bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Morbid Obesity on the Single-Dose Pharmacokinetics of Daptomycin
Authors: Pai Manjunath P. , Norenberg Jeffrey P. , Anderson Tamara , Goade Diane W. , Rodvold Keith A. , Telepak Robert A. , Mercier Renee-Claude
Published: June 2007

The present study characterized the single-dose pharmacokinetics of daptomycin dosed as 4 mg/kg of total body weight (TBW) in seven morbidly obese and seven age-, sex-, race-, and serum creatinine-matched healthy subjects. The glomerular filtration rate (GFR) was measured for both groups following a single bolus injection of [
125
I]sodium iothalamate. Noncompartmental analysis was used to determine the pharmacokinetic parameters, and these values were normalized against TBW, ideal body weight (IBW), and fat-free weight (FFW) for comparison of the two groups. All subjects enrolled in this study were female, and the mean (±standard deviation) body mass index was 46.2 ± 5.5 kg/m
2
or 21.8 ± 1.9 kg/m
2
for the morbidly obese or normal-weight group, respectively. The maximum plasma concentration and area under the concentration-time curve from dosing to 24 h were approximately 60% higher (
P
< 0.05) in the morbidly obese group than in the normal-weight group, and these were a function of the higher total dose received in the morbidly obese group. No differences in daptomycin volume of distribution (
V
), total clearance, renal clearance, or protein binding were noted between the two groups. Of TBW, FFW, or IBW, TBW provided the best correlation to
V
. In contrast, TBW overestimated GFR through creatinine clearance calculations using the Cockcroft-Gault equation. Use of IBW in the Cockcroft-Gault equation or use of the four-variable modification of diet in renal disease equation best estimated GFR in morbidly obese subjects. Further studies of daptomycin pharmacokinetics in morbidly obese patients with acute bacterial infections and impaired renal function are necessary to better predict appropriate dosage intervals.
Investigating Toll-Like Receptor Agonists for Potential To Treat Hepatitis C Virus Infection
Authors: Thomas Amy , Laxton Carl , Rodman Joanne , Myangar Nisha , Horscroft Nigel , Parkinson Tanya
Published: June 2007

Toll-like receptors (TLRs) are key mediators of innate immunity, and their activation by microbial components leads to the production of cytokines and interferons. Recombinant alpha interferon has been used to treat several viral diseases and is the current standard of care for hepatitis C virus (HCV) infection. Recently, agonists of TLR7 and TLR9 have been shown to have clinical efficacy in HCV patients, and this is correlated with their ability to induce endogenous type I interferon production. We have carried out a comprehensive study of agonists of TLRs 1 to 9 to determine if any additional TLRs can induce antiviral molecules from human peripheral blood mononuclear cells (PBMCs). The agonists were incubated with PBMCs, and the supernatant was then removed and added to HCV replicon cells to assess antiviral activity. Agonists of TLRs 3, 4, 7, 8, and 9 were found to be potent inducers of antiviral activity in PBMC supernatants, and the activity correlated with the induction of alpha interferon and the interferon-induced antiviral biomarker 2′,5′-oligoadenylate synthase. Antiviral activity of TLR7 and TLR8 agonists was blocked by an antibody that binds to the type I interferon receptor, confirming that the antiviral activity results from type I interferon induction. TLR4 and TLR8 agonists were found to strongly induce the proinflammatory cytokines interleukin 1β and tumor necrosis factor alpha at concentrations similar to those inducing antiviral activity. This raises concerns about adverse side effects if these were to be used as antiviral agents. We therefore conclude that TLRs 3, 7, and 9 represent the most attractive targets for the development of new HCV therapies.
Net Replication ofSalmonella entericaSerovars Typhimurium and Choleraesuis in Porcine Intestinal Mucosa and Nodes Is Associated with Their Differential Virulence
Authors: Paulin Susan M. , Jagannathan Aparna , Campbell June , Wallis Timothy S. , Stevens Mark P.
Published: June 2007

