bluuebunny/crossref_metadata_2025 huggingface dataset:
The Integrated Genome Browser: free software for distribution and exploration of genome-scale datasets
Authors: Nicol John W. , Helt Gregg A. , Blanchard Steven G. , Raja Archana , Loraine Ann E.
Published: August 2009

Summary: Experimental techniques that survey an entire genome demand flexible, highly interactive visualization tools that can display new data alongside foundation datasets, such as reference gene annotations. The Integrated Genome Browser (IGB) aims to meet this need. IGB is an open source, desktop graphical display tool implemented in Java that supports real-time zooming and panning through a genome; layout of genomic features and datasets in moveable, adjustable tiers; incremental or genome-scale data loading from remote web servers or local files; and dynamic manipulation of quantitative data via genome graphs.

Availability: The application and source code are available from http://igb.bioviz.org and http://genoviz.sourceforge.net.

Contact:  aloraine@uncc.edu
Multiple testing in genome-wide association studies via hidden Markov models
Authors: Wei Zhi , Sun Wenguang , Wang Kai , Hakonarson Hakon
Published: August 2009

Motivation: Genome-wide association studies (GWAS) interrogate common genetic variation across the entire human genome in an unbiased manner and hold promise in identifying genetic variants with moderate or weak effect sizes. However, conventional testing procedures, which are mostly P-value based, ignore the dependency and therefore suffer from loss of efficiency. The goal of this article is to exploit the dependency information among adjacent single nucleotide polymorphisms (SNPs) to improve the screening efficiency in GWAS.

Results: We propose to model the linear block dependency in the SNP data using hidden Markov models (HMMs). A compound decision–theoretic framework for testing HMM-dependent hypotheses is developed. We propose a powerful data-driven procedure [pooled local index of significance (PLIS)] that controls the false discovery rate (FDR) at the nominal level. PLIS is shown to be optimal in the sense that it has the smallest false negative rate (FNR) among all valid FDR procedures. By re-ranking significance for all SNPs with dependency considered, PLIS gains higher power than conventional P-value based methods. Simulation results demonstrate that PLIS dominates conventional FDR procedures in detecting disease-associated SNPs. Our method is applied to analysis of the SNP data from a GWAS of type 1 diabetes. Compared with the Benjamini–Hochberg (BH) procedure, PLIS yields more accurate results and has better reproducibility of findings.

Conclusion: The genomic rankings based on our procedure are substantially different from the rankings based on the P-values. By integrating information from adjacent locations, the PLIS rankings benefit from the increased signal-to-noise ratio, hence our procedure often has higher statistical power and better reproducibility. It provides a promising direction in large-scale GWAS.

Availability: An R package PLIS has been developed to implement the PLIS procedure. Source codes are available upon request and will be available on CRAN (http://cran.r-project.org/).

Contact:  zhiwei@njit.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Route of delivery and baseline left ventricular ejection fraction, key factors of bone‐marrow‐derived cell therapy for ischaemic heart disease
Authors: Brunskill Susan J. , Hyde Christopher J. , Doree Carolyn J. , Watt Suzanne M. , Martin‐Rendon Enca
Published: August 2009

Aims

Previous evaluation of autologous bone‐marrow stem‐cell (BMSC) therapy following acute myocardial infarction (AMI) suggests that cell dose and timing of stem‐cell administration post‐MI are important factors in the efficacy of cellular therapy. This study aimed to assess whether route of delivery and baseline left ventricular ejection fraction (LVEF) of the participants may also affect the outcome of BMSC treatment in patients with AMI and ischaemic heart disease (IHD).

Methods and results

Randomized controlled trials of BMSCs as treatment for AMI and IHD were identified by searching MEDLINE, EMBASE, the Cochrane Library, and the Current Controlled Trials Register through to November 2008. Twenty‐one trials (25 comparisons) with a total of 1091 participants were eligible. Data were analysed using a random‐effects model. Improvement in LVEF in favour of the control was observed when BMSC were adminstered by intracoronary infusion [−0.19% (95% CI, −0.24 to −0.14; P < 0.00001)] in IHD patients. However, the effect on LVEF was statistically significant and in favour of BMSC when cells were delivered by intra‐myocardial injection [5.85% (95% CI, 2.50–9.19; P = 0.0006)]. The significant improvement in LVEF observed in AMI patients was independent from the baseline LVEF of the participants. However, in patients suffering from chronic IHD, increase in LVEF was significant only in the group with lower LVEF at baseline [4.42% (CI, 1.87–6.96; P = 0.0007)].

Conclusion

Clinical evidence suggests that route of delivery and baseline LVEF influence the effect of BMSC therapy in treating AMI and chronic IHD.
Partial Resistance ofMedicago truncatulatoAphanomyces euteichesIs Associated with Protection of the Root Stele and Is Controlled by a Major QTL Rich in Proteasome-Related Genes
Authors: Djébali Naceur , Jauneau Alain , Ameline-Torregrosa Carine , Chardon Fabien , Jaulneau Valérie , Mathé Catherine , Bottin Arnaud , Cazaux Marc , Pilet-Nayel Marie-Laure , Baranger Alain , Aouani Mohamed Elarbi , Esquerré-Tugayé Marie-Thérèse , Dumas Bernard , Huguet Thierry , Jacquet Christophe
Published: August 2009

