bluuebunny/crossref_metadata_2025 huggingface dataset:
Tsn1-Mediated Host Responses to ToxA from Pyrenophora tritici-repentis
Authors: Adhikari Tika B. , Bai Jianfa , Meinhardt Steven W. , Gurung Suraj , Myrfield Mary , Patel Jaimin , Ali Shaukat , Gudmestad Neil C. , Rasmussen Jack B.
Published: August 2009

The toxin sensitivity gene Tsn1 interacts with Ptr ToxA (ToxA), a host-selective toxin produced by the necrotrophic fungus Pyrenophora tritici-repentis. The molecular mechanisms associated with cell death in sensitive wheat cultivars following ToxA application are not well understood. To address this question, we used the Affymetrix GeneChip Wheat Genome Array to compare gene expression in a sensitive wheat cultivar possessing the Tsn1 gene with the insensitive wheat cv. Nec103, which lacks the Tsn1 gene. This analysis was performed at early timepoints after infiltration with ToxA (e.g., 0.5 to 12 h postinfiltration [hpi]); at this time, ToxA is known to internalize into mesophyll cells without visible cell death symptoms. Gene expression also was monitored at later timepoints (24 to 48 hpi), when ToxA causes extensive damage in cellular compartments and visible cell death. At both early and late timepoints, numerous defense-related genes were induced (2- to 197-fold increases) and included genes involved in the phenylpropanoid pathway, lignification, and the production of reactive oxygen species (ROS). Furthermore, a subset of host genes functioning in signal transduction, metabolism, and as transcription factors was induced as a consequence of the Tsn1–ToxA interaction. Nine genes known to be involved in the host defense response and signaling pathways were selected for analysis by quantitative real-time polymerase chain reaction, and the expression profiles of these genes confirmed the results obtained in microarray experiments. Histochemical analyses of a sensitive wheat cultivar showed that H2O2 was present in leaves undergoing cell death, indicating that ROS signaling is a major event involved in ToxA-mediated cell death. The results suggest that recognition of ToxA via Tsn1 triggers transcriptional reprogramming events similar to those reported for avirulence–resistance gene interactions, and that host-derived genes play an important role in the modulation of susceptibility to P. tritici-repentis.
Analysis of Class III Peroxidase Genes Expressed in Roots of Resistant and Susceptible Wheat Lines Infected by Heterodera avenae
Authors: Simonetti Ester , Veronico Pasqua , Melillo M. Teresa , Delibes Ángeles , Andrés María Fe , López-Braña Isidoro
Published: August 2009

The response of resistant wheat–Aegilops ventricosa introgression line H-93-8 and its susceptible parent, Triticum aestivum H-10-15, to Ha71 Spanish population of Heterodera avenae was studied to determine the changes in peroxidase gene expression during incompatible and compatible wheat–nematode interactions. Twenty peroxidase genes were characterized from both 211 expressed sequence tags and 259 genomic DNA clones. Alignment of deduced amino acid sequences and phylogenetic clustering with peroxidases from other plant species showed that these enzymes fall into seven different groups (designated TaPrx108 to TaPrx114) which represent peroxidases secreted to the apoplast by a putative N-terminal peptide signal. TaPrx111, TaPrx112, and TaPrx113 were induced by nematode infection in both genotypes but with differing magnitude and timing. TaPrx112 and TaPrx113 groups increased more in resistant than in susceptible infected lines. In addition, in situ hybridization analyses of genes belonging to TaPrx111, TaPrx112, and TaPrx113 groups revealed a more intense signal in cells close to the vascular cylinder and parenchyma vascular cells of resistant than susceptible wheat when challenged by nematodes. These data seem to suggest that wheat apoplastic peroxidases, because of their different expression in quantity and timing, play different roles in the plant response to nematode infection.
Identification of a Hydroxyproline Transport System in the Legume Endosymbiont Sinorhizobium meliloti
Authors: MacLean Allyson M. , White Catharine E. , Fowler Jane E. , Finan Turlough M.
Published: August 2009

Hydroxyproline-rich proteins in plants offer a source of carbon and nitrogen to soil-dwelling microorganisms in the form of root exudates and decaying organic matter. This report describes an ABC-type transport system dedicated to the uptake of hydroxyproline in the legume endosymbiont Sinorhizobium meliloti. We have designated genes involved in hydroxyproline metabolism as hyp genes and show that an S. meliloti strain lacking putative transport genes (ΔhypMNPQ) is unable to grow with or transport trans-4-hydroxy-l-proline when this compound is available as a sole source of carbon. Expression of hypM is upregulated in the presence of trans-4-hydroxy-l-proline and cis-4-hydroxy-d-proline, as modulated by a repressor (HypR) of the GntR/FadR subfamily. Although alfalfa root nodules contain hydroxyproline-rich proteins, we demonstrate that the transport system is not highly expressed in nodules, suggesting that bacteroids are not exposed to high levels of free hydroxyproline in planta. In addition to hypMNPQ, we report that S. meliloti encodes a second independent mechanism that enables transport of trans-4-hydroxy-l-proline. This secondary transport mechanism is induced in proline-grown cells and likely entails a system involved in l-proline uptake. This study represents the first genetic description of a prokaryotic hydroxyproline transport system, and the ability to metabolize hydroxyproline may contribute significantly toward the ecological success of plant-associated bacteria such as the rhizobia.
Mechanical strain enhances survivability of collagen micronetworks in the presence of collagenase: implications for load-bearing matrix growth and stability
Authors: Bhole Amit P. , Flynn Brendan P. , Liles Melody , Saeidi Nima , Dimarzio Charles A. , Ruberti Jeffrey W.
Published: August 2009