Salmonella entericais a facultative intracellular pathogen of worldwide importance and causes a spectrum of diseases depending on serovar- and host-specific factors. Oral infection of pigs withS. entericaserovar Typhimurium strain 4/74 produces acute enteritis but is rarely fatal, whereas serovar Choleraesuis strain A50 causes systemic disease with a high mortality rate. With a porcine ligated ileal loop model, we observed that systemic virulence of serovar Choleraesuis A50 is not associated with enhanced intestinal invasion, secretory responses, or neutrophil recruitment compared to serovar Typhimurium 4/74. The net growth in vivo of serovar Choleraesuis A50 and serovar Typhimurium 4/74 was monitored following oral inoculation of pigs with strains harboring pHSG422, which exhibits temperature-sensitive replication. Analysis of plasmid partitioning revealed that the enteric virulence of serovar Typhimurium 4/74 relative to that of serovar Choleraesuis A50 is associated with rapid replication in the intestinal wall, whereas systemic virulence of serovar Choleraesuis A50 is associated with enhanced persistence in intestinal mesenteric lymph nodes. Faster replication of serovar Typhimurium, compared to that of serovar Choleraesuis, in the intestinal mucosa was associated with greater induction of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-8 (IL-8), and IL-18 as detected by reverse transcriptase PCR analysis of transcripts from infected mucosa. During replication in batch culture and porcine alveolar macrophages, transcription of genes encoding components of type III secretion systems 1 (sipC) and 2 (sseC) was observed to be significantly higher in serovar Typhimurium 4/74 than in serovar Choleraesuis A50, and this may contribute to the differences in epithelial invasion and intracellular proliferation. The rapid induction of proinflammatory responses by strain 4/74 may explain why pigs confine serovar Typhimurium infection to the intestines, whereas slow replication of serovar Choleraesuis may enable it to evade host innate immunity and thus disseminate by stealth.
Scavenger Receptor A Dampens Induction of Inflammation in Response to the Fungal PathogenPneumocystis carinii
Authors: Hollifield Melissa , Ghanem Elsa Bou , de Villiers Willem J. S. , Garvy Beth A.
Published: June 2007

Alveolar macrophages are the effector cells largely responsible for clearance ofPneumocystis cariniifrom the lungs. Binding of organisms to β-glucan and mannose receptors has been shown to stimulate phagocytosis of the organisms. To further define the mechanisms used by alveolar macrophages for clearance ofP. carinii, mice deficient in the expression of scavenger receptor A (SRA) were infected withP. carinii, and clearance of organisms was monitored over time. SRA-deficient (SRAKO) mice consistently clearedP. cariniifaster than did wild-type control mice. Expedited clearance corresponded to elevated numbers of activated CD4+T cells in the alveolar spaces of SRAKO mice compared to wild-type mice. Alveolar macrophages from SRAKO mice had increased expression of CD11b on their surfaces, consistent with an activated phenotype. However, they were not more phagocytic than macrophages expressing SRA, as measured by an in vivo phagocytosis assay. SRAKO alveolar macrophages produced significantly more tumor necrosis factor alpha (TNF-α) than wild-type macrophages when stimulated with lipopolysaccharide in vitro but less TNF-α in response toP. cariniiin vitro. However, upon in vivo stimulation, SRAKO mice produced significantly more TNF-α, interleukin 12 (IL-12), and IL-18 in response toP. cariniiinfection than did wild-type mice. Together, these data indicate that SRA controls inflammatory cytokines produced by alveolar macrophages in the context ofP. cariniiinfection.
The Secreted Pyomelanin Pigment of
Legionella pneumophila
Confers Ferric Reductase Activity
Authors: Chatfield Christa H. , Cianciotto Nicholas P.
Published: June 2007

The virulence of
Legionella pneumophila
is dependent upon its capacity to acquire iron. To identify genes involved in expression of its siderophore, we screened a mutagenized population of
L. pneumophila
for strains that were no longer able to rescue the growth of a ferrous transport mutant. However, an unusual mutant was obtained that displayed a strong inhibitory effect on the
feoB
mutant. Due to an insertion in
hmgA
that encodes homogentisate 1,2-dioxygenase, the mutant secreted increased levels of pyomelanin, the
L. pneumophila
pigment that is derived from secreted homogentisic acid (HGA). Thus, we hypothesized that
L. pneumophila
-secreted HGA-melanin has intrinsic ferric reductase activity, converting Fe
3+
to Fe
2+
, but that hyperpigmentation results in excessive reduction of iron that can, in the case of the
feoB
mutant, be inhibitory to growth. In support of this hypothesis, we demonstrated, for the first time, that wild-type
L. pneumophila
secretes ferric reductase activity. Moreover, whereas the hyperpigmented mutant had increased secreted activity, an
lly
mutant specifically impaired for pigment production lacked the activity. Compatible with the nature of HGA-melanins, the secreted ferric reductase activity was positively influenced by the amount of tyrosine in the growth medium, resistant to protease, acid precipitable, and heterogeneous in size. Together, these data represent the first demonstration of pyomelanin-mediated ferric reduction by a pathogenic bacterium.
Mutation of
traP
in
Staphylococcus aureus
Has No Impact on Expression of
agr
or Biofilm Formation
Authors: Tsang Laura H. , Daily Sonja T. , Weiss Elizabeth C. , Smeltzer Mark S.
Published: June 2007

To investigate the regulatory role of
traP
(
t
arget of
R
NAIII-
a
ctivating
p
eptide) in
Staphylococcus aureus
, we generated
traP
mutations in the clinical isolates UAMS-1 and USA300. In neither case did mutation of
traP
affect expression of the accessory gene regulator (
agr
) or the ability to form a biofilm. We were also unable to confirm that mutation of
traP
in the prototype 8325-4 laboratory strain RN6390 results in reduced expression of
agr
, reduced hemolytic activity, or an altered capacity to form a biofilm.
Assessing basketball ability in players with mental retardation
Authors: Guidetti L , Franciosi E , Emerenziani G P , Gallotta M C , Baldari C
Published: June 2007

Background:

Although athletes with mental retardation (MR) have achieved an important role, literature concerning the evaluation tests in basketball is still poor.

