eGFR) vs eGFR ≥90 ml min 1.73 m was a risk factor for total CVD events: (HR [95% CI] 1.14 [1.01-1.29] for eGFR 60-89 ml min 1.73 m; 1.59 [1.28-1.98] for eGFR 30-59 ml min 1.73 m; p < 0.001; adjusted for other characteristics). Albuminuria increased CVD risk, with microalbuminuria and macroalbuminuria increasing total CVD (HR 1.25 [1.01-1.54] and 1.19 [0.76-1.85], respectively; p = 0.001 for trend) when eGFR ≥90 ml min 1.73 m. CVD risk was further modified by renal status changes over the first 2 years. In multivariable analysis, 77% of the effect of eGFR and 81% of the effect of albumin:creatinine ratio were accounted for by other variables, principally low HDL-cholesterol and elevated blood pressure. Conclusions/interpretation: Reduced eGFR and albuminuria are independent risk factors for cardiovascular events and mortality rates in a low-risk population of mainly European ancestry. While their independent contributions to CVD risk appear small when other risk factors are considered, they remain excellent surrogate markers in clinical practice because they capture risk related to a number of other characteristics. Therefore, both should be considered when assessing prognosis and treatment strategies in patients with diabetes, and both should be included in risk models. [ABSTRACT FROM AUTHOR]

The apolipoprotein B (ApoB):apolipoprotein A (ApoA)-I ratio may be a better indicator of cardiovascular disease (CVD) risk in people with type 2 diabetes than traditional lipid risk markers (LDL-cholesterol, HDL-cholesterol and triacylglycerol), but whether the ApoB:ApoA-I ratio should be used to indicate lipid-lowering therapy is still debated. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study randomised 9,795 patients with type 2 diabetes to fenofibrate (200 mg daily) or placebo and followed them up for a median of 5 years. We compared ApoB, ApoA-I, ApoAII and the ApoB:ApoA-I ratio with traditional lipid variables as predictors of CVD risk. We estimated the HR of the effect of 1 SD difference in baseline concentrations of lipids, apolipoproteins and respective ratios on the risk of CVD events and also used receiver operating characteristic curve analysis. In the placebo group, the variables best predicting CVD events were non-HDL-cholesterol:HDL-cholesterol, total cholesterol:HDL-cholesterol (HR 1.21, p < 0.001 for both), ApoB:ApoA-I (HR 1.20, p < 0.001), LDL-cholesterol:HDL-cholesterol (HR 1.17, p < 0.001), HDL-cholesterol (HR 0.84, p < 0.001) and ApoA-I (HR 0.85, p < 0.001). In the fenofibrate group, the first four predictors were very similar (but ApoB:ApoA-I was fourth), followed by non-HDL-cholesterol and ApoB. Lipid ratios and ApoB:ApoA-I performed better than any single lipid or apolipoprotein in predicting CVD risk. In patients with type 2 diabetes in the FIELD study, traditional lipid ratios were as strong as the ApoB:ApoA-I ratio in predicting CVD risk. The data provide little evidence for replacement of traditional lipids and their ratios with measures of ApoB, ApoA-I and their ratio. [ABSTRACT FROM AUTHOR]

We present a computational model and corresponding computer simulations that mimic phenomenologically the eye movement trajectories observed in a conjunctive visual search task. The element of randomness is captured in the model through a Monte Carlo selection of a particular eye movement based on its probability, which depends on three factors, adjusted to match to the observed saccade amplitude distribution, forward bias in consecutive saccades, and return rates. Memory is assumed to operate through tagging of objects already recognized as nontargets, which, in turn, requires their processing within the attentional area of conspicuity (AC). That AC is adjusted so that computer simulations optimally reproduce the distribution of the number of saccades, the failure rate for capturing the target, and the return rate to previously inspected locations. For their viability, computer simulations critically depend on memory's being long-ranged. In turn, the simulations confirm the formation of circulating or spiraling patterns in the observed eye trajectories. We also relate consistently the average number of saccades per trial to the saccade amplitude distribution by modeling analytically the combined roles of the AC in attention and memory. The full Supplemental Appendix A for this article may be downloaded from http:// app.psychonomic-journals.org/content/supplemental. [ABSTRACT FROM AUTHOR]