A pathosystem between Aphanomyces euteiches, the causal agent of pea root rot disease, and the model legume Medicago truncatula was developed to gain insights into mechanisms involved in resistance to this oomycete. The F83005.5 French accession and the A17-Jemalong reference line, susceptible and partially resistant, respectively, to A. euteiches, were selected for further cytological and genetic analyses. Microscopy analyses of thin root sections revealed that a major difference between the two inoculated lines occurred in the root stele, which remained pathogen free in A17. Striking features were observed in A17 roots only, including i) frequent pericycle cell divisions, ii) lignin deposition around the pericycle, and iii) accumulation of soluble phenolic compounds. Genetic analysis of resistance was performed on an F7 population of 139 recombinant inbred lines and identified a major quantitative trait locus (QTL) near the top of chromosome 3. A second study, with near-isogenic line responses to A. euteiches confirmed the role of this QTL in expression of resistance. Fine-mapping allowed the identification of a 135-kb sequenced genomic DNA region rich in proteasome-related genes. Most of these genes were shown to be induced only in inoculated A17. Novel mechanisms possibly involved in the observed partial resistance are proposed.
Signaling by the Pathogenicity-Related MAP Kinase of Cochliobolus heterostrophus Correlates With Its Local Accumulation Rather Than Phosphorylation
Authors: Lev Sophie , Tal Hila , Rose Mark S. , Horwitz Benjamin A.
Published: August 2009

Phosphorylated mitogen-activated protein kinases (MAPK) transmit signals by activation of their targets. The extent of signal transduction could depend on MAPK phosphorylation level, concentration, and subcellular localization. The pathogenicity MAPK Chk1 of the fungal corn pathogen Cochliobolus heterostrophus is required for central developmental functions, including appressoria formation, conidiation, melanization, virulence, and female fertility. We followed CHK1 transcript level, protein localization, quantity, phosphorylation, and expression of downstream genes during conidial germination on a surface inductive for appressoria formation and in suspension. The Chk1-GFP protein representing a translational fusion of Chk1 and GFP (green fluorescent protein) was very abundant in ungerminated conidia, accumulated in maturating appressoria and appressorial nuclei, but was uniformly distributed in suspension-grown hyphae. Expression of Chk1-dependent genes was upregulated in appressoria-forming hyphae but not in suspension. Despite Chk1 activation, there was no change in its phosphorylation and total protein quantity. Of all conditions tested, a temperature shift caused a decrease whereas hyperosmotic stress caused an increase in Chk1 phosphorylation. Activation of Chk1 during appressoria formation is apparently manifested by its local accumulation but not by significant changes in phosphorylation.
Disease-Specific Expression of Host Genes During Downy Mildew Infection of Arabidopsis
Authors: Huibers Robin P. , de Jong Mark , Dekter René W. , Van den Ackerveken Guido
Published: August 2009

Here, we report on the identification of Arabidopsis genes that are induced during compatible but not during incompatible interactions with the downy mildew pathogen Hyaloperonospora arabidopsidis. This set of so-called compatible specific (CS) genes contrasts with the large group of defense-associated genes that is differentially expressed during both compatible and incompatible interactions. From the 17 identified CS genes, 6 belong to the ethylene response factor (ERF) family of transcription factor genes, suggesting that these ERF have a role during compatibility. The majority of CS genes are differentially regulated in response to various forms of abiotic stress. In silico analysis of the CS genes revealed an over-representation of dehydration-responsive element/C-repeat binding factor (DREB1A/CBF3) binding sites and EveningElement motifs in their promoter regions. The CS-ERF are closely related to the CBF transcription factors and could potentially bind the DREB1A/CBF3 promoter elements in the CS genes. Transcript levels of CS genes peak at 2 to 3 days postinoculation, when pathogen growth is highest, and decline at later stages of infection. The induction of several CS genes was found to be isolate specific. This suggests that the identified CS genes could be the direct or indirect targets of downy mildew effector proteins that promote disease susceptibility.
Three Combined Quantitative Trait Loci from Nonhost Lactuca saligna Are Sufficient to Provide Complete Resistance of Lettuce Against Bremia lactucae
Authors: Zhang Ningwen W. , Pelgrom Koen , Niks Rients E. , Visser Richard G. F. , Jeuken Marieke J. W.
Published: August 2009

The nonhost resistance of wild lettuce (Lactuca saligna) to downy mildew (Bremia lactucae) is based on at least 15 quantitative trait loci (QTL), each effective at one or more plant developmental stages. We used QTL pyramiding (stacking) to determine how many of these QTL from L. saligna are sufficient to impart complete resistance towards B. lactucae to cultivated lettuce, L. sativa. The alleles of four of the most promising QTL, rbq4, rbq5, rbq6+11, and rbq7 are effective at both the young and adult plant stages. Lines with these four QTL in all possible combinations were generated by crossing the respective backcross inbred lines (BIL). Using the 11 resulting lines (combiBIL), we determined that combinations of three QTL, rbq4, rbq5, and rbq6+11, led to increased levels of resistance; however, one QTL, rbq7, did not add to the resistance level when combined with the other QTL. One line, tripleBIL268, which contains the three QTL rbq4, rbq5, and rbq6+11, was completely resistant to B. lactucae at the young plant stage. This suggests that these three QTL are sufficient to confer the complete resistance of the nonhost L. saligna and any additional QTL in L. saligna are redundant. Histological analysis of B. lactucae infection in L. saligna, the BIL, and the combiBIL 48 h after inoculation revealed different microscopical phenotypes of resistance. The QTL differed with respect to the stage of the infection process with which they interfered.
Continuum model of epithelial morphogenesis during
Caenorhabditis elegans
embryonic elongation
Authors: Ciarletta P. , Ben Amar M. , Labouesse M.
Published: August 2009

