bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR® (long‐acting repeatable octreotide) in the primary therapy of patients with acromegaly
Authors: Mercado Moises , Borges Fatima , Bouterfa Hakim , Chang Tien‐Chun , Chervin Alberto , Farrall Andrew J. , Patocs Attila , Petersenn Stephan , Podoba Jan , Safari Mitra , Wardlaw Joanna ,   on behalf of the SMS995B2401 Study Group
Published: May 2007

SummaryObjective  To evaluate the efficacy, safety and tolerability of octreotide LAR® (long‐acting repeatable octreotide) in the primary therapy of acromegaly.Design and patients  Ninety‐eight previously untreated acromegalics were recruited into this prospective multicentre study. A total of 68 patients successfully completed 48 weeks of the study period, received 12 doses of octreotide LAR 10–30 mg every 4 weeks, and constituted the population used for this analysis.Measurements and results  A clinically relevant reduction (i.e. to ≤ 5 µg/l) in mean GH (mGH) was recorded in 72% of patients after 24 weeks of treatment, and 42% reached a ‘safe’ GH value (≤ 2·5 µg/l). At week 48, 16 more patients were considered partial GH responders (GH > 2·5 µg/l and ≤ 5 µg/l) and 44% had reached a GH level ≤ 2·5 µg/l. IGF‐1 levels normalized in 38% and 34% of patients after 24 and 48 weeks of treatment, respectively. At study completion, 10 patients (14·7%) who had not normalized their IGF‐1 levels had achieved at least a 50% decrement in this marker. In eight microadenoma patients, tumour volume decreased from a mean baseline level of 298 ± 145 mm3 to 139 ± 94 mm3 after 24 weeks and to 99 ± 70 mm3 after 48 weeks of therapy. In 60 patients with macroadenoma, the corresponding values were 3885 ± 5077 mm3 at baseline and 2723 ± 3435 and 2406 ± 3207 mm3 after 24 and 48 weeks, respectively. At weeks 24 and 48, a significant (> 20%) tumour volume reduction was reported in 63% and 75% of patients, respectively. A reduction in the severity of symptoms of acromegaly was observed early in treatment and was maintained throughout the study period.Conclusion  Octreotide LAR represents a viable alternative to surgery for primary treatment of acromegaly leading to a progressive regression of tumour volume, a sustained control of biochemical abnormalities and an adequate relief of symptoms of the disease.
Radioiodine treatment for benign thyroid diseases
Authors: Weetman Anthony P. 
Published: May 2007

SummaryRadioiodine has been in use for over 60 years as a treatment for hyperthyroidism. Major changes in clinical practice have occurred with the realization that accurate dosimetry is incapable of avoiding the risks of hypothyroidism, while more accurate assessment of the risks of other adverse effects of radioiodine such as ophthalmopathy and carcinogenesis have become available. More is also known of the potential for pretreatment with an antithyroid drug to affect the outcome of radioiodine treatment. However, we are still uncertain of the benefits of radioiodine treatment in subclinical hyperthyroidism. During the last two decades there has been wider acceptance of radioiodine as a safe and effective therapy for benign, nontoxic goitre, coupled with waning enthusiasm for the use of levothyroxine, as the risks and benefits of this option have become more apparent. The use of recombinant TSH offers the prospect that radioiodine treatment of nontoxic goitre can be simplified and improved, although more studies of this strategy are urgently required.
l‐selectin gene polymorphisms in Graves' disease
Authors: Chen Hao‐Yan , Cui Bin , Wang Shu , Zhao Ze‐Fei , Sun Hua , Zhao Yong‐Ju , Li Xiao‐Ying , Ning Guang 
Published: May 2007