We relate the roles of attention, memory, and spatial constraints to pattern formation in eye movement trajectories previously measured in a conjunctive visual search task. Autocorrelations and power spectra of saccade direction cosines confirm a bias to progress forwardly, while turning at the display boundaries, plus a long-range memory component for the search path. Analyses of certain measures of circulation and imbalance in the eye trajectories, and their relations with the display area correspondingly subtended, bear signatures of spiraling or circulating patterns. We interpret their prevalence as mainly due to the interactions between three basic psychoneural mechanisms (conspicuity area, forward bias, long-range memory) and two task-specific geometric- spatial constraints on the eye trajectories (central start and display confinement). Conversely, computer simulations of random walks in which all psychoneural mechanisms are eliminated, while geometric-spatial constraints are maintained, show no prevalence of circulating patterns by those measures. We did find certain peculiarities of some individual participants in their pattern selections, but they appear too casual and incidental to suggest more systematic or complex search strategies in our randomized displays of uninformative stimuli. [ABSTRACT FROM AUTHOR]

Objective:To investigate the relationships between plasma leptin and adiponectin levels and recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes.Design, subjects and measurements:A nested case–control study examined circulating leptin and adiponectin levels in plasma obtained 4–6 years after entry into the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial. Plasma was assayed from 184 men who suffered recurrent events within 4.4 years after blood collection and 184 matched controls who remained free of further events. The association between cardiovascular events and the explanatory variables was examined by conditional logistic regression analysis.Results:Relative risk (RR) increased across increasing leptin quartiles; the highest quartile compared with the lowest quartile was related to the highest risk (P for trend=0.002); the increased risk remained after adjustment for risk factors (P=0.018) or for obesity (P=0.038), but in the final model (adjusted for randomized treatment, other drugs, LIPID risk score, age and body mass index), the risk was attenuated (RR=1.61, 95% CI: 0.72–3.57, P for trend=0.34). Adiponectin did not predict cardiovascular events. Subjects randomly allocated to pravastatin had 6% lower leptin levels (P=0.04) than those allocated to placebo.Conclusion:Plasma leptin was a significant and independent predictor of recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes.International Journal of Obesity (2009) 33, 123–130; doi:10.1038/ijo.2008.224; published online 9 December 2008 [ABSTRACT FROM AUTHOR]

Seasonal influenza is a prevalent and highly contagious acute respiratory disease that, year on year, results in increased morbidity and mortality on a global scale. Because of the widespread and debilitating nature of the disease, annual influenza epidemics result in substantial workplace absenteeism, and the associated cost of lost productivity is a significant component of the substantial financial burden of the disease to society. The objective of this review was to identify studies that had attempted to quantify the impact of influenza upon otherwise healthy adults in terms of working days lost associated with an episode of influenza. Studies were included if they reported estimates of working days lost due to clinical, physician and/or self-diagnosis in adult patients or their dependants, or where this figure could be estimated from the data. Searches were conducted in MEDLINE, EMBASE, BIOSIS and the Cochrane Collaboration for articles published since 1995 in English, French or German. Of the 289 papers identified in the search, 28 (9.7%) met the inclusion criteria. The studies, involving study sites in North America, Western Europe, Asia and Australia, were categorized into three groups: (i) those reporting influenza diagnoses confirmed by laboratory testing, i.e. studies where influenza was the unambiguous cause of the working days lost (n = 7 studies reported in ten publications); (ii) those where influenza was confirmed by a physician without an accompanying laboratory test (n = 4 studies); and (iii) those where influenza was self-reported by study participants (n = 14 studies). Qualitative reporting of results was performed because of the large degree of heterogeneity observed between studies, potentially complicating the interpretation of any meta-analysis.The results from studies involving a laboratory-confirmed influenza diagnosis suggested that the mean number of working days lost ranged between 1.5 and 4.9 days per episode. Those papers that detailed working days lost per episode following physician diagnosis of influenza reported a range of 3.7–5.9 days per episode. Finally, estimates from papers reporting working days lost per episode of self-reported influenza ranged from <1 day to 4.3 days per episode.Influenza imposes a significant burden on society, and this review highlights the significant economic impact it causes, i.e. the loss of productivity caused by both absenteeism and by staff functioning at reduced capacity even after they have returned to work. A number of prophylaxis and treatment options exist for influenza and should be given serious consideration in an attempt to reduce the economic burden on society. [ABSTRACT FROM AUTHOR]