There has been great interest in understanding the methods by which collagen-based load-bearing tissue is constructed, grown and maintained in vertebrate animals. To date, the responsibility for this process has largely been placed with mesenchymal fibroblastic cells that are thought to fully control the morphology of load-bearing extracellular matrix (ECM). However, given clear limitations in the ability of fibroblastic cells to precisely place or remove single collagen molecules to sculpt tissue, we have hypothesized that the material itself must play a critical role in the determination of the form of structural ECM. We here demonstrate directly, using live, dynamic, differential interference contrast imaging, that mechanically strained networks of collagen fibrils, exposed to collagenase (
Clostridium histolyticum
), degrade preferentially. Specifically, unstrained fibrils are removed ‘quickly’, while strained fibrils persist significantly longer. The demonstration supports the idea that collagen networks are mechanosensitive in that they are stabilized by mechanical strain. Thus, collagen molecules (together with their complement enzymes) may comprise the basis of a smart, load-adaptive, structural material system. This concept has the potential to drastically simplify the assumed role of the fibroblast, which would need only to provide ECM molecules and mechanical force to sculpt collagenous tissue.
Population genomics in a disease targeted primary cell model
Authors: Grundberg Elin , Kwan Tony , Ge Bing , Lam Kevin C.L. , Koka Vonda , Kindmark Andreas , Mallmin Hans , Dias Joana , Verlaan Dominique J. , Ouimet Manon , Sinnett Daniel , Rivadeneira Fernando , Estrada Karol , Hofman Albert , van Meurs Joyce M. , Uitterlinden André , Beaulieu Patrick , Graziani Alexandru , Harmsen Eef , Ljunggren Östen , Ohlsson Claes , Mellström Dan , Karlsson Magnus K. , Nilsson Olle , Pastinen Tomi
Published: August 2009

The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P< ∼10−3) were tested forcis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of convergingcis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strongcis-effects on gene expression in HObs (P= 6 × 10−10− 7 × 10−16) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n= 3014), providing evidence for two novel BMD loci (SRRandMSH3). These variants were then tested in the Rotterdam Study (n= 2090), yielding converging evidence for BMD association at the 17p13.3SRRlocus (Pcombined= 5.6 × 10−5). Thecis-regulatory effect was further fine-mapped to the proximal promoter of theSRRgene (rs3744270,r2= 0.5,P= 2.6 × 10−15). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.
The Jurisdiction of Internal Auditing and the Quest for Professionalization: The Danish Case
Authors: Arena Marika , Jeppesen Kim K.
Published: August 2009

For decades, the Institute of Internal Auditors has promoted the professionalization of internal auditing. Prior research on the subject has focused mainly on the achievement of professional characteristics as an indicator of the degree of professionalism. The results seem to vary suggesting that focus should be on exploring the contextual dependency of the professionalization of internal auditing. Based on a case study of Danish internal auditing, this paper analyzes the process of professionalization through the lenses of Abbott's theory of the system of professions. From this perspective, the process of professionalization is driven by inter‐professional competition with the external audit profession over the internal audit jurisdiction. The results indicate that in the Danish case external auditing has maintained an intellectual jurisdiction over internal auditing by controlling its knowledge base, thus preventing Danish internal auditing from obtaining a distinct jurisdiction of its own.
Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice
Authors: Jiang Xian , Li Hali , Qiao Haiquan , Jiang Hongchi , Xu Ruian , Sun Xueying
Published: August 2009

Hepatocellular carcinoma (HCC) is one of the most common cancer‐related causes of death, and conventional treatments offer unsatisfactory response. We have previously reported that kallistatin gene therapy suppressed the growth of HCC tumors by its anti‐angiogenic activity, and meloxicam, a selective COX‐2 inhibitor, inhibited proliferation and induced apoptosis of human HCC cells in vitro. The aim of this study was to determine whether combining kallistatin gene therapy and meloxicam could offer a better therapeutic effect to combat HCC in mice. A kallistatin expression plasmid was constructed and its expression was detected after intratumoral gene transfer. Both kallistatin gene therapy and meloxicam suppressed the growth of subcutaneous human HepG2 tumors established in BALB/c nude mice, and the combinational therapy showed a stronger effect in suppressing tumor growth, tumor angiogenesis and cell proliferation, and increasing cell apoptosis, than the respective monotherapies. Gene transfer of kallistatin inhibited tumor angiogenesis, and slightly inhibited cell proliferation and increased cell apoptosis in situ, but had no effect on expression of vascular endothelial growth factor, basic fibroblast growth factor, proliferating cell nuclear antigen, Bcl‐2, Bax, or activation of caspase‐3. Meloxicam therapy inhibited cell proliferation, induced cell apoptosis, reduced expression of proliferating cell nuclear antigen, increased activation of caspase‐3, and upregulated Bax. Meloxicam also slightly inhibited tumor angiogenesis with no effect on the expression of vascular endothelial growth factor or basic fibroblast growth factor. Combining two novel anticancer agents, kallistatin targeting tumoral vascularization and meloxicam targeting cell proliferation and apoptosis, warrants investigation as a therapeutic strategy to combat HCC. (Cancer Sci 2009)
Development of the Assistance to Participate Scale (APS) for children's play and leisure activities
Authors: Bourke‐Taylor H. , Law M. , Howie L. , Pallant J. F.
Published: August 2009

Aim This paper describes the development and psychometric evaluation of the Assistance to Participate Scale (APS). The APS measures the assistance that a school‐aged child with a disability requires to participate in play and leisure activities from the primary carer's perspective.