SummaryObjective   Graves’ disease (GD) is an autoimmune disorder with genetic predisposition. There is strong evidence that members of the selectin family participate in the interaction between leucocytes and the endothelium, as well as in inflammatory cell recruitment. Moreover, a high serum level of a soluble form of l‐selectin (sl‐selectin) has been reported in untreated GD patients. However, the impact of l‐selectin polymorphisms on GD has not yet been investigated. The aim of the present study was to elucidate whether l‐selectin gene polymorphisms were associated with the development of GD.Subjects and design  l‐selectin gene polymorphisms were investigated in 230 Chinese GD patients and 208 healthy control subjects without antithyroid autoantibodies or a family history of autoimmune disorders. Two l‐selectin SNPs were genotyped by the PCR‐restriction fragment length polymorphism (PCR‐RFLP) method.Results  A C/T polymorphism at position –642 of the promoter region and a Pro213Ser (c.725 C‐T) polymorphism in exon 6 were examined using PCR‐RFLP. There was a significant increase in –642T allele frequency in GD patients compared with healthy controls (70 vs. 62%; P = 0·0126; Pc = 0·0252). The frequency of the c.725C allele in exon 6 also appeared higher in GD patients than in controls. Haplotype analysis showed a significant decrease in the –642C/c.725T haplotype in GD patients (26 vs. 34%; P = 0·0095; Pc = 0·0190). However there was no association between polymorphisms and certain GD clinical phenotypes, including age of onset and ophthalmopathy.Conclusions  l‐selectin gene polymorphisms are associated with GD susceptibility in Chinese patients.
Molecular evidence‐based medicine
Authors: Ioannidis J. P. A. 
Published: May 2007

AbstractEvidence‐based medicine and molecular medicine have both been influential in biomedical research in the last 15 years. Despite following largely parallel routes to date, the goals and principles of evidence‐based and molecular medicine are complementary and they should be converging. I define molecular evidence‐based medicine as the study of medical information that makes sense of the advances of molecular biological disciplines and where errors and biases are properly appreciated and placed in context. Biomedical measurement capacity improves very rapidly. The exponentially growing mass of hypotheses being tested requires a new approach to both statistical and biological inference. Multidimensional biology requires careful exact replication of research findings, but indirect corroboration is often all that is achieved at best. Besides random error, bias remains a major threat. It is often difficult to separate bias from the spirit of scientific inquiry to force data into coherent and ‘significant’ biological stories. Transparency and public availability of protocols, data, analyses and results may be crucial to make sense of the complex biology of human disease and avoid being flooded by spurious research findings. Research efforts should be integrated across teams in an open, sharing environment. Most research in the future may be designed, performed, and integrated in the public cyberspace.
The PPARδ agonist GW501516 suppresses interleukin‐6‐mediated hepatocyte acute phase reaction via STAT3 inhibition
Authors: Kino T. , Rice K. C. , Chrousos G. P. 
Published: May 2007

AbstractBackground  Interleukin‐6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator‐activated receptor δ (PPARδ), which binds to and is activated by a variety of fatty acids, was recently shown to have anti‐inflammatory actions.Materials and methods  We examined the ability of the synthetic PPARδ agonist GW501516 to suppress interleukin‐6‐induced expression of acute phase proteins in human hepatoma HepG2 cells and rat primary hepatocytes.Results  GW501516 dose‐dependently suppressed interleukin‐6‐induced mRNA expression of the acute phase protein α1‐antichymotrypsin in HepG2 cells. The compound also suppressed interleukin‐6‐induced mRNA expression of α2‐acid glycoprotein, β‐fibrinogen and α2‐macroglobulin in and the secretion of C‐reactive protein by rat primary hepatocytes. Depletion of the PPARδ receptor, but not of PPARα or γ, attenuated the suppressive effect of GW501516 on interleukin‐6‐induced α1‐antichymotrypsin mRNA expression, indicating that PPARδ specifically mediated this effect. Since interleukin‐6 stimulates the transcriptional activity of the α1‐antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPARδ on this promoter. Overexpression of PPARδ enhanced the suppressive effect of GW501516 on STAT3‐activated transcriptional activity of the α1‐antichymotrypsin promoter, while GW501516 suppressed interleukin‐6‐induced binding of this transcription factor to this promoter.Conclusions  These findings indicate that agonist‐activated PPARδ interferes with interleukin‐6‐induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPARδ agonists might be useful for the suppression of systemic inflammatory reactions in which IL‐6 plays a central role.
Endothelial dysfunction in a murine model of thyroid hormone resistance
Authors: Owen P. J. D. , Ying H. , Lang D. , Tomlinson D. , Lewis M. J. , Cheng S. Y. , Lazarus J. H. 
Published: May 2007