Objective:

To assess basketball ability before and after a 4-month training performed before championship for athletes with MR and to correlate ability variations with MR levels.

Methods:

15 trained basketball players with MR (11 men and 4 women; age range 21–43 years; MR: 3 mild, 8 moderate, 8 severe and 1 profound). Athletes were tested before (pre) and after (post) 4 month training preceding the championship. The tests assessed 4levels of ability, each one characterised by 4fundamental areasof this game: ball handling, reception, passing and shooting. Each area was divided into 5specific components.

Results:

The team average score, based on the score of each athlete’s 4levels, improved by 6.6 points (41.6 (SD 11.9) vs 48.2 (14.7)). The comparison between pre and post scores in each level showed increases (p<0.01), especially in level II (14.4 (3.5) vs 16.5 (3.3)) and in level III (7.1 (5.7) vs 9.2 (6.6)). Within level II, ball handling (3.67 (1.2) vs 4.37 (0.5); p<0.05) and passing (3.20 (1.2) vs 3.97 (1.3); p<0.01) improved; in level III reception (3.21 (1.1) vs 3.73 (1.1); p = 0.01) and shooting (1.82 (1.1) vs 2.45 (1.3); p<0.05) increased.

Conclusions:

A 4 month training caused a general improvement, especially evident in levels II and III. Total score reached in level II was negatively correlated with MR level (r = −0.56; p<0.05), indicating that athletes with lower MR obtained higher scores.
Consumption of anabolic steroids in sport, physical activity and as a drug of abuse: an analysis of the scientific literature and areas of research
Authors: Agulló-Calatayud V , González-Alcaide G , Valderrama-Zurián J C , Aleixandre-Benavent R
Published: June 2007

Objective:

The consumption of anabolic steroids (AS) has been growing continuously in recent years. It has gone beyond the sports world; AS are now widely used as drugs of abuse in connection with bodybuilding. This study sets out to assess the state of scientific research in the area.

Design:

Bibliometrics were employed to evaluate the literature retrieved from the principal relevant bibliographic databases: MEDLINE, SportDiscus, the Science Citation Index Expanded and the Social Sciences Citation Index. The core journals were identified along with the leading authors and research groups and their institutional affiliations. Techniques based on social network analysis were applied in order to build up a concept map of research.

Results:

1325 documents were retrieved. They were produced by 3131 different researchers giving a Collaboration Index of 3.32. The institutions with the most productive authors were Ball State University (Muncie, IN, USA), the École Nationale Vétérinaire de Nantes (ENVN), the Institut Municipal dInvestigació Mèdica (IMIM) (Barcelona, Spain), the Institute of Biochemistry of the German Sport University Cologne (DSHS), Iowa State University, Maastricht University and the University of Iowa.

Conclusions:

It was concluded that there has been an upward trend in the number of research projects. The sources used complemented one another, as 78.04% of the documents retrieved were unique to one source. The productivity ranking was headed by sports medicine journals, followed by journals of chemistry, physiology, endocrinology and substance abuse. Besides sporting activities, the most important research clusters were those connected with bodybuilding and with youth groups.
Management of end stage cardiac failure
Authors: Johnson Miriam J
Published: June 2007

Optimum heart failure medication and an increasing array of interventions have had an enormous effect on morbidity and mortality over the past 10 years. However, patients with end stage disease can still be highly symptomatic. Moreover, such patients are disadvantaged compared with patients with malignant disease. They are less likely to have an understanding of their illness or have access to supportive care. They are also less likely to have the opportunity to plan for care with regard to death and dying. There is increasing demand that the multi-professional clinical team gain good communication and supportive care skills, and that appropriate access to specialist palliative care services is available.
Cocaine use and stroke
Authors: Treadwell Sean D , Robinson Tom G
Published: June 2007