Method Mixed methodology using an instrument design model was used to complete two studies. First, a qualitative research design was used to generate items and scoring criteria for the APS. Second, a quantitative study evaluated the instrument using data collected from 152 mothers with children aged 5–18 years. Statistical analysis assessed the underlying structure, internal consistency and construct validity of the APS.

Results Exploratory factor analysis revealed two correlated components, reflecting home‐based and community‐based play activities. Both subscales and the total APS scale showed good internal consistency. The APS correlated as predicted with individual domains and overall scores for other validated measures (Pediatric Evaluation of Disability Inventory caregiver scales and Pediatric Quality of Life Inventory) with correlations ranging from rho = 0.42 to rho = 0.77. The APS was able to discriminate between groups of children based on type of schooling (regular or segregated), need for equipment/assistive devices, frequency of lifting and disability.

Conclusions The APS provides professionals with a brief psychometrically sound tool that measures the amount of caregiver assistance provided to a child with a disability to participate in play and recreation. The APS may be used as an outcome measure and to evaluate and predict the amount and type of additional assistance families need to facilitate their child's participation in an important aspect of the child's daily life and development: play and recreation.
Identifying predators clarifies predictors of nest success in a temperate passerine
Authors: Benson Thomas J. , Brown Jeremy D. , Bednarz James C.
Published: July 2009

1. Nest predation negatively affects most avian populations. Studies of nest predation usually group all nest failures when attempting to determine temporal and parental activities, habitat or landscape predictors of success. Often these studies find few significant predictors and interpret patterns as essentially random.

2. Relatively little is known about the importance of individual predator species or groups on observed patterns of nest success, and how the ecology of these predators may influence patterns of success and failure.

3. In 2006 and 2007, time‐lapse, infrared video systems were deployed at nests of Swainson’s warblers (Limnothlypis swainsonii Audubon) in east‐central Arkansas to identify dominant nest predators and determine whether factors predicting predation differed among these predators.

4. Analysis of pooled data yielded few predictors of predation risk, whereas separate analyses for the three major predator groups revealed clear, but often conflicting, patterns.

5. Predation by ratsnakes (Elaphe obsoleta) and raptors was more common during the nestling period, whereas predation by brown‐headed cowbirds (Molothrus ater) occurred more during incubation. Additionally, the risk of predation by raptors and cowbirds decreased throughout the breeding season, whereas ratsnake predation risk increased.

6. Contrary to expectations, predation by ratsnakes and cowbirds was more common far from edges, whereas raptor predation was more common close to agricultural edges.

7. Collectively, our results suggest that associating specific predators with the nests they prey on is necessary to understand underlying mechanisms.
Abiotic and biotic drivers of seedling survival in a hurricane‐impacted tropical forest
Authors: Comita Liza S. , Uriarte Maria , Thompson Jill , Jonckheere Inge , Canham Charles D. , Zimmerman Jess K.
Published: August 2009

1. Many forests experience periodic, large‐scale disturbances, such as hurricanes and cyclones, which open the forest canopy, causing dramatic changes in understorey light conditions and seedling densities. Thus, in hurricane‐impacted forests, large variations in abiotic and biotic conditions likely shape seedling dynamics, which in turn will contribute to patterns of forest recovery.

2. We monitored 13 836 seedlings of 82 tree and shrub species over 10 years following Hurricane Georges in 1998 in a subtropical, montane forest in Puerto Rico. We quantified changes in the biotic and abiotic environment of the understorey and linked seedling dynamics to changes in canopy openness and seedling density, and to spatial variation in soil type, topography and tree density.

3. Canopy openness was highest when first measured after Hurricane Georges and dropped significantly withinc.3 years, while seedling densities remained high forc.5 years post‐hurricane. When all species and census intervals were analysed together, generalized linear mixed effects models revealed that canopy openness, seedling and adult tree densities were significant drivers of seedling survival.

4. The relative importance of abiotic and biotic factors changed over time. Separate analyses for each census interval revealed that canopy openness was a significant predictor of survival only for the first census interval, with lower survival at the highest levels of canopy openness. The effect of conspecific seedling density was significant in all intervals except the first, and soil type only in the final census interval.

5. When grouping species into life‐history guilds based on adult tree susceptibility to hurricane damage, we found clear differences among guilds in the effects of biotic and abiotic factors on seedling survival. Seedlings of hurricane‐susceptible and intermediate guilds were more strongly influenced by canopy openness, while seedlings of the hurricane‐resistant group were less affected by conspecific seedling density. Individual species‐level analyses for 12 common species, however, showed considerable variation among species within guilds.