The purpose of this work is to provide a biomechanical model to investigate the interplay between cellular structures and the mechanical force distribution during the elongation process of
Caenorhabditis elegans
embryos. Epithelial morphogenesis drives the elongation process of an ovoid embryo to become a worm-shaped embryo about four times longer and three times thinner. The overall anatomy of the embryo is modelled in the continuum mechanics framework from the structural organization of the subcellular filaments within epithelial cells. The constitutive relationships consider embryonic cells as homogeneous materials with an active behaviour, determined by the non-muscle myosin II molecular motor, and a passive viscoelastic response, related to the directional properties of the filament network inside cells. The axisymmetric elastic solution at equilibrium is derived by means of the incompressibility conditions, the continuity conditions for the overall embryo deformation and the balance principles for the embryonic cells. A particular analytical solution is proposed from a simplified geometry, demonstrating the mechanical role of the microtubule network within epithelial cells in redistributing the stress from a differential contraction of circumferentially oriented actin filaments. The theoretical predictions of the biomechanical model are discussed within the biological scenario proposed through genetic analysis and pharmacological experiments.
Hierarchical poroelasticity: movement of interstitial fluid between porosity levels in bones
Authors: Cowin Stephen C. , Gailani Gaffar , Benalla Mohammed
Published: August 2009

The governing equations for the theory of poroelastic materials with hierarchical pore space architecture and compressible constituents undergoing small deformations are developed. These equations are applied to the problem of determining the exchange of pore fluid between the vascular porosity (PV) and the lacunar–canalicular porosity (PLC) in bone tissue due to cyclic mechanical loading and blood pressure oscillations. The result is basic to the understanding of interstitial flow in bone tissue that, in turn, is basic to understanding of nutrient transport from the vasculature to the bone cells buried in the bone tissue and to the process of mechanotransduction by these cells. A formula for the volume of fluid that moves between the PLC and PV in a cyclic loading is obtained as a function of the cyclic mechanical loading and blood pressure oscillations. Formulas for the oscillating fluid pore pressure in both the PLC and the PV are obtained as functions of the two driving forces, the cyclic mechanical straining and the blood pressure, both with specified amplitude and frequency. The results of this study also suggest a PV permeability greater than 10
−9
 m
2
and perhaps a little lower than 10
−8
 m
2
. Previous estimates of this permeability have been as small as 10
−14
 m
2
.
Towards a unified theory for morphomechanics
Authors: Taber Larry A.
Published: August 2009

Mechanical forces are closely involved in the construction of an embryo. Experiments have suggested that mechanical feedback plays a role in regulating these forces, but the nature of this feedback is poorly understood. Here, we propose a general principle for the mechanics of morphogenesis, as governed by a pair of evolution equations based on feedback from tissue stress. In one equation, the rate of growth (or contraction) depends on the difference between the current tissue stress and a target (homeostatic) stress. In the other equation, the target stress changes at a rate that depends on the same stress difference. The parameters in these morphomechanical laws are assumed to depend on stress rate. Computational models are used to illustrate how these equations can capture a relatively wide range of behaviours observed in developing embryos, as well as show the limitations of this theory. Specific applications include growth of pressure vessels (e.g. the heart, arteries and brain), wound healing and sea urchin gastrulation. Understanding the fundamental principles of tissue construction can help engineers design new strategies for creating replacement tissues and organsin vitro.
International variations in infection supportive care practices for paediatric patients with acute myeloid leukaemia
Authors: Lehrnbecher Thomas , Ethier Marie‐Chantal , Zaoutis Theoklis , Creutzig Ursula , Gamis Alan , Reinhardt Dirk , Aplenc Richard , Sung Lillian
Published: August 2009

This study described infection‐related supportive care practices amongst centres participating in two large paediatric acute myeloid leukaemia (AML) cooperative groups, Children’s Oncology Group (COG) and Berlin‐Frankfurt‐Muenster (BFM). We surveyed 216 COG and 55 BFM institutions. The overall survey response rate was 83·8%. Antibacterial prophylaxis was more common among BFM (15/46, 32·6%) compared to COG (24/180, 13·3%, P < 0·0001) institutions. Antifungal prophylaxis also was more common among BFM (42/46, 91·3%) compared to COG (137/178, 77·0%, P = 0·03). There were systematic differences in infection‐related supportive care practices. This information may be used to encourage harmonization of supportive care practices and future randomized trials.
Private channel: a single unusual compound assures specific pollinator attraction in Ficus semicordata
Authors: Chen Chun , Song Qishi , Proffit Magali , Bessière Jean‐Marie , Li Zongbo , Hossaert‐McKey Martine
Published: August 2009

1. Floral scents have been suggested to play a key role in the obligate pollination mutualism between figs and fig wasps. However, few studies have determined whether pollinator‐attractive compounds could alone assure species‐specificity (‘private channel’), or whether specificity is mediated by more complex ‘floral filters’, of which scent is only one component.

2. We examined changes in the floral volatile compounds of Ficus semicordata, a dioecious fig species, during and after pollination using headspace collection and compound identification by Gas Chromatography/Mass Spectrometry (GC/MS). One benzenoid compound, 4‐methylanisole, was strongly predominant (94–98%) among the volatile compounds emitted by both male and female receptive figs of F. semicordata, whereas it was totally absent in the volatiles emitted by figs 4 days after pollination, as well as in receptive‐stage volatiles emitted by two other sympatric fig species, Ficus racemosa and Ficus hispida.