Stroke is the third most common cause of death in developed countries. In England and Wales, 1000 people under the age of 30 have a stroke each year. Cocaine is the most commonly used class A drug, and the first report of cocaine-induced stroke was in 1977. Since the development of alkaloidal “crack” cocaine in the 1980s, there has been a significant rise in the number of case reports describing both ischaemic and haemorrhagic stroke associated with cocaine use. Cocaine is a potent central nervous system stimulant, and acts by binding to specific receptors at pre-synaptic sites preventing the reuptake of neurotransmitters. The exact mechanism of cocaine-induced stroke remains unclear and there are likely to be a number of factors involved including vasospasm, cerebral vasculitis, enhanced platelet aggregation, cardioembolism, and hypertensive surges associated with altered cerebral autoregulation. The evidence surrounding each of these factors will be considered here.
Hyponatraemia in clinical practice
Authors: Biswas M , Davies J S
Published: June 2007

Hyponatraemia is defined as a serum sodium concentration below 135 mmol/l. It causes major diagnostic and management problems in practice. Hyponatraemic disorders are divided into euvolaemic, hypervolaemic and hypovolaemic. In the evaluation of the hyponatraemic patient, history taking should focus on identifying the potential cause, duration and symptomatology. Clinical examination should include assessment of volume status. Acute hyponatraemia of less than 48 h duration requires prompt correction. Treatment may involve hypertonic saline, isotonic saline and appropriate hormone replacement therapy depending on the aetiology. Chronic hyponatraemia should be treated with caution because of the risk of central pontine myelinolysis.
Effect of serum creatine kinase-MBmass on the early and hierarchical diagnosis of related artery reperfusion in acute myocardial infarction
Authors: Xing Shan-Shan , Xing Qi-Chong , Zhang Yun , Zhang Wei
Published: June 2007

Aim

To evaluate creatine kinase-MBmass (CK-MBmass) for the early diagnosis of infarct-related artery (IRA) patency after thrombolysis and the hierarchical diagnosis of related artery reperfusion (RAR).

Patients and methods

CK-MBmass and creatine kinase-MBactivity (CK-MBactivity) were measured kinetically in 48 patients treated with thrombolysis and 96 patients treated with routine drugs.

Results

In the continuous-RAR (CRAR) group, the peak values of CK-MBmass and CK-MBactivity appeared at ⩽12 h, the peak durations were maintained for ⩽8 h before decreasing to normal at ⩽42 h, which occurred more quickly than those values in the non-RAR (NRAR) group. In the temporary-RAR (TRAR) group, the peak values appeared at ⩽12 h, but no significant differences were found between the TRAR and NRAR groups in the time that the peak durations lasted before decreasing to normal values. In the reobliteration group after RAR, the peak values appeared at ⩽12 h, and the peak durations were maintained for ⩽8 h. After returning to the normal, a second peak appeared, and the time required for the values to return to normal was prolonged significantly.

Conclusions

CK-MBmass could be used as an indicator of RAR after thrombolysis; and the kinetic changes of serum CK-MBmass could be used for the hierarchical diagnosis of RAR in acute myocardial infarction.
Screening for Addison's disease in patients with type 1 diabetes mellitus and recurrent hypoglycaemia
Authors: Likhari Taruna , Magzoub Saeed , Griffiths Melanie J , Buch Harit N , Gama R
Published: June 2007

Background

Addison's disease may present with recurrent hypoglycaemia in subjects with type 1 diabetes mellitus. There are no data, however, on the prevalence of Addison's disease presenting with recurrent hypoglycaemia in patients with diabetes mellitus.

Methods

Three year retrospective study of diabetic patients with “unexplained” recurrent hypoglycaemia investigated with a short Synacthen test to exclude adrenocortical insufficiency.

Results

95 patients with type 1 diabetes mellitus were studied. Addison's disease was identified as the cause of recurrent hypoglycaemia in one patient with type 1 diabetes mellitus.

Conclusion

Addison's disease is a relatively rare but remedial cause of recurrent hypoglycaemia in patients with type 1 diabetes mellitus. A low threshold for investigating patients with type 1 diabetes mellitus and recurrent hypoglycaemia to detect Addison's disease is therefore suggested.
Peroxisome proliferator-activated receptor γ agonists inhibit the proliferation and invasion of human colon cancer cells
Authors: Shen Dan , Deng Changsheng , Zhang Ming
Published: June 2007

Background and aims

Data regarding the effect of peroxisome proliferator-activated receptor γ (PPAR-γ) ligands on the invasive ability of colon cancer cells are currently limited. This study was designed to examine the effects of PPAR-γ agonists on the proliferation and invasion of two colon cancer cells to identify the role of PPAR-γ in colon cancer growth and metastasis.

Methods

SW480 and LS174T cells were treated with PPAR-γ ligands, pioglitazone and 15-deoxy-δ(12,14)-prostaglandin J2 (15d-PGJ2), as well as their combinations with the PPAR-γ antagonist GW9662. MTT assay was used to determine the antiproliferative effects. Cell cycle analysis was conducted by flow cytometry. The mRNA and protein expression were detected by reverse transcriptase polymerase chain reaction (RT-PCR) and western blot, respectively. The invasive ability of cells was determined by the BD BioCoat Matrige invasion chamber.