Low HDL-cholesterol (HDL-C) is frequently accompanied by high triacylglycerol levels in diabetic dyslipidaemia, increasing the risk of CHD. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate treatment lowered triacylglycerol levels, but the initial 5% increase in HDL-C attenuated over 5 years. We explored the changes in VLDL and HDL subspecies during fenofibrate treatment in a statin-free FIELD cohort. We randomised 171 participants with type 2 diabetes mellitus, who had been recruited to the FIELD study in Helsinki, to micronised fenofibrate (200 mg/day) or placebo in double-blind study design. VLDL and HDL subspecies were separated by ultracentrifugation at baseline and at the second and fifth year. Apolipoprotein (apo)A-I and apoA-II were measured by immunoturbidometric methods and lipoprotein (Lp)A-I and LpAI-AII particles by differential immunoassay. Fenofibrate reduced plasma triacylglycerol levels by 26%, resulting from a marked reduction in VLDL1 triacylglycerol (0.62 vs 0.29 mmol/l, p < 0.001). Fenofibrate caused an increase in LDL size (Δ0.80 nm, p < 0.001). HDL-C was similar between the groups. HDL2-C was decreased by fenofibrate (−27.5% at 5th year, p < 0.001) and HDL3-C increased (13.0% at 5th year, p < 0.001). Fenofibrate had no effect on apoA-I, whereas apoA-II increased. Thus, LpA-I decreased while LpAI-AII increased. Activities of cholesteryl ester transfer protein, phospholipids transfer protein and lecithin:cholesterylacyl transferase were unchanged by fenofibrate. High homocysteine levels were associated with a slight decrease in HDL-C and apoA-I. Fenofibrate markedly reduced large VLDL particles and produced a clear shift in HDL subspecies towards smaller particles. The HDL3-C increase in conjunction with unchanged apoA-II levels is a dilemma with regard to cardiovascular disease. [ABSTRACT FROM AUTHOR]

In Swedish boreal forests, areas dominated by the dwarf shrubEmpetrum hermaphroditumHagerup are known for their poor regeneration of trees and one of the causes of this poor regeneration has been attributed to allelopathy (i.e. chemical interferences) byE. hermaphroditum. Fire-produced charcoal is suggested to play an important role in rejuvenating those ecosystems by adsorbing allelopathic compounds, such as phenols, released byE. hermaphroditum. In this study, we firstly investigated whether the adsorption capacity of charcoal of different plant species varies according to the wood anatomical structures of these, and secondly we tried to relate the adsorption capacity to wood anatomical structure. Charcoal was produced from eight boreal and one temperate woody plant species and the adsorption capacity of charcoal was tested by bioassays technique. Seed germination was used as a measurement of the ability of charcoal to adsorb allelochemicals. The charcoal porosity was estimated and the pore size distribution was then calculated in order to relate the wood anatomical features to the adsorption capacity. The results showed that the adsorption capacity of charcoal was significantly different between plant species and that deciduous trees had a significantly higher adsorption capacity than conifers and ericaceous species. The presence of macro-pores rather than a high porosity appears to be the most important for the adsorption capacity. These results suggest that fire-produced charcoal has different ability to adsorb phenols in boreal forest soil, and therefore may have differing effects on the germination of seeds of establishing tree seedlings. [ABSTRACT FROM AUTHOR]

Simple indoles undergo electrolytic degradation at potentials near +1 V vs the normal hydrogen electrode at a Pb/ PbO2 anode. Oxidation is first order in both current and indole concentration. The reaction is characterized by low CO2 yields and high TOC values, that is, most of the carbon of the starting material remained in the solution after electrolysis. Monomeric, isolable oxidation products were not found even at high conversion. These results are consistent with the intermediacy of hydroxyl radicals, which are produced at the surface of the Pb/PbO2 anode by electrolysis of water, initiating the polymerization of the starting materials to water soluble products with high net current efficiency. [ABSTRACT FROM AUTHOR]

Within the pharmaceutical industry, there is increasing interest in collecting health outcomes data in order to inform decision-making, both internally and externally. The overall aim of generating the health outcomes information is to determine the value of the product, from the perspective of all the stakeholders. In addition to studies carried out during phase II and III of clinical development, pharmaceutical companies have recently begun to collect health outcomes information earlier, with the expected requirements for reimbursement and market access considered during the preclinical and phase I stages. However, there are a number of challenges to the demonstration of product value during drug development, particularly relating to the limitations of clinical trials. One way that pharmaceutical companies are addressing these challenges is through the use of economic modelling, to provide a framework to test assumptions and assess uncertainty, and examine the budget impact of treatments. Although different countries may use the information differently, health outcomes evidence generated by the pharmaceutical industry is generally used to inform decision-making about pricing, reimbursement, treatment guidelines and inclusion of drugs on formularies. A wide variety of health outcomes information is produced by the industry in order to provide data on product value that are appropriate for the different perspectives of the stakeholders in the healthcare system. [ABSTRACT FROM AUTHOR]