3. Bioassays using the specific pollinator of F. semicordata, Ceratosolen gravelyi, in a Y‐tube olfactometer showed that 4‐methylanisole was attractive to C. gravelyi in a wide range of concentrations (from 1·22 × 10−2 ng/100 μL to 1·22 × 106ng/100μL). Moreover, chemical blends lacking 4‐methylanisole were unattractive to C. gravelyi. These non‐active odour sources included volatile compounds emitted by receptive figs of the two other sympatric fig species and volatiles of F. semicordata post‐pollination figs.

4. All these results suggest that 4‐methylanisole is the main signal compound in the floral scent of F. semicordata that attracts its obligate pollinator to the host figs at the precise stage required for pollination and oviposition. Furthermore, the high proportion of 4‐methylanisole in the odours of receptive figs of both sexes was consistent with the hypothesis of chemical mimicry in dioecious figs.

5. A simple signal comprised of one compound that is unusual among Ficus and that is an infrequent, usually minor, component of other floral odours, may thus function as a private channel in this specialized obligate mutualism.
Response of recruitment to light availability across a tropical lowland rain forest community
Authors: Rüger Nadja , Huth Andreas , Hubbell Stephen P. , Condit Richard
Published: August 2009

1. Many hypotheses about species coexistence involve differential resource use and trade‐offs in species’ life‐history traits. Quantifying resource use across most species in diverse communities, although, has seldom been attempted.

2. We use a hierarchical Bayesian approach to quantify the light dependence of recruitment in 263 woody species in a 50‐ha long‐term forest census plot in Panama. Data on sapling recruitment were obtained using the 1985–1990 and 1990–1995 census intervals. Available light was estimated for each recruit from yearly censuses of canopy density.

3. We use a power function (linear log–log relationship) to model the light effect on recruitment. Different responses of recruitment to light are expressed by the light effect parameterb. The distribution ofbhad a central mode at 0.8, suggesting that recruitment of many species responds nearly linearly to increasing light.

4. Nearly every species showed increases in recruitment with increasing light. Just nine species (3%) had recruitment declining with light, while 198 species (75%) showed increasing recruitment in both census intervals. Most of the increases in recruitment were decelerating, i.e. the increase was less at higher light (b < 1). In the remaining species, the response to light varied between census intervals (24 species) or species did not have recruits in both intervals (41 species).

5. Synthesis.Nearly all species regenerate better in higher light, and recruitment responses to light are spread along a continuum ranging from modest increase with light to a rather strict requirement for high light. These results support the hypothesis that spatio‐temporal variation in light availability may contribute to the diversity of tropical tree species by providing opportunities for niche differentiation with respect to light requirements for regeneration.
Smoking induces insulin resistance—a potential link with the insulin resistance syndrome
Authors: ATTVALL S. , FOWELIN J. , LAGER I. , VON SCHENCK H. , SMITH U.
Published: August 2009

Abstract. Objectives. The acute effect of smoking and snuffing on insulin sensitivity was studied in a group of healthy habitual smokers.

Design The euglycaemic clamp technique was combined with the subcutaneous injection of a bolus (0.1 U kg−1) of fast‐acting insulin (Actrapid®). Randomized subjects smoked either one cigarette per hour for 6 h, took one bag‐packed snuff per hour for 6 h or refrained from nicotine for 48 h before as well as during the clamp.

Subjects. Seven healthy smokers, four females and three males, of normal weight (BMI, mean ± SKM. 21 ± 0.7 kg m−2 with a range of 18.6–23.9), aged 31 ± 2 years (range 24–35 years), who had consumed at least 20 cigarettes per day for at least 5 years were studied. They were recruited through an advertisement in a newspaper. Results. The steady‐state plasma nicotine levels were similar during smoking and snuffing. The insulin and glucose levels were also similar during all three clamps. Smoking, but not snuffing, impaired insulin action (P < 0.05) mainly due to a lower peripheral glucose uptake. The mean growth hormone levels during the 6‐h study were more than doubled during smoking (P < 0.01) while no significant differences were seen in the other counter‐regulatory hormones.

Conclusion. Smoking (also in habitual smokers) acutely impairs insulin action and leads to insulin resistance. Thus, smoking can be of importance for the development of the insulin resistance syndrome associated with risk for cardiovascular disease.
Accelerated coronary artery disease after heart transplantation: the role of enhanced platelet aggregation and thrombosis
Authors: de LORGERIL M. , LOIRE R. , GUIDOLLET J. , BOISSONNAT P. , DUREAU G. , RENAUD S.
Published: August 2009