Results

Pioglitazone and 15d-PGJ2 inhibited the proliferation of both colon cancer cell lines in a dose-dependent manner. This growth inhibitory effect was reversed by GW9662. Results from flow cytometry demonstrated G1 arrest following treatment with pioglitazone and 15d-PGJ2. The expression of matrix metalloproteinase-7 (MMP-7) was only detected in LS174T cells, while its tissue inhibitor-1 (TIMP-1) was expressed in both colon cancer cells. 15d-PGJ2 and pioglitazone downregulated MMP-7 expression and upregulated TIMP-1 expression. PPAR-γ agonists can only inhibit invasive activity of LS174T cells.

Conclusions

PPAR-γ agonists have inhibitory effects on the proliferation of colon cancer cell lines associated with G1 cell cycle arrest and invasive activity. The latter effect is demonstrated in certain cell lines through the down-regulation of MMP-7 synthesis.
TRANSPORT COURSE OF INSOLUBLE AND SOLUBLE SUBSTANCES OF FOG WATER IN AKITA PREFECTURE IN NORTHERN JAPAN
Authors: KIKUCHI RYOEI , INOTUME JUNKO , YOSHIMURA KEIJI , KAJIKAWA MASAHIRO , OGAWA NOBUAKI , SERA KOICHIRO , OZEKI TORU
Published: June 2007

Fog water samples were collected at the Akita Hachimantai mountain range in northern Japan from August to September 1997 and from June to September 1988 to 2000 to investigate the pollution mechanism of fog. Ionic components and insoluble substances in fog water were analyzed using ion chromatography and particle induced X-ray emission (PIXE) analysis, respectively. Combining a 72 h back trajectory and principal component analysis (PCA) to chemical analysis data elucidated the effect of the transport course of an air mass on samples insoluble substances and ionic components. When the air mass was transported from northern China to the Hachimantai range, the nss- SO 42- was greater than in other cases. That fog contained "Kosa" as an insoluble substance from northern China. Our PCA analysis revealed that the score of PC1 (which was about –0.5) was a measure of containing "Kosa".
SUMMARY OF THE WORKSHOP ON PRACTICAL PROBLEMS IN BIOLOGICAL APPLICATIONS OF MICRO-PIXE ANALYSIS
Authors: Yamazaki H. , Ishii K. , Matsuyama S. , Komori Y. , Mizuma K. , Izukawa T.
Published: June 2007

A workshop on practical problems in biological applications of micro-PIXE analysis was held in one of the evening sessions at the 8th International Conference on Nuclear Microprobe Technology and Application which was held in Takasaki, Japan, throughout September 8-13, 2002. We summarize the participants' exchange of observations and suggestions on technical aspects of biological sample target preparation and specimen damage due to beam irradiation, which occur in micro-PIXE analysis under vacuum.
Effect of scatter and attenuation correction in ROI analysis of brain perfusion scintigraphy
Authors: Hashimoto J. , Ogawa K. , Kubo A. , Fukunaga A. , Onozuka S. , Bai J.
Published: June 2007

The aim of this study was to evaluate the effect of scatter and attenuation correction in region of interest (ROI) analysis of brain perfusion single-photon emission tomography (SPECT), and to assess the influence of selecting the reference area on the calculation of lesion-to-reference count ratios. Patients, methods: Data were collected from a brain phantom and ten patients with unilateral internal carotid artery stenosis. A simultaneous emission and transmission scan was performed after injecting 123I-iodoamphetamine. We reconstructed three SPECT images from common projection data: with scatter correction and nonuniform attenuation correction, with scatter correction and uniform attenuation correction, and with uniform attenuation correction applied to data without scatter correction. Regional count ratios were calculated by using four different reference areas (contralateral intact side, ipsilateral cerebellum, whole brain and hemisphere). Results: Scatter correction improved the accuracy of measuring the count ratios in the phantom experiment. It also yielded marked difference in the count ratio in the clinical study when using the cerebellum, whole brain or hemisphere as the reference. Difference between nonuniform and uniform attenuation correction was not significant in the phantom and clinical studies except when the cerebellar reference was used. Calculation of the lesion-to-normal count ratios referring the same site in the contralateral hemisphere was not dependent on the use of scatter correction or transmission scan-based attenuation correction. Conclusion: Scatter correction was indispensable for accurate measurement in most of the ROI analyses. Nonuniform attenuation correction is not necessary when using the reference area other than the cerebellum.
Administration of additional inactive iodide during radioiodine therapy for Graves' disease
Authors: Moka D. , Reinholz U. , Schmidt M. , Schomäcker K. , Schicha H. , Wellner U. , Dietlein M.
Published: June 2007