6. Synthesis. Our results suggest that hurricanes shape species composition by altering understorey conditions that differentially influence the success of seedlings. Thus, predicted increases in the intensity and frequency of hurricanes in the Caribbean will likely alter seedling dynamics and ultimately the species composition in hurricane‐impacted forests.
Changes in insulin and lipid metabolism in males with asymptomatic hyperuricaemia
Authors: ZAVARONI I. , MAZZA S. , FANTUZZI M. , DALL'AGLIO E. , BONORA E. , DELSIGNORE R. , PASSERI M. , REAVEN G. M.
Published: August 2009

Abstract.Objectives. To define the effect of asymptomatic hyperuricaemia on various facets of glucose, insulin, and lipoprotein metabolism.

Design. Case control study in health volunteers.

Setting. The volunteers for this study were selected on the basis of their laboratory results from a larger population participating in a general survey in one large factory.

Subjects. The study population consisted of 40 healthy males: 20 with asymptomatic hyperuricaemia (serum uric acid concentration equal to or greater than 420 mmol l−1) and 20 with normal serum uric acid concentrations (180–320 mmol l−1). The two groups were similar in terms of age, general obesity (estimated by body mass index), smoking and alcohol intake, and estimate of work and leisure time activity.Interventions. All subjects received a 75 g oral glucose challenge, with blood taken before and at frequent intervals thereafter.

Main outcome measures. Fasting plasma glucose, insulin, and lipid concentrations and plasma glucose and insulin responses to the oral glucose challenge.Results. By selection, mean (±sem) serum uric acid concentration was higher in the hyperuricaemic individuals (454 ± 7 vs. 274 ± 12 mmol l−1). In addition, the plasma insulin response to oral glucose was increased in individuals with asymptomatic hyperuricaemia (P< 0.005) as were both systolic (136 ± 3 vs. 126 ± 3 mmHg,P< 0.05) and diastolic (91 ± 1 vs. 82 ± 1,P< 0.01) blood pressure. Furthermore, subjects with asymptomatic hyperuricaemia were dyslipidaemic (higher plasma TG and cholesterol and lower HDL‐cholesterol concentrations) as compared to the normouricaemic control group (P< 0.07–0.005).

Conclusions. These results provide a possible explanation for the well‐known association of hyperuricaemia with coronary heart disease, as well as suggesting that hyperuricaemia be added to the cluster of metabolic and haemodynamic abnormalities associated with insulin resistance and/or hyperinsulinaemia and designated as Syndrome X.
Treatment of primary hypercholesterolaemia. Short‐term efficacy and safety of increasing doses of simvastatin and pravastatin: a double‐blind comparative study
Authors: STALENHOEF A. F. H. , LANSBERG P. J. , KROON A. A. , KORTMANN B. , DE HAAN A. F. J. , STUYT P. M. J. , KASTELEIN J. J. P.
Published: August 2009

Abstract. Objectives. To compare the efficacy and safety of increasing doses (0, 10, 20 and 40 mg day−1, each dose for 6 weeks) of the inhibitors of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, simvastatin and pravastatin, in the treatment of primary hypercholesterolaemia.

Design. Randomized, double‐blind study with two parallel groups.

Setting. Two specialist lipid clinics in the Netherlands.

Subjects. Forty‐eight patients aged 25–66 years with primary hypercholesterolaemia (mean serum cholesterol 10.2 mmol−1).

Main outcome measures. Total serum cholesterol, triglycerides, lipoproteins, apolipoproteins A‐I and B, laboratory safety parameters and sleep questionnaires.

Results. Both drugs induced a dose‐dependent reduction in the mean total and low‐density lipoprotein cholesterol concentration (P < 0.001); low‐density lipoprotein cholesterol decreased from 32 to 43% by simvastatin and from 23 to 33% by pravastatin. There was an overall difference in the mean relative change from baseline in favour of simvastatin (total cholesterol, P < 0.01; LDL cholesterol P < 0.001). Both drugs reduced serum triglycerides by 10–15%. The changes in apolipoprotein B and the differences in efficacy between the two drugs paralleled those of total and low‐density lipoprotein cholesterol. Adverse experiences were mild and did not differ between treatment groups; in each group, one subject discontinued medication because of complaints of dizziness. Sleep questionnaires revealed different degrees of sleep problems, unaffected by active treatment. Conclusions. Simvastatin appeared to be more potent than pravastatin in lowering total cholesterol, low‐density lipoprotein cholesterol and apolipoprotein B, whereas both drugs had the same short‐term safety profile.
Efficacy of subcutaneous sumatriptan in the acute treatment of early‐morning migraine: a placebo‐controlled trial
Authors: BOUSSER M. G. , D'ALLENS H. , RICHARD A. ,   Early‐Morning Migraine Sumatriptan Study Group
Published: August 2009

Abstract. Objectives. To evaluate the efficacy of self‐administered subcutaneous sumatriptan in the acute treatment of early‐morning migraine attacks.

Design. A double‐blind, randomized, placebo‐controlled, cross‐over study.

Setting. Thirteen neurology centres in France.

Subjects. Patients of either sex, 18–65 years old, with two to six attacks of migraine (according to the International Headache Society (IHS) criteria, with or without aura) per month, of which at least two had to be early‐morning migraine attacks. One‐hundred‐and‐one patients were included, 96 being evaluable for the first attack and 81 for the cross‐over design.

Interventions. Two migraine attacks (grade 2/3) were treated with sumatriptan (6 mg) or placebo, with an optional second injection 1–24 h later.

Main outcome measures. The primary end‐point was headache relief: reduction in headache severity from grade 2/3 (moderate/severe) to grade 1/0 (mild/none) 2 h after treatment.