Abstract. The present study is a prospective examination of the relationship between platelet aggregation and the occurrence of graft failure in a single cohort of heart transplantation (HT) recipients. One‐hundred‐and‐twenty‐four patients underwent platelet function study and were then followed for 1 to 24 months (mean 6.7 months). There were nine re‐transplantations and 13 deaths (11 related to ischaemic events, and two others). In 15 patients, pathologic examination confirmed or revealed that recent acute myocardial infarction was the obvious cause of the graft failure. In five patients, myocardial fibrosis related to severe and diffuse coronary disease was the only microscopic finding. In the last two patients, the cause of the heart failure was not clearly identified. In recent myocardial infarction there was a high incidence (14/15) of coronary thrombi. Thrombi were multiple, disseminated in the coronary tree end of different age. Their presence at autopsy or after explantation was associated with an enhanced ex vivo platelet aggregability as compared with patients without coronary thrombi (n = 8): 43.3 ± 1.7% of maximal aggregation vs. 34.4 ± 2.4 (P = 0.006) and 48.4 ± 5.2 vs. 22.6 ± 4.9 (P = 0.003) for the primary and secondary waves of ADP‐induced aggregation. These results suggest that thrombosis and platelets may play a major role in the process of accelerated coronary artery disease after HT.
Effect of coffee on ambulatory blood pressure in patients with treated hypertension
Authors: EGGERTSEN R. , ANDREASSON Å. , HEDNER T. , KARLBERG B. E. , HANSSON L.
Published: August 2009

Abstract. Effects of caffeine on ambulatory blood pressure, heart rate, renin‐angiotensin system, and ANP were studied in patients treated for mild to moderate hypertension in a randomized, double‐blind, placebo‐controlled, cross‐over trial comparing 2 weeks of caffeine‐free diet with 2 weeks of regular coffee use. Twenty‐three patients (13 men; aged 28–74 years) with treated, mild to moderate essential hypertension and a regular intake of 3–4 cups of coffee daily completed the study.

Mean 24‐h, day‐ or night‐time ambulatory blood pressure and heart rate were not different between regimens. Nor were there any effects on the renin‐angiotensin system while ANP was significantly increased during caffeine intake. Compliance of the dietary regimen was excellent as assessed by serum caffeine concentration measurements. We conclude that habitual coffee drinking did not influence the 24‐h blood pressure profiles or cardiovascular hormones in treated hypertensives.
The predictability of risk factors with respect to incidence and mortality of myocardial infarction and total mortality. A 12‐year follow‐up of the Oslo Study, Norway
Authors: HÅHEIM L. LUND , HOLME I. , HJERMANN I. , LEREN P.
Published: August 2009

Abstract.Objectives. To study the prognostic value of several risk factors on incidence and mortality of myocardial infarction (MI) and total mortality in men.

Design. Prospective cohort study of 12 years' follow‐up.

Setting. All men in Oslo aged 40–49 and a 7% sample of men aged 20–39 were invited for screening.Subjects. Of all 30025 invited men, of whom 25015 were aged 40–49, a total of 16209 men aged 40–49 attended the screening and risk factors were recorded for these men.

Main outcome measures. Incidence of first MI (nonfatal and fatal), mortality of MI, total mortality.Results. When examining the rate ratio of the fifth to the first quintile of risk factors we found that systolic and diastolic blood pressures were stronger predictors for mortality than incidence of MI. The rate ratios (95% confidence interval) of systolic blood pressure were 3.73 (2.56, 5.44) and 2.56 (2.01, 3.25) respectively. For diastolic blood pressure the corresponding rate ratios were 4.14 (2.84, 6.04) and 2.78 (2.18, 3.54). Small differences in the rate ratios for these end‐points were found for total serum cholesterol and triglycerides. Daily cigarette smoking versus non‐cigarette smoking was a stronger predictor for MI mortality than incidence, with rate ratios of 3.16 (2.45, 4.24) and 2.34 (2.00, 2.79) respectively. The Cox proportional hazards regression analysis confirmed the above results.

Conclusions. Total serum cholesterol and triglycerides predicted incidence and mortality of MI equally well. Whereas blood pressure and daily cigarette smoking predicted mortality of MI more strongly.
Captopril does not acutely enhance insulin sensitivity
Authors: HELVE E. , TUOMINEN J. A. , KOIVISTO V. A.
Published: August 2009

Abstract. Objectives. To examine the acute effects of captopril administration on insulin sensitivity in normotensive type 1 diabetic patients.

Design. An euglycaemic insulin clamp (150 min) was performed in a randomized order twice in each subject: once with the oral administration of captopril (25 mg), once with placebo, both given in the beginning of the insulin infusion.

Setting. The study was performed at the clinical research laboratory of Helsinki University Hospital, Second and Third Departments of Medicine.

Subjects. We studied seven male, normotensive type 1 diabetic patients with normal body weight, duration of diabetes 15 ± 2 years, HbA, 9.8 ± 0.7% and daily insulin dose 47 ± 4 units. In addition, nine matched healthy control subjects were examined.

Results. During placebo administration glucose disposal rate in the diabetic patients was not significantly different from that in the control subjects. Captopril administration reduced blood pressure in both groups, whereas glucose disposal rate did not change significantly in diabetic or control subjects. When diabetic and control subjects were analysed together, captopril decreased glucose disposal by 9% (P < 0.05).

Conclusions. Acute captopril administration does not improve insulin sensitivity in normotensive type 1 diabetic patients or control subjects.
Lower tocopherol serum levels in subjects with abdominal adiposity
Authors: ÖHRVALL M. , TENGBLAD S. , VESSBY B.
Published: August 2009

Abstract. Objectives. Peroxidation of lipoproteins may be of critical importance in the development of atherosclerosis. Tocopherol is considered to be the most effective lipid‐soluble antioxidant. The main aim of this study was to measure the serum tocopherol concentrations in a Swedish reference population and to relate them to family history, lifestyle and serum lipoprotein composition.

Design. A health survey of risk factors for coronary heart disease was carried out among the employees of a Swedish company.

Subjects. Ninety per cent (906) of the employees participated.