Aim: Graves' hyperthyroidism and antithyroid drugs empty the intrathyroid stores of hormones and iodine. The consequence is rapid 131I turnover and impending failure of radioiodine therapy. Can administration of additional inactive iodide improve 131I kinetics? Patients, methods: Fifteen consecutive patients, in whom the 48 h post-therapeutically calculated thyroid dose was between 150 and 249 Gy due to an unexpectedly short half-life, received 3 × 200 μg inactive potassium-iodide (127I) daily for 3 days (Group A), while 17 consecutive patients with a thyroid dose of ≥ 250 Gy (Group B) served as the non-iodide group. 48 hours after 131I administration (M1) and 4 or 5 days later (M2) the following parameters were compared: effective 131I half-life, thyroid dose, total T3, total T4, 131I-activity in the T3- and T4-RIAs. Results: In Group A, the effective 131I half-life M1 before iodine (3.81 ± 0.93 days) was significantly (p <0.01) shorter than the effective 131I half-life M2 (4.65 ± 0.79 days). Effective 131I half-life M1 correlated with the benefit from inactive 127I (r = –0.79): Administration of 127I was beneficial in patients with an effective 131I half-life M1 of <3 or 4 days. Patients from Group A with high initial specific 131I activity of T3 and T4 showed lower specific 131I activity after addition of inactive iodine compared with patients from the same group with a lower initial specific 131I activity of T3 and T4 and compared with the patient group B who was given no additional inactive iodide. This correlation was mathematically described and reflected in the flatter gradient in Group A (y = 0.5195x + 0.8727 for 131I T3 and y = 1.0827x – 0.4444 for 131I T4) and steeper gradient for Group B (y = 0.6998x + 0.5417 for 131I T3 and y = 1.3191x – 0.2901 for 131I T4). Radioiodine therapy was successful in all 15 patients from Group A. Conclusion: The administration of 600 μg inactive iodide for three days during radioiodine therapy in patients with Graves' hyperthyroidism and an unexpectedly short half-life of <3 or 4 days was a safe and effective alternative to the administration of a second radioiodine capsule
Management of multinodular goiter in Germany (Papillon 2005)
Authors: Wegscheider K. , Vaupel R. , Schmidt M. , Schicha H. , Dietlein M.
Published: June 2007

Aim: Large-scale survey to focus on management of multinodular goiter and to compare the approaches of practitioners in primary care and thyroid specialists in Germany. Methods: Replies to a questionnaire were received from 2,191 practitioners and 297 thyroid specialists between June 1 and September 30, 2005. The hypothetical cases and their modifications described multinodular goiters of different sizes with and without toxic nodules. Results: In the workup, TSH determination and thyroid sonography were found to be standard procedures. Scintigraphy was selected by 80.2% of practitioners and 92.9% of specialists (p <0.001), in preference to fine needle aspiration cytology (17.9% of practitioners and 34.5% of the specialists, p <0.001). Only 6.1% of practitioners and 24.4% of specialists (p <0.001) advocated calcitonin screening. Euthyroid multinodular goiter (50-80 ml) was treated medically by 67.1% of practitioners and 65.6% of specialists, the combination of levothyroxine with iodine being clearly preferred (54.5% of practitioners, 52.3% of specialists). For toxic nodular goiter the preference for radioiodine therapy was significantly higher (p <0.001) among specialists (67.7%) than among practitioners (47.5%). Referral to surgery was recommended for cold nodules with negative cytology by 64.9% of practitioners and 73.5% of specialists (p = 0.004). Conclusions: Treatment and diagnostic procedures are used to nearly the same extent in primary care and specialist institutions, but the opinions diverge over the issues of calcitonin screening and referral for radioiodine therapy.
Tissue factor-enriched vesicles are taken up by platelets and induce platelet aggregation in the presence of factor VIIa
Authors: Lopez-Vilchez Irene , Diaz-Ricart Maribel , Fuste Berta , Galan Ana , White James , Escolar Gines
Published: June 2007