Results. Sumatriptan was superior to placebo for headache relief (32 [78%] vs. 11 [28%] at the first attack; 29 [73%] vs. 8 [20%] at the second; P < 0.001). Because of a significant carry‐over effect for some of the secondary end‐points, a parallel‐group analysis of the first attack was performed, which confirmed a significantly higher efficacy of sumatriptan for all end‐points: pain‐free rate (22 [46%] vs. 7 [15%]; P = 0.001) and use of a second injection (26 [53%] vs. 38 [81%]; P = 0.004). Sumatriptan was preferred by 74% of patients vs. 17% for placebo, and 9% expressed no preference (P < 0.0001). After complete relief, headache reappeared in 8/23 (35%) patients with sumatriptan and 3/7 (43%) with placebo. Adverse events were significantly more frequent with sumatriptan but they were minor and transient.

Conclusion. Subcutaneous sumatriptan auto‐injection is an effective and well‐tolerated acute treatment of early‐morning migraine attacks allowing earlier return to normal activity.
Lipoprotein abnormalities in hypertriglyceridaemic patients on long‐term haemodialysis
Authors: ZAMBON S. , ZAMBON A. , STABELLINI N. , TARRONI G. , GILLI P. , CREPALDI G. , MANZATO E.
Published: August 2009

Abstract. Objectives. To analyse by ultracentrifugation in a zonal rotor the plasma lipoproteins in hypertriglyceridaemic patients on long‐term haemodialysis.

Design. Case‐control study.

Setting. Tertiary referred care centre.

Subjects. Ten consecutive hypertriglyceridaemic patients on haemodialysis and 12 consecutive healthy controls.

Main outcome measures. Plasma lipid and lipoprotein cholesterol concentrations, lipoprotein physical properties and compositions, apolipoprotein concentrations.

Results. Hypertriglyceridaemia in patients undergoing haemodialysis is characterized by an increased amount of small and slow floating very‐low density lipoproteins (VLDL), higher concentrations of intermediate density lipoproteins (IDL) and small and dense low‐density lipoprotein (LDL) particles; reduced levels of high‐density lipoproteins (HDL), in particular of HDL2. The lipoprotein composition of such patients indicates reduced cholesterol ester and increased triglyceride content. Compared to controls, they have lower levels of plasma apolipoprotein A‐I and A‐II and higher B, C‐II, C‐III and E values.

Conclusions. The lipoprotein abnormalities observed in hypertriglyceridaemic patients undergoing haemodialysis have recently been associated with an increased incidence of vascular complications and may in part explain the high incidence of vascular disease reported in these subjects.
Decreased serum levels of insulin‐like growth factors and IGF binding protein 3 in osteoporosis
Authors: WÜSTER C. , BLUM W. F. , SCHLEMILCH S. , RANKE M. B. , ZIEGLER R.
Published: August 2009

Abstract. Objectives. The aim of the study was to investigate endogenous growth hormone (GH) secretion in patients with osteoporosis and in patients with degenerative bone diseases or no spinal disease by measuring serum insulin‐like growth factors 1 and 2 (IGFs) and their major binding protein 3 (BP‐3) as an indirect parameter of GH secretion.

Design. A cross‐sectional study.

Setting. All patients were seen as out‐patients of the Endocrinology Department of the University of Heidelberg where all bone parameters were measured. IGFs and BP‐3 serum levels were measured at the Children's Hospital of the University of Tübingen.

Subjects. A total number of 310 patients were studied. The group with primary osteoporosis and vertebral fractures (OPO) consisted of 141 patients (98 females, 43 males). Spinal degenerative bone disease or osteoarthritis (DEG) was present in 108 patients (91 females, 17 males). Sixty‐one control patients (56 females, 5 males) had no spinal disease on X‐ray, but presented with lower back pain.

Main outcome measures. Serum levels of IGFs, BP‐3, PTH and 25‐vitamin D3 were measured by radioimmunoassay. Bone mineral density (BMD) was determined using absorptiometry; anthropometric parameters and menopausal status were recorded.

Results. There was no difference in age and years after menopause between OPO and DEG, but control individuals were younger. Mean IGFs and BP‐3 serum levels in patients with OPO were lower (P < 0.001) than those in patients with DEG or in controls. Patients with DEG had significantly higher BP‐3 levels than controls (P < 0.001). There was a significant (P < 0.05) negative correlation of BP‐3 with age in females with OPO, but not in controls or in DEG patients. The IGFs did not decrease with age in any of the three groups. Binding protein 3 was positively correlated (P < 0.05) with BMD in postmenopausal women with OPO but not in controls or DEG patients.