Infectious microorganisms have evolved molecules which mimic the host in order to aid in their undetected propagation. In response, mammalian hosts have evolved a highly diverse immune repertoire designed to eradicate rapidly changing pathogens. The generation of diversity in the immune repertoire results in potentially damaging self cross-reactivities which require multiple regulatory controls to keep autoreactive lymphocytes in check. Here, we review how molecular mimicry at the T cell level might be important in the development of systemic autoimmunity. [ABSTRACT FROM AUTHOR]

The 67-ha site of Sincu Bara was discovered and extensively excavated in the 1970s. Three primary aspects of its archaeological interest were its vast size, its location in the Middle Senegal Valley, where some of the earliest regional polities in West Africa arose, and the extensive and diverse assortment of copper-based metal artifacts it produced. Deposits with brass appeared to be associated with radiocarbon dates as early as the fifth century AD. It appeared that most of the deposits related to a single, long-lasting occupation by people who arrived with sophisticated copper-based metallurgy in the fifth century and remained at least until the eleventh century, without discernible modification in their material culture. Results of new excavations in 1991–1992 indicate that this interpretation must be substantially modified, since considerable change in material culture, including the introduction of copper-based metals between AD 800 and AD 900, has now been documented. This article summarizes the data from these new excavations and suggests that earlier interpretations were based largely on material from disturbed, severely mixed deposits, which gave a false picture of homogeneity through time. [ABSTRACT FROM AUTHOR]

A novel experimental model was established in normal rats for studying the localisation and tissue distribution of a murine monoclonal antibody directed against kappa light chain B cell malignancies. The antibody, K-1-21 was raised against human kappa Bence Jones Proteins and reacts with a cell membrane antigen KMA which is restricted to some kappa myeloma and lymphoma cells. In the rat model, kappa or lambda Bence Jones protein-conjugated sepharose was implanted subcutaneously on either flank 24 h before the injection of I-labelled K-1-21 or its F(ab′)2 fragment. Gamma camera imaging and tissue distribution studies showed specific localisation of the K-1-21 antibody in the kappa sepharose. Injection of F(ab′)2 antibody fragments resulted in faster background clearance, earlier delineation of the specific image and significantly higher target to blood ratios than those obtained with the intact antibody. These results suggest that the model may provide an alternative system to tumour xenograft bearing nude mice for studying localisation of antibodies with therapeutic potential. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of bismuth subcitrate were studied in plasma and urine under conditions of single and multiple dosing (28-56 days) using atomic absorption technique. Single dose plasma pharmacokinetics showed peak concentrations of 5.5-57.5 µg·l (mean=24.7 µg·l), reached between 30 and 60 min post dosing with an apparent biphasic elimination pattern. Multiple dose studies showed a continuing rise in plasma concentration and urine excretion rate reaching apparent steady-state levels over 7-29 days (mean=18 days). Washout studies in 6 individuals reciprocated accumulation. Maximum equilibrated plasma levels of 7.6-58.3 µg·l (mean=38.3 µg·l) were well below those associated with encephalopathy. The half-life of bismuth elimination was 20.7 days. Present patterns of intermittent dosing with bismuth are unlikely to be associated with bismuth accumulation despite slow accumulation and elimination. [ABSTRACT FROM AUTHOR]

Chronic coadministration of oral verapamil with oral atenolol resulted in a variable increase in atenolol steady-state plasma concentrations in a group of 10 patients on chronic maintenance therapy. Individual subjects showed changes in area under the plasma atenolol concentration-time curve (AUC) of more than 100%, however group comparisons did not achieve statistical significance unless normalized for verapamil dose. Renal clearance of atenolol was shown to be decreased by more than 25% in 2 subjects studied using intravenous dosing of atenolol. This interaction is likely to contribute to the documented clinical intolerance of combinations of atenolol and verapamil. [ABSTRACT FROM AUTHOR]

Examines the political viability of rule-based monetary policy. Consequences of following a rule-based policy; Measure of the desirability of monetary policy; Problem of developing a political support function which relates presidential popularity to economic performance; Key features of a naive voter model.