We investigated the interactions of vesicles containing human tissue factor (TF) with platelets and evaluated responses induced by rFVIIa using standard aggregometry, ultrastructural and flow-cytometry techniques. Washed platelets were exposed to a preparation of placental human TF (pTF) or to a relipidated formulation of recombinant humanTF (rTF). Under stirring conditions, pTF induced reversible aggregation with platelets returning to their resting state after 5 minutes. This reversible response to pTF was partially inhibited by antibodies against CD62-P, but not by antithrombin agents, and was not observed with rTF. Sequential ultrastructural studies revealed uptake of both TF preparations by platelets involving traffic of vesicles through channels of the open canalicular system (OCS). Immunocytochemical studies on cryosections identified TF in the OCS, and occasionally in the alpha-granules of the platelets. These processes were faster with pTF than with rTF, but bothTF preparations accumulated in platelets at the end of incubation periods. Flow cytometry studies revealed the presence of other cellular antigens (CD62-P, CD14 and CD45) associated to the pTF. Addition of rFVIIa to washed platelets exposed to pTF or rTF, caused a thrombin dependent irreversible platelet aggregation. Our studies demonstrate that platelets possess mechanisms to capture and incorporate TF-rich vesicles. These processes are accelerated by the presence of other cellular antigens in the vesicles. Our findings may explain the hemostatic action of rFVIIa in severely hemodiluted patients, but are also relevant for the understanding of potential implications of TF-associated to platelets in the propagation of thrombus.
Platelet activation by collagen is increased in retinal vein occlusion
Authors: Bruzzese Debora , Signorello Maria , Armani Ugo , Piana Antonietta , Ghiglione Davidina , Camicione Paola , Leoncini Giuliana
Published: June 2007

Retinal vein occlusion (RVO) is the most common retinal vascular disorder second to diabetic retinopathy. The main risk factors in patients with RVO are hypertension, diabetes, hyperlipidemia, increased blood viscosity and glaucoma. The pathogenesis of RVO has not yet been clarified. In these events platelets could play a very important role. In the present study the platelet response to collagen was deeply investigated. Experiments were carried out on a selected group of RVO patients, which were compared to a group of healthy subjects matched for age, sex, clinical and metabolic characteristics. In resting and activated platelets of both groups of subjects p72syk phosphorylation, phospholipase Cγ 2 phosphorylation, protein kinase C activation, intracellular calcium levels and nitric oxide formation were measured. Results show that platelets of patients were more responsive to collagen or ADP than healthy subjects and that the response was significantly different (p < 0.0005) at low concentrations of these agonists. In platelets of patients stimulated with collagen increased phosphorylation of p72syk and phospholipase C γ 2 was found. Also protein kinase C was more activated in patients. In addition intracellular calcium rise induced by collagen was significantly higher in patients than in healthy subjects. RVO patients showed a lower basal level of nitric oxide both in resting and stimulated platelets compared to healthy subjects. Altogether these results suggest that the platelet hyperaggregability described in patients might be an important factor in the development of RVO contributing to the thrombogenic effects.
Thrombin activation of endometrial endothelial cells: A possible role in intrauterine growth restriction
Authors: Huang Se-Te , Schatz Frederick , Salafia Carolyn , Stocco Carlos , Lockwood Charles , Krikun Graciela
Published: June 2007

Preeclampsia (PE), intrauterine growth restriction (IUGR) and abruption with or without fetal loss are associated with reduced uteroplacental blood flow, decidual vasculopathy, endothelial cell dysfunction, thrombosis, inflammation and hemorrhage. Our hypothesis is that reduced uteroplacental blood flow causes focal decidual hypoxia that generates vascular endothelial growth factor (VEGF). The latter acts directly on decidual endothelial cells to induce aberrant expression of tissue factor (TF), the primary initiator of coagulation. This in turn generates thrombin that induces: i) further TF expression; and ii) inflammatory cytokines. BothVEGF and TF induce aberrant angiogenesis-vessel maintenance reflected by endothelial cell fenestrations and induction of a prothrombotic surface causing both the decidual hemorrhage (i.e.abruption) and thrombosis (i.e.uteroplacental vascular insuf- ficiency) observed in these adverse pregnancy outcomes. This novel hypothesis is supported by our finding of TF expression in decidual endothelium of pregnancies complicated by IUGR and/ or fetal loss. Moreover, treatment of cultured endometrial endothelial cells with VEGF or thrombin induces TF protein and mRNA expression. Quantitative RT-PCR analysis indicates that thrombin enhances (>10-fold) the output of diverse inflammatory cytokines in these cultures. The greatest effect (>2-log) was seen on macrophage inflammatory protein 3 α (MIP3 α ). In vitro, thrombin results in endometrial endothelial cell aggregations and changes in the apoptotic pathway. Thus, we postulate that reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes.
Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis
Authors: Murad Sarwa , de Maat Moniek , Tanck Michael , Haagsma Elizabeth , van Hoek Bart , Rosendaal Frits , Janssen Harry , Leebeek Frank , de Bruijne Emile ,   for the Liver and Thrombosis Study Group
Published: June 2007