Conclusion. We conclude that systemic IGFs and IGF binding protein 3 are decreased in patients with osteoporosis. Further studies are needed to investigate whether this is as a result of diminished secretion of endogenous GH and whether this reflects the local circumstances of IGFs and IGF binding proteins in bone.
Essential cryofibrinogenaemia, leukocytoclastic vasculitis and chronic purpura
Authors: JANTUNEN E. , SOPPI E. , NEITTAANMÄKI H. , LAHTINEN R.
Published: August 2009

Abstract. Cryofibrinogenaemia refers to the presence of cold‐precipitable proteins in plasma but not in serum. It is usually associated with malignancy, tromboembolic diseases or various inflammatory processes; rarely it may be essential. The most common clinical presentations of cryofibrinogenaemia are cold‐intolerance, purpura, skin necrosis and ulcers. We describe a middle‐aged woman with essential cryofibrinogenaemia, leukocytoclastic vasculitis, and chronic purpura for over 25 years with several exacerbations. In patients with otherwise unexplained purpura or skin necrosis, determination of plasma cryofibrinogen should be considered.
Modulation of the haematopoietic toxicity associated with zidovudine in vivo with lithium carbonate
Authors: GALLICCHIO V. S. , HUGHES N. K. , TSE K. F.
Published: August 2009

Abstract. The drug zidovudine (AZT), a synthetic thymidine analogue, has been used in the treatment of acquired immunodeficiency syndrome (AIDS). Clinical use of zidovudine has induced haematopoietic toxicity manifested by anaemia, neutropenia, and overall bone marrow suppression. The monovalent cation lithium has been shown to be an effective agent capable of modulating several aspects of haematopoiesis such as the induction of neutrophilia, thrombopoiesis, and protection against suppression of haematopoietic progenitor stem cells following exposure to anti‐cancer drugs and/or radiation at doses commonly used in the treatment of malignant disease. We report here the result of studies designed to evaluate the effectiveness of lithium in reversing zidovudine‐induced haematopoietic suppression when administered to normal mice in vivo in the presence of dose‐escalation zidovudine. Lithium carbonate (Li2CO3) reversed zidovudine toxicity as measured by increases in peripheral WBC. platelets, and CFU‐GM and CFU‐Meg haematopoietic progenitors; however lithium was insufficient in reversing the reduction of erythropoiesis associated with zidovudine use in vivo. These results further confirm the effective use of lithium to reverse the development of myelosuppression and thrombocytopenia associated with the anti‐viral drug zidovudine, but is less effective in ameliorating the induction of anaemia.
Hyperammonaemic encephalopathy as the presenting feature of IgD multiple myeloma
Authors: CAMINAL L. , CASTELLANOS E. , MATEOS V. , ASTUDILLO A. , MORENO C. , DIEGUEZ M. A.
Published: August 2009

Abstract. We observed a case of hyperammonaemic encephalopathy in a patient without liver dysfunction which revealed meningeal involvement of IgD multiple myeloma. We have reviewed briefly the hyperammonaemic syndrome and we believe that this diagnosis has to be considered in differential diagnosis of encephalopathies in patients with multiple myeloma.
HLA‐DR3, DQ2 homozygosity in two patients with insulin‐dependent diabetes mellitus superimposed with ulcerative colitis and primary sclerosing cholangitis
Authors: IVARSSON S.‐A. , ERIKSSON S. , KOCKUM I. , LERNMARK Å. , LINDGREN S. , NILSSON K. O. , SUNDKVIST G. , WASSMUTH R.
Published: August 2009

Abstract. Two unrelated young males with the unusual simultaneous presence of insulin‐dependent diabetes mellitus, ulcerative colitis and primary sclerosing cholangitis are reported. Both patients manifested homozygosity for the DR3‐DQw2 (DQB*0201) HLA genotypes. We believe that homozygosity for this genotype may predispose for this type of multi‐organ autoimmune disease.
Unstable haemoglobin causing haemolytic anaemia: de novo mutation in Sweden identified by PCR
Authors: LANDIN B. , ÅSTROM M.
Published: August 2009

Abstract. A 38‐year‐old Swedish woman was investigated because of mild anaemia resistant to iron therapy. Mild haemolytic disease was found by routine blood tests. Neither HPLC (HbA1c quantification) nor Hb‐electrofocusing revealed any major abnormal fraction, although in vitro testing of haemoglobin instability indicated the presence of unstable haemoglobin. PCR was used to amplify coding regions of the β globin gene. Direct nucleotide sequencing of this material revealed heterozygosity for a substitution corresponding to the haemoglobin variant α2β2135(H13)Ala→Pro. This clearly unstable variant, named Hb Altdorf, has earlier been described only in a family of Italian descent. Examination of β globin genes from six family members of the proposita by PCR followed by specific cleavage with the restriction enzyme Ban I, revealed the mutation in her two children but not in her parents or siblings. This case demonstrates that haemoglobin variants can not be ruled out as a cause of haematological disease even if the parents lack symptoms and standard tests, such as HPLC and electrophoresis/electrofocusing, do not reveal major abnormalities.
Thiazide‐induced kidney damage with circulating antibodies against myeloperoxidase and cardiolipin
Authors: LARSSON G. B. , LANGER L. , NÄSSBERGER L.
Published: August 2009

Abstract. A 79‐year‐old man developed a renal insufficiency while on thiazide. Extrarenal symptoms were absent. Screening for antibodies revealed high titre for anti‐myeloperoxidase and anti‐cardiolipin antibodies, but no other antibodies were present. After withdrawal of the drug the progression of renal insufficiency ceased. Four months later the both antibodies had disappeared. We conclude, that antibodies against granulocytes will become a valuable diagnostic tool in diagnosing drug‐induced vasculitis.
Weight maintenance after a very low calorie diet (VLCD) weight reduction period and the effects of VLCD supplementation: A prospective, randomized, comparative, controlled long‐term trial
Authors: RYTTIG KJELD R. , RÖSSNER STEPHAN
Published: August 2009

Abstract. Objectives. To evaluate the efficacy of a structured very low calorie diet (VLCD) weight reduction/weight maintenance behaviour programme on weight maintenance in obese patients (BMI ≥ 30 kg/m2).