Results. Mean alpha, beta and gamma tocopherol levels corrected for lipids were 1.57 (SD 0.24), 0.04 (SD 0.01) and 0.20 (SD 0.07) μg ml−1, respectively. Alpha tocopherol levels were slightly higher in women than in men, but there was no difference between different ages. Smokers had a lower alpha tocopherol level than non‐smokers (1.54 and 1.59 μg ml−1; P = 0.03) and persons with low physical activity had a lower level than those with high activity (1.53 and 1.62 μg ml−1, respectively; P = 0.002). Alpha tocopherol concentration was inversely correlated to abdominal sagittal diameter (r = –0.24, P = 0.0001).

Conclusions. The average tocopherol concentrations in this Swedish population were higher than in countries with a high incidence of coronary heart disease but similar to those in countries with a similar, intermediate incidence. The inverse correlation to abdominal adiposity may partly explain why this adiposity is a risk factor for coronary heart disease.
Clinical index to predict bacteraemia caused by staphylococci
Authors: LEIBOVICI L. , GRANSDEN W. R. , EYKYN S. J. , KONSIBERGER H. , DRUCKER M. , PITLIK S. D. , PHILLIPS I.
Published: August 2009

Abstract. Objectives. To define risk factors associated with bacteraemia caused by Staphylococcus aureus or coagulase‐negative staphylococci; and to use them to define patients in need of empiric anti‐staphylococcal antibiotic treatment.

Design, Derivation set: observational, prospective study; validation set: retrospective analysis of a prospectively collected database.

Setting. Derivation set: Beilinson Medical Centre, Petah Tiqva, Israel—a 900‐bed university hospital. Validation set: St Thomas's Hospital, London, UK—an 800‐bed teaching hospital.

Subjects. All episodes of bacteraemia detected at Beilinson Medical Centre between March 1988 and September 1990 (derivation set, n = 1410), and at St Thomas's Hospital during 1987–1990 (validation set, n = 1040).

Interventions. None.

Main outcome measures. Percentage of staphylococcal bacteraemia in groups of patients defined by the models.

Results. The following factors were associated with Staphylococcus aureus bacteraemia: focus of infection (whether high or low risk), haemodialysis, intravenous drug abuse and infection acquired in the orthopaedic ward. A logistic model was used to divide the derivation set into three groups with percentages of Staphylococcus aureus bacteraemia of 1.8%, 13.2% and 33.7% (P < 0.0001); and the validation group 2.5%, 18.2% and 53.2% (P < 0.0001). Factors associated with coagulase‐negative staphylococcal bacteraemia were: central or peripheral intravenous catheter as the focus of infection, a preterm neonate, the presence of a central intravenous catheter, low temperature, and a low white blood cell count. A second model including those factors was used to divide the derivation set into three groups with percentages of coagulase‐negative staphylococcal bacteraemia of 1.9%, 22.8%, and 43% (P < 0.0001). In the validation set, the percentages were 2.9%, 22.4% and 31.0% (P < 0.001).

Conclusions. The present study defines groups at high risk for staphylococcal bloodstream infection, in which empiric treatment should include an anti‐staphylococcal drug.
Thrombocytopenia following administration of phenytoin, dexamethasone and cimetidine: a case report and a potential mechanism
Authors: ARBISER J. L. , GOLDSTEIN A. M. , GORDON D.
Published: August 2009

Abstract.Cimetidine and phenytoin are useful medications often used together in patients with seizure disorders secondary to brain masses or metabolic abnormalities. We describe a case of thrombocytopenia in the setting of concurrent phenytoin, dexamethasone and cimetidine administration, and compare it with previously described cases of thrombocytopenia induced by concurrent use of phenytoin, cimetidine, and glucocorticoids. The similarities between these cases suggest mechanisms by which these agents may induce thrombocytopenia, specifically through potential downregulation of epoxide hydrolase by glucocorticoids.
Drug expectations and drug choices of hospital physicians
Authors: DENIG P. , HAAIJER‐RUSKAMP F. M. , WESSELING H. , VERSLUIS A.
Published: August 2009

Abstract. Objectives. To assess whether differences in drug choices of hospital physicians are related to differences in the underlying decision‐making process.

Design. A survey study was conducted addressing drug choices in six therapeutic fields with existing interprescriber variations; prescribers and non‐prescribers of drugs of which the merits were not sufficiently proven (i.e. the ‘target drugs’) were compared.

Setting. A 1000‐bed university hospital in The Netherlands.

Subjects. All 85 hospital physicians working in specialities involving one of the selected fields were asked to participate; 72 physicians completed the interviews.

Main outcome measures. Comparisons were made regarding three elements of the decision‐making process: (1) the physicians' expectations of the target drugs and frequently used alternatives, (2) the weights attached to the principal treatment aspects, and (3) the extent to which their actual choice is based on these expectations and weights.

Results. In three fields, i.e. anti‐emetics, vasodilators, and platelet inhibitors, the prescribers of the less desirable target drugs had higher expectations of these drugs in comparison to the non‐prescribers. In the other therapeutic fields, choosing target drugs was related either to attaching less importance to side‐effects and costs, or to attaching less importance to reports from clinical trials. Twenty of the 46 treatment choices of the prescribers of target drugs could not be predicted from their expressed views as opposed to 5 of the 36 choices of the non‐prescribers (P < 0.05).