AbstractBackground  The development of a knockin mouse model of resistance to thyroid hormone (RTH) has led to a greater understanding of both the molecular and clinical behaviour of this syndrome. We have investigated the vascular response in RTH using a specific (TRβ PV) knockin mouse model targeting the PV mutation to the thyroid hormone receptor β gene locus.Materials and methods  Ring segments of the thoracic aorta were used to assess the response of homozygous, heterozygous and wild‐type controls to contractile agents, potassium chloride and phenylephrine. Each genotype after maximal contraction was exposed to increasing concentrations of relaxing agents, acetylcholine (ACh) and sodium nitroprusside (SNP).Results  The response of these aortic ring segments to ACh and SNP demonstrates that endothelium‐dependent relaxation to ACh was significantly impaired in both heterozygous and homozygous mice compared to controls (69·8 ± 2·0%, 59·7 ± 1·4% and 75·0 ± 1·7%, respectively; P < 0·001). However, endothelium independent responses to SNP showed no difference between genotypes (114·4 ± 3·2%, 116·8 ± 2·6% and 106·9 ± 4·9%; P = NS).Conclusion  These data suggest that endothelial function is impaired in the RTH mouse aorta. The respective roles of elevated thyroid stimulating hormone (TSH), elevated thyroid hormone concentrations and the mutated thyroid hormone β receptor require further elucidation.
Alteration of bone cell function by RANKL and OPG in different in vitro models
Authors: Lin J. M. , Callon K. E. , Lin C. Q. , Bava U. , Zheng M. H. , Reid I. R. , Cornish J. 
Published: May 2007

AbstractBackground  Receptor activator of nuclear factor‐κB ligand (RANKL) and osteoprotegerin (OPG) are well‐documented potent regulators of osteoclast development. However, their effects in mature bone cells and in organ cultures have not been well studied. It is uncertain whether their activities in different experimental models are comparable.Materials and methods  RANKL and OPG were evaluated for their activities in mouse calvarial organ cultures, mouse bone marrow cultures, isolated rat mature osteoclast assays and rat primary osteoblast cultures.Results  In murine calvarial organ culture, both muRANKL (≥ 10 ng mL−1) and rRANKL (≥ 100 ng mL−1) significantly stimulated 45Ca release, while OPG (≥ 50 ng mL−1) was an inhibitor of bone resorption. Meanwhile, [3H]‐thymidine incorporation in this assay was also modulated (indicating proliferation increases in the osteoblast lineage of cells) although these peptides had no direct effect on [3H]‐thymidine incorporation in isolated osteoblast assays. In mouse bone marrow cultures, muRANKL (≥ 1 ng mL−1) and rRANKL (≥ 5 ng mL−1) significantly stimulated osteoclastogenesis. The number of nuclei per osteoclast was also significantly increased. OPG strongly inhibited this index, with over 90% suppression at 1 ng mL−1. Both muRANKL (10 ng mL−1) and rRANKL (100 ng mL−1) stimulated, while OPG (10 ng mL−1) inhibited osteoclast activity in isolated mature osteoclast assays.Conclusion  The current study demonstrated that bone resorption modulated by RANKL and OPG, in murine calvarial organ culture, leads to changes in osteoblast proliferation, suggesting a feedback mechanism from osteoclasts to osteoblasts. In addition, it was found that RANKL and OPG have more potent effects on osteoclastogenesis than on the activity of mature osteoclasts.
NF‐κB and apoptosis in colorectal tumourigenesis
Authors: Aranha M. M. , Borralho P. M. , Ravasco P. , Moreira da Silva I. B. , Correia L. , Fernandes A. , Camilo M. E. , Rodrigues C. M. P. 
Published: May 2007

AbstractBackground  Nuclear factor‐κB (NF‐κB) may play an important role in colorectal tumourigenesis, controlling cell cycle and apoptosis gene expression. In addition, imbalances between cell proliferation and cell death are thought to underlie neoplastic development. The aims of this study were to investigate apoptosis and expression of several apoptosis‐related proteins, and to determine correlations with colorectal tumour progression.Materials and methods  Apoptosis was evaluated by the TUNEL assay in 48 patient samples, including adenomas, adenocarcinomas and adjacent normal mucosas. Immunohistochemistry was performed for Bcl‐2 and NF‐κB. Expression levels of p53, Bax and IκB proteins were determined by immunoblotting. Cultured human colon cancer cells were used to evaluate NF‐κB expression and nuclear translocation by immunocytochemistry and immunoblotting.Results  Apoptosis and NF‐κB immunoreactivity were significantly higher in tumour tissue compared with normal mucosa (P < 0·01), increasing in association with histological tumour progression (P < 0·01). Bcl‐2 was consistently higher in normal mucosa (P < 0·01) and inversely correlated with the percentage of apoptosis (P < 0·01). Phosphorylated p53 and Bax levels were similar in tumour tissue and normal mucosa; however, the NF‐κB inhibitor, IκB, tended to decrease in tumours. In vitro, nuclear translocation of NF‐κB was greater in proliferative than in resting phases of colon cancer cells.Conclusions  NF‐κB expression and apoptosis are increased from adenoma to poorly differentiated adenocarcinoma tissues. Apoptosis is correlated with suppression of Bcl‐2 expression, but appears to proceed through a p53‐ and Bax‐independent pathway. Activation of NF‐κB may play an important role in colorectal tumour progression.
Development of a heterologous, multigenotype vaccine against hepatitis C virus infection
Authors: Encke J. , Radunz W. , Eisenbach C. , Geib J. , Gehrke S. , Pfaff E. , Stremmel W. 
Published: May 2007