Design. Prospective, randomized, controlled intervention trial.

Setting. University out‐patient obesity clinic.

Subjects. A total of 114 obese patients from the waiting list were invited to participate in the structured weight reduction/weight maintenance programme lasting for 64 weeks. Sixty patients agreed to participate.

Intervention. All 60 patients were placed on a Cambridge 330 kcal day‐1diet during the first 12 weeks. Fifty‐two were subsequently randomized to either a well balanced hypocaloric diet (1600 kcal day‐1), of which 220 kcal were provided by two sachets of Cambridge diet (group 1), or the same energy provided by the same principal diet (group 2) during the following 52‐week weight maintenance period.

Main outcome measures. During the VLCD period, the mean body weight decreased significantly from 112.4 ± 19.8 to 91.6 ± 17.7 kg (P < 0.0001). Seventy‐one per cent of the weight loss was fat. During the weight maintenance period the average body weight increased significantly in group 1: 8.0 ± 8.2 vs. 12.3 ± 9.7 kg in group 2 (P < 0.0001). After the 64‐week treatment period the mean body weight in group 1 was 93.7 ± 18.1 kg and significantly lower compared to 109.9 ± 23.8 kg in group 2 (P = 0.008). Compliance was high: 87% completed the VLCD period and 75% completed the whole 64‐week treatment programme.

Conclusion. Very low calorie diet as part of the dietary allowance during the weight maintenance programme partly prevents weight regain. This finding can be translated into practical treatment recommendations.
Clinical use of molecular information in the management of multiple endocrine neoplasia type 2A
Authors: GAGEL R. F. , COTE G. J. , BUGALHO M. J. G. MARTINS , III A. E. BOYD , CUMMINGS T. , GOEPFERT H. , EVANS D. B. , CANGIR A. , KHORANA S. , SCHULTZ P. N.
Published: August 2009

Abstract. One hundred and ninety‐seven members of 28 kindreds with multiple endocrine neoplasia type 2A (MEN 2A) were screened for RET proto‐oncogene exon 10 and 11 mutations. Seventy‐one known affected individuals had mutations of codons 609, 618, 620 or 634, whereas 53 unaffected individuals had no abnormalities. Nineteen out of 54 individuals of unknown status, mostly children, had RET mutations. Four of these children had thyroidectomy based on this analysis and were found to have C‐cell abnormalities. We identified one false negative mutation analysis because of a codon 691 polymorphism. We conclude that RET mutational analysis is a cost‐effective and accurate method for determination of gene carrier status in MEN 2A.
Hormone replacement therapy and cardiovascular risk: the cardiovascular physicians' viewpoint
Authors: LIP GREGORY Y. H. , BEEVERS GARETH , ZARIFIS JOHN
Published: August 2009

Abstract. Sufficient evidence has accumulated showing that hormone replacement therapy (HRT) does protect against cardiovascular disease in women, although data regarding the true magnitude of that protection remains incomplete. There is no evidence that HRT increases the risk of hypertension or thromboembolism, and beneficial effects have been found for plasma lipids, clotting factors and cardiovascular haemodynamics. However, the evidence is not convincing of any beneficial effect of HRT in preventing strokes, and concerns about the risk of cancer with HRT remain.

Despite this, considerable uncertainty continues to exist amongst clinicians as to the balance of beneficial and harmful effects from administering HRT. Overall, HRT seems to do no harm and may be protective. A much greater awareness of the long‐term consequences of the menopause and the potential benefits of HRT should be encouraged so that women (and their doctors) can make informed decisions about their requirements.
The dissemination of false data through inadequate citation
Authors: Larsson K. Sune
Published: August 2009

Abstract. Objectives. That occupational exposure to mercury causes reproductive failure in dental personnel has been propagated by repeated reference to a single epidemiological study in Poland, published in 1987. The present paper scrutinizes the results of this study, and monitors its subsequent citation in the literature.

Method. Articles referring to the study were located in the Science Citation Index. From references in these papers and through other references, further articles were found. These papers were reviewed, and their content organized in relation to the way in which the Polish study was cited.

Result. Most authors referred to the findings in the Polish study without critical evaluation of the data presented.

Conclusions. Citation of irrelevant or misleading scientific data in the literature raises unfounded concerns in nonscientific circles and may lead to unwarranted regulations. It is therefore essential that editors and reviewers of scientific articles also scrutinize the literature quoted.
The prevalence of peripheral vascular disease in familial hypercholesterolaemia
Authors: KROON A. A. , AJUBI N. , VAN ASTEN W. N. J. C. , STALENHOEF A. F. H.
Published: August 2009

Abstract. Objectives. In patients with familial hypercholesterolaemia (FH), the prevalence of haemodynamically significant peripheral vascular disease (PVD) was measured in relation to lipoproteins, general risk factors and the presence of coronary artery disease (CAD).

Design. A case control study.

Setting. The outpatient lipid clinic of a university hospital (tertiary referral centre).

Subjects. Patients with heterozygous FH [n = 68; age 45.8 ± 11.6 years; untreated LDL‐cholesterol 9.2 ± 2.0 mmol L‐1] were compared with control subjects matched for gender, age, weight, smoking and presence of hypertension [n = 27; age 44.0 years; LDL‐cholesterol 3.8 ± 1.3 mmol L‐1].