Conclusions. Choosing less desirable drugs is not always related to having too high expectations of the drug. Assigning a different importance to certain aspects of the drug and resorting to decision strategies that do not include the weighing of all pros and cons provide alternative explanations for such treatment choices.
Reactivation of chronic hepatitis C after withdrawal of immunosuppressive therapy
Authors: GRUBER A. , LUNDBERG L.‐G. , BJÖRKHOLM M.
Published: August 2009

Abstract. A patient with immune‐mediated thrombocytopenia (ITP) and chronic hepatitis C virus (HCV) infection for 11 years was given immunosuppressive treatment because of an activation of his ITP. After 6 weeks of treatment with cyclophosphamide, cyclosporin A and cortisone the patient decided not to continue taking his medication. One month later he was readmitted to hospital due to fever, cough and jaundice. Clinical investigation revealed his condition to be caused by an activation of his HCV infection. It is concluded that, in parallel to the situation in hepatitis B, immunosuppressive treatment of patients with HCV infection may lead to increased viral replication, resulting in severe liver damage when immunocompetence is regained.
Glucocorticoid‐induced osteoporosis: pathogenesis, prevention and treatment, with special regard to the rheumatic diseases
Authors: OLBRICHT T. , BENKER G.
Published: August 2009

Abstract. Objectives. To review factors associated with development of osteoporosis in patients with rheumatic diseases, as well as the preventive and therapeutic measures.

Design. A MEDLINE literature search.

Results. 1 Pathogenesis. Rheumatoid arthritis in itself causes reduction of bone mass; this process can be aggravated by glucocorticoid treatment. With glucocorticoid treatment, bone mineral density decrease is most pronounced during the first months of treatment. There is no agreement on the effects of daily dose, cumulative dose, and duration of glucocorticoid treatment on the rate of bone loss. However, with treatment by low doses (< 10 mg of prednisone equivalent per day), bone loss appears to be minimal or even undetectable compared to controls. Alternate day treatment, or treatment with steroid ‘pulses’ have not been shown to protect from bone loss. 2 Prevention and treatment. Prophylactic and therapeutic measures for glucocorticoid‐induced osteoporosis include calcium supplementation, vitamin D in physiological doses and oestrogen in perimenopausal female patients. Efficacy has not always been shown in this particular indication but is extrapolated from other forms of osteoporosis. Limited data exist on treatment with anabolic steroids, calcitonin (with an additional analgesic effect) and biphosphonates and reduction of fracture rates has not yet been investigated. At present, there is insufficient evidence to show that altered steroid molecules can dissociate adverse effects on bone from clinically desirable effects.

Conclusion. In view of the paucity of study data, prophylaxis and therapy of glucocorticoid‐induced osteoporosis should receive more attention in future clinical studies.
The influence of antihypertensive therapy on the structural arteriolar changes in essential hypertension: different effects of enalapril and hydrochlorothiazide
Authors: DAHLÖF B. , HANSSON L.
Published: August 2009

Abstract. Objectives. To assess the peripheral and central haemodynamics, in particular the effect on minimal resistance in the hand, with an ACE inhibitor in comparison with a diuretic.

Design. Double‐blind randomized parallel group study.

Subjects. Twenty‐eight previously untreated men with essential hypertension (supine diastolic blood pressure > 95 mmHg repeatedly on placebo).

Methods/intervention. Casual and intra‐arterial blood pressure, dye‐dilution technique, water plethysmography at rest and at ischaemia, enalapril (n = 14), hydrochlorothiazide (n = 14).

Results. After 6 months the mean arterial pressure was reduced from 112.7 to 96.9 mmHg (change –15.9 mmHg; 95% confidence interval (CI) –21.9, –9.8) on enalapril and from 110.1 to 101.5 mmHg (change –8.6 mmHg; CI –14.4, –2.8). Heart rate did not change on any of the therapies. Enalapril reduced blood pressure mainly through a reduction in total peripheral resistance (Δ –3.0 PRU100; CI –5.6, –0.4) while hydrochlorothiazide reduced blood pressure mainly through a reduction in cardiac output (Δ –0.8 l/min−1 CI –1.5, –0.07). Minimal vascular resistance (mean of right and left hand) displayed a significant time × treatment interaction indicating a different trend with enalapril than hydrochlorothiazide with a change of –0.12 PRU100 (CI –0.33, 0.05) on enalapril and a change of 0.14 (CI –0.29, 0.56) on hydrochlorothiazide. The resistance level after 6 months was significantly higher on hydrochlorothiazide than on enalapril (P = 0.0105).

Conclusion. Enalapril reduced blood pressure through vasodilatation and hydrochlorothiazide through decreased cardiac output. The two therapies also affected minimal vascular resistance (an indirect measure of vascular wall thickness) differently; with enalapril showing a favourable response in contrast to hydrochlorothiazide.
Liver damage from low‐dose oral contraceptives
Authors: LINDGREN A. , OLSSON R.
Published: August 2009

Abstract. Objective. To study whether the decrease in the content of oestrogen and gestagen in modern low‐dose oral contraceptives (OC) has yielded a lower incidence of adverse liver reactions, and to describe the biochemical pattern of the adverse liver reactions from low‐dose OC.

Design. We surveyed all liver reactions from OC reported to SADRAC (Swedish Adverse Drug Reactions Advisory Committee) from 1966 to 1989.

Main outcome measure. Incidence of reported adverse liver reactions (number of reported adverse reactions/OC sales in defined daily dose [DDD]).