AbstractBackground Unquestionably viral diversity and genetic heterogeneity in hepatitis C virus (HCV) infection and other viral diseases play an essential role in viral immune escape and the development of chronicity. Despite this knowledge most vaccine approaches against HCV have excluded this important issue. Moreover the feasibility of developing an effective HCV vaccine has been questioned, mainly because prophylactic immunity against HCV cannot be achieved in chimpanzees by either vaccination or previous HCV infection, and reinfection in men has been reported, most likely due to genetic shift and immune escape. To analyse and characterize a new technique of a ‘multigenotype’‐ and/or ‘library’‐vaccine, we established an envelope 1 (E1) plasmid vaccine against HCV and characterized humoral and cellular immune responses after vaccination in a mouse model.Material and methods Normally genetic information of one or two target proteins is cloned into a DNA‐vaccine. In our approach we cloned a defined number of different genotypes and subtypes (defined vaccine, DV) or the genetic information from 20 patients (undefined) into a plasmid (library vaccine, LV).Results As expected, immunized animals showed both stronger humoral (ELISA) and cellular (T‐cell proliferation, ELISPOT) immune responses against genotype 1, since the stimulating antigen was genotype 1 derived. However, not all genotype 1 immunized animals recognized this viral antigen leading to the assumption that some epitopes lost their immunogenicity through a change in the amino acid sequence. Interestingly, some of the genotype 4 and 5 immunized mice sera were able to react against E1 protein.Conclusion Most of the assays showed immune reactivity against the DV or LV vaccine demonstrating the cross‐reactive potential of such a vaccination approach. This cloning and immunization strategy based on the viral heterogeneity of the virus has in our view major implications for HCV, a virus with a broad viral genetic diversity, and may become in the future in the context of DNA‐ or viral‐based vaccination strategies a possibility to overcome viral immune escape both in the prophylactic or therapeutic setting.
Elevated levels of interleukin‐1β‐converting enzyme and caspase‐cleaved cytokeratin‐18 in acute myocardial infarction
Authors: Adlbrecht C. , Hoetzenecker K. , Posch M. , Steiner S. , Kopp C. , Hacker S. , Auer J. , Horvath R. , Moser B. , Roth G. , Wolner E. , Lang I. M. , Ankersmit H. J. 
Published: May 2007

AbstractBackground  Systemic inflammation and apoptosis‐specific immune activation play a major role in acute coronary syndromes (ACS) including acute myocardial infarction (AMI). The role of systemic and coronary obtained inflammatory plasma protein interleukin‐1β precursor (IL‐1βp), IL‐1β‐converting enzyme (ICE) and the apoptosis‐specific caspase‐cleaved cytokeratin‐18 (ccCK‐18) are not known in ACS.Materials and methods  Plasma samples were obtained from stable angina (SA, n = 34), unstable angina (UA, n = 37) and patients with AMI (n = 39). Coronary blood was acquired by means of thrombectomy devices (X‐sizer) in AMI patients. IL‐1βp, ICE and ccCK‐18 were determined by enzyme‐linked immunosorbent assay (ELISA). Group comparisons were evaluated by parametric Tukey test. Multivariate logistic regression analysis was performed to determine predictive values of IL‐1βp, ICE and ccCK‐18 as compared to creatine kinase (CK) and troponin T (TnT) in order to relate these markers with the occurrence of myocardial damage.Results  IL‐1βp, ICE and ccCK‐18 were identified to be significantly altered in the peripheral blood of patients suffering from AMI as compared to SA and UA. ROC curves were plotted and revealed that ccCK‐18 is a novel sensitive marker for the detection of myocardial damage as compared to TnT or CK. (AUC ccCK‐18 0·925, TnT AUC 0·62 and CK AUC 0·858.) Moreover, ICE and ccCK‐18 were significantly increased at the site of coronary occlusion as compared to peripheral blood samples in AMI patients (both P < 0·001).Conclusion  Our data suggest that ACS is related to increased concentration of systemic soluble ICE and ccCK‐18. Moreover, soluble ccCK‐18 was identified to be a superior marker as compared to TnT or CK, for detection of myocardial damage.
Endothelial function in familial combined hyperlipidaemia
Authors: Ter Avest E. , Holewijn S. , Van Tits L. J. H. , De Wit H. M. , Stalenhoef A. F. H. , De Graaf J. 
Published: May 2007