Main outcome measures. PVD was assessed during cholesterol‐lowering treatment using ankle/arm blood pressure ratios and analyses of Doppler‐derived blood flow velocities in the femoral artery at rest and during reactive hyperaemia. The diagnosis of CAD was assessed clinically.

Results. Haemodynamically significant PVD was found in 21 (31%) FH patients and in one (3.7%) control subject, predominantly localized in the femoro‐popliteal vessels. CAD was present in 30 (44.1%) FH patients and in one (3.7%) control subject. PVD could be demonstrated in 50% of FH patients with CAD [relative risk 3.2 (95% CI 1.4–7.2)] and in 19% as the first manifestation of vascular disease. Males and females were equally affected. Mean arterial blood pressure of FH patients with PVD was higher compared to FH patients without PVD.

Conclusions. Haemodynamically significant PVD appears to be more prevalent in FH patients than is generally assumed, especially in those with CAD. A relation with lipoprotein levels could not be demonstrated.
Immunological mechanisms in atherosclerosis
Authors: YOKOTA T. , HANSSON G. K.
Published: August 2009

Abstract. Immunological mechanisms seem to be potent modulators of the atherosclerotic process. The presence of substantial numbers of T‐lymphocytes in the lesion and local and circulating autoantibodies to plaque components suggests that a specific immune response is operating. Focal expression of adhesion molecules and local secretion of chemoattractants could mediate the recruitment of inflammatory cells to the lesion. Local cytokine and growth factor networks may operate later, controlling cell migration and proliferation. Although it is still important to realize the complexity of these mechanisms, the ongoing characterization of the molecular mechanisms in atherogenesis may lead to new strategies for intervention with the disease process.
Research ethics – a brief historical review to 1965
Authors: LOCK STEPHEN
Published: August 2009

Abstract. Most discussions on modern research ethics – particularly the formation of research ethics committees (institutional review boards) – focus on the revelations of the dreadful practices in the Nazi concentration camps at the Nuremberg trial after the second world war, with the subsequent production of the Nuremberg and Helsinki Codes. In fact, however, these trials were not pivotal: there was a long history of such concerns, going back at least to the 1830s, when William Beaumont introduced a contract with his patient Alexis St Martin, as well as the later part of the century when the celebrated leprosy worker Hansen was prosecuted in Bergen for having experimented on a patient without her consent, losing his post as a result. Probably, had it not been for the entry of the USA into the First World War, public indignation at the growing number of reports of unethical experimentation in public hospitals would have resulted in regulations, while official codes were introduced in Prussia at the turn of the century and in Berlin again in 1931. Nevertheless, the impetus for modern developments came principally from the furore aroused by the proselytising of two physicians: Henry Beecher, an anesthesiologist at Harvard, and Maurice Pappworth in London, whose respective books Experimentation in Man and Human Guinea Pigs, documented case histories of egregiously less than ethical research practices that went largely unquestioned by other clinical research workers. Here I shall discuss the reactions to and influence of some of these episodes, as well as more recent developments.
Medical ethics in a multicultural context
Authors: GILLETT GRANT R.
Published: August 2009

Abstract. One contemporary challenge for medical ethics is to formulate an approach to ethics that will enable us to adapt to a multicultural or pluralistic setting. This challenge has had to be met in New Zealand where there is an explicit biculturalism at the heart of social policy. The two cultures involved are very different but, when examined closely, it can be seen that they have significant moral intuitions in common. Some common threads include the unique value of the parent–child bond, the principle of respect for the individual, and the idea of belonging. I note a number of specific examples where similar intuitions are expressed in different ways. I then suggest that it is in the common and shared experiences of development as a human being that we are more likely to find common ethical intuitions rather than in attempts to agree on abstract rules. This suggests an ethic based in narrative and imaginative sensitivity to the situation of another person. Such an approach to ethics needs to attend both to the meanings and symbols of another culture but also to their history when it has involved significant dealings between cultures.
Causal link between neonatal hydronephrosis and later development of hypertension
Authors: Carlström Mattias
Published: August 2009

1. Although congenital ureteral obstruction is a common disorder in infants, its pathophysiology remains poorly understood and its clinical management continues to be debated. During the past decade, the surgical management of non‐symptomatic hydronephrosis in children has become more conservative, but the long‐term physiological consequences of this new policy are unclear.

2. In experimental models with complete ureteral obstruction, tubular atrophy and interstitial inflammation occur rapidly. Although this type of obstruction is very rare in clinical practice, it is often referred to in clinical discussions. New studies, using a model with chronic partial ureteral obstruction, have demonstrated that hydronephrosis is associated with renal injuries and is causally related to hypertension.

3. The mechanisms underlying the development of hypertension in experimental hydronephrosis are complex and involve changes in both the renin–angiotensin system and renal sympathetic nerve activity. Furthermore, oxidative stress and nitric oxide deficiency in the diseased kidney, with consequent resetting of the tubuloglomerular feedback mechanism, appear to play a pivotal role in the development and maintenance of hyper‐tension.

4. In view of the new knowledge regarding the long‐term effects of partial ureteral obstruction, today’s non‐operative management of hydronephrosis should be reconsidered to prevent obstructive nephropathy and hypertension in later life.