Splanchnic vein thrombosis (SVT) has been associated with a hypercoagulable state. Thrombin-activatable fibrinolysis inhibitor (TAFI) may contribute to a hypercoagulable state, and therefore we were interested in the role of TAFI in SVT. Since the disease is frequently associated with liver insufficiency, which affects plasma levels ofTAFI, we studied the role of variation in theTAFI gene in SVT. In a multicenter case-control study on 118 patients with SVT (39 Budd-Chiari syndrome and 85 portal vein thrombosis) and 118 population-based controls, the relationship of SVT with single nucleotide polymorphisms (SNPs) and haplotypes in the TAFI gene (- 438G/A, Ala147Thr, Thr325Ile and 1583A/T) was determined. The risk for SVT was decreased (OR 0.2,95% CI 0.1–0.7) in 147Thr/Thr homozygotes and slightly,but not significantly,increased in carriers of the 325Ile allele (OR 1.6, 95%CI 0.9–2.7). Haplotype analysis confirmed that the Ala147Thr SNP has the strongest association with risk of SVT. In conclusion, genetic variation in the TAFI gene is associated with risk of SVT, suggesting a role for TAFI in the pathogenetic mechanism of SVT.
Recombinant human activated factor VII is thrombogenic in a rabbit model of cyclic flow reduction and does not reduce intra-abdominal bleeding
Authors: Charbonneau Sonia , Girard François , Boudreault Daniel , Ruel Monique , Blais Normand , Hardy Jean-François
Published: June 2007

Recombinant human activated factor VII (rHuFVIIa) can reduce bleeding but may be associated with arterial thrombosis. We hypothesized that rHuFVIIa would increase the occurrence of cyclic flow reductions (CFR) and reduce intra-abdominal bleeding in an experimental model. An adapted Folts’ model of carotid artery lesion and stenosis was used. Twenty four rabbits were randomized to receive rHuFVIIa (group F) or placebo (group P) in a double-blind fashion. A standardized injury to the common carotid artery resulted in CFR and/or thrombosis. Hematological values, coagulation and thromboelastographic (TEG) variables were compared. Intra-abdominal bleeding was evaluated by measuring blood loss from standardized hepatosplenic lesions. The median number (range) of spontaneous CFR [group P: 6 (0–15); group F: 8 (0–16)] was comparable between groups. The number of induced CFR (by “shaking” of the artery) needed to avert thrombosis (group F: 2; group P: 0 ; p < 0.05) and the incidence of complete carotid artery thrombosis (group F: 3; group P : 0; p < 0.05) were higher in group F. Intra-abdominal bleeding was similar in both groups. TEG analysis demonstrated a hypercoagulable state in both groups but the magnitude of the change was statistically more important in group F. rHuFVIIa increases thrombosis in a rabbit model of carotid artery injury. The bleeding from hepatic and splenic lesions is not reduced by administration of rHuFVIIa despite a hypercoagulable state confirmed by standard TEG analysis.
Inhibition of thrombin-induced platelet aggregation using human single-chain Fv antibodies specific for TREM-like transcript-1
Authors: Chisholm Maia , Quigley Laura , McMahon James , Mori Toshiyuki , Giomarelli Barbara , Washington Valance , McVicar Daniel
Published: June 2007

TREM-like transcript-1 (TLT-1) is a novel platelet membrane receptor, which has been recently characterized in mice. TLT-1 is expressed exclusively in platelets and megakaryocytes, and its expression is dramatically upregulated upon platelet activation, suggesting that it plays a unique role in hemostasis and/or thrombosis. In this study we identified and characterized highly specific human monoclonal antibodies that bind to TLT-1 by screening a naïve library of single chain Fv fragments (scFvs) displayed on filamentous phage (Thomlinson I library). These scFvs detected plate-bound TLT-1, captured soluble TLT-1, and readily reacted with cell-bound TLT-1 on transfectants and primary human platelets. Most importantly, anti-TLT-1 scFvs inhibited thrombin-mediated human platelet aggregation. This inhibition was specific for thrombin-induced aggregation and was reversible with higher doses of agonist. These data are the first to demonstrate a biological role for TLT-1 and its potential as a therapeutic target. The human scFvs isolated in this study may represent novel anti-platelet therapeutic agents.
Plasminogen binds to plasmin-modulated factor Xa by Ca2+- and C-terminal lysine-dependent and -independent interactions
Authors: Grundy Jean E. , Hancock Mark A. , Meixner Scott C. , MacKenzie Roger C. , Koschinsky Marlys L. , Pryzdial Edward L. G.
Published: June 2007

Plasminogen binding to receptors involves both C-terminal lysine-dependent and -independent interactions. The latter are poorly understood. Our earlier work demonstrated a novel Ca2+-enhanced bivalent interaction between plasmin-cleaved FXa (FXa33/13) and plasminogen truncated at Lys78 (Lys-Pg). Here we hypothesized that the effects of Ca2+may enable dissection of the C-terminal lysine-dependent and -independent interactions. To evaluate the role of the Glu-plasminogen (Glu-Pg) amino acids 1–77, binding of FXa33/13 to immobilized Glu-Pg was compared to Lys-Pg by surface plasmon resonance. Under identical conditions, approximately half the amount of FXa33/13 bound to Glu-Pg. The