AbstractBackground  Familial combined hyperlipidaemia (FCH) is characterized by dyslipidaemia, visceral obesity and insulin resistance, and is associated with an increased intima‐media thickness (IMT) and an increased risk for cardiovascular disease. In the present study, we investigated whether FCH is associated with early functional vascular wall changes, as represented by endothelial dysfunction, and we determined whether endothelial function in FCH is related to any of the cardiovascular risk factors associated with the FCH phenotype, or to the (increased) IMT.Design  In 98 patients with FCH [mean age 51 (48–54) years, 43% male] and 230 unaffected relatives [mean age 44 (42–46) years, 48% male], venous blood was drawn in the fasting state after discontinuation of lipid lowering drugs for at least 4 weeks (if used). IMT was measured by B‐mode ultrasound and endothelial function was assessed by determination of flow mediated dilation (FMD) and by measurement of plasma concentrations of various soluble adhesion molecules, including soluble vascular cell adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM) and soluble E‐selectin.Results  There were no significant differences between FCH patients and their non‐affected relatives in FMD [2·9 (2·3–3·6%) vs. 2·8 (2·5–3·2%)] or in the plasma concentrations of the various adhesion molecules. None of the individual clinical and biochemical cardiovascular risk factors was an independent predictor of endothelial function in patients with FCH, nor was IMT. However, subgroup analysis revealed that IMT was an independent and powerful predictor of FMD in subjects with carotid artery plaques (St. β = 4·11, P < 0·004), whereas IMT was no significant predictor in subjects without plaques.Conclusions  FCH patients have no impaired endothelial function when compared to their unaffected relatives. IMT is an important predictor of FMD when advanced morphological wall changes are present. Our results question the value of FMD measurements for cardiovascular risk stratification in populations with an anticipated high cardiovascular risk.
A review of non‐equilibrium water flow and solute transport in soil macropores: principles, controlling factors and consequences for water quality
Authors: Jarvis N. J. 
Published: May 2007

SummaryThis review discusses the causes and consequences of ‘non‐equilibrium’ water flow and solute transport in large structural pores or macropores (root and earthworm channels, fissures and interaggregate voids). The experimental evidence suggests that pores larger thanc. 0.3 mm in equivalent cylindrical diameter allow rapid non‐equilibrium flow. Apart from their large size and continuity, this is also due to the presence of impermeable linings and coatings that restrict lateral mass exchange. Macropores also represent microsites in soil that are more biologically active, and often more chemically reactive than the bulk soil. However, sorption retardation during transport through such pores is weaker than in the bulk soil, due to their small surface areas and significant kinetic effects, especially in larger macropores. The potential for non‐equilibrium water flow and solute transport at any site depends on the nature of the macropore network, which is determined by the factors of structure formation and degradation, including the abundance and activity of soil biota such as earthworms, soil properties (e.g. clay content), site factors (e.g. slope position, drying intensity, vegetation) and management (e.g. cropping, tillage, traffic). A conceptual model is proposed that summarizes these effects of site factors on the inherent potential for non‐equilibrium water flow and solute transport in macropores. Initial and boundary conditions determine the extent to which this potential is realized. High rain intensities clearly increase the strength of non‐equilibrium flow in macropores, but the effects of initial water content seem complex, due to the confounding effects of soil shrinkage and water repellency. The impacts of macropore flow on water quality are most significant for relatively immobile solutes that are foreign to the soil and whose effects on ecosystem and human health are pronounced even at small leached fractions (e.g. pesticides). The review concludes with a discussion of topics where process understanding is still lacking, and also suggests some potential applications of the considerable knowledge that has accumulated in recent decades.