Results. There was a sharp decline in the number of reports during the studied period, suggesting changes in reporting habits. However, there was also a significantly lower incidence of reports for medium‐compared to high‐oestrogen dose OC, and a further decrease, albeit non‐significant, in incidence with low‐oestrogen dose OC. Furthermore, in three comparisons of pairs of OC that differed only in the gestagen dose, there was a strong trend towards a higher reporting rate with higher gestagen dose. Cholestatic and hepatoceullular liver enzyme patterns were equally frequent in patients with adverse reactions from low‐dose oestrogen OC. There was no report of liver tumours related to use of low‐oestrogen dose OC.

Conclusion. There seems to be a decrease in the incidence of adverse liver reactions related to lower contents of both oestrogens and gestagens in OC of the combined‐preparation type.
Tracking of cardiovascular disease risk factors including maximal oxygen uptake and physical activity from late teenage to adulthood An 8‐year follow‐up study
Authors: ANDERSEN L. B. , HARALDSDÓTTIR J.
Published: August 2009

Abstract. Objectives. The aim of the study was to analyse changes in coronary heart disease (CHD) risk factors from adolescence to young adulthood, and how changes in risk factors relate to changes in lifestyle.

Design. A randomized sample of school children was tested in 1983 and followed‐up 8 years later. In 1983 a dropout of 0.7% was found and the sample was representative of 16–19‐year‐old Danes.

Subjects. Subjects followed‐up 8 years later (two‐thirds of the original sample) were 88 male and 115 female 15–19‐year‐old school children attending 18 high schools, nine vocational and nine trade schools, throughout Denmark.

Main outcome measures. Height, body weight, body fat, occupation and coronary heart disease risk factors including physical activity (PA), fitness, blood pressure (BP), serum cholesterol, HDL cholesterol, triglyceride (TG) and smoking habits were assessed.

Results. In males all risk factors increased: the increases in total cholesterol level and systolic and diastolic BP were large, 0.85 mmol l−1 and 11 mmHg, respectively. In females, the risk for some factors increased (total cholesterol and BP), others decreased (higher HDL cholesterol), and triglyceride did not change. Significant tracking was found in both sexes, with the highest correlation coefficients in men. A total risk score was calculated by categorizing risk factors into six groups—1 to 6—and then adding the scores. Pearson correlation between the total risk scores in 1983 and 1991 in men was r = 0.67 (P < 0.001). Only a weak association was found for the total risk score in women. Nearly 50% of the boys, who were initially in the upper quintile of risk, were still in the upper quintile 8 years later for most risk factors. In men, the changes in risk factors were related to social factors. Blue‐collar workers and the unemployed had the highest increase in risk factors, and the largest decrease in Vo2max (ml min−1 kg−1) when analysed together. In both sexes the best relationship between 1983 and 1991 values was found in body mass index (BMI). Leisure time physical activity (PA) and triglyceride (TG) had a low correlation between 1983 and 1991 values. Physical activity had a non‐significant correlation over time for women, indicating that PA in 1983 did not predict PA in 1991 at all.

Conclusion. Coronary heart disease risk factors tracked in both males and females, but only in males was a strong relationship found for total risk from adolescence to young adulthood, indicating the influence of a poor lifestyle in high‐risk men. Lower social status related to higher risk.
Spontaneous resolution of acquired factor X deficiency in amyloidosis
Authors: le QUELLEC A. , SOTTO A. , CIURANA A. J.
Published: August 2009

Abstract. We describe the case of a 51‐year‐old man with systemic amyloidosis in whom factor X activity was initially 6% of the normal. Amyloidosis was responsible for congestive heart failure and a nephritic syndrome but there was no bleeding diathesis. A 12‐month trial of melphalan and prednisone failed to improve cardiac and renal dysfunction; factor X levels remained low. Eighteen months after this treatment was stopped, factor X spontaneously normalized although renal insufficiency persisted. We suggest that the possibility of a spontaneous factor X recovery must be considered when evaluating efficacy of therapeutic agents in amyloidosis.
Venographic assessment of deep vein thrombosis and risk of developing post‐thrombotic syndrome: a prospective study
Authors: MONREAL M. , MARTORELL A. , CALLEJAS J. M. , VALLS R. , LLAMAZARES J. F. , LAFOZ E. , ARIAS A.
Published: August 2009

Abstract. It is well known that patients with deep vein thrombosis (DVT) constitute a risk group for development of pulmonary embolism. However, the relation of DVT and the extent thereof with the subsequent sequelae (post‐thrombotic syndrome) are insufficiently investigated. We have prospectively studied a series of consecutive patients admitted because of DVT on lower limbs, trying to correlate venographic findings during acute DVT with post‐thrombotic (PTS) symptoms that develop later.

Seventy‐nine patients (84 limbs) with acute DVT were followed‐up in our out‐patient clinic at 4‐monthly intervals for 3 years. At each visit patients were carefully examined regarding the appearance of PTS symptoms and/or signs from the DVT‐affected leg. Three years after discharge, presence of PTS signs was assessed according to a simple scoring system. And then correlated to venographic findings during acute DVT.

Patients were classified as having no (37 legs), mild (30 legs), or severe PTS signs (17 legs). Patients with popliteal vein involvement showed a significantly higher incidence of PTS 3 years later (P < 0.001). The risk of PTS also increased as DVT extent increased (P < 0.001). Nevertheless, the logistic regression analysis showed that DVT location explained all the differences (P < 0.001). In other words, DVT extent was overriden by the significance of DVT location, being popliteal the only location that showed a relevant contribution to the PTS incidence (95% confidence interval = 2.49–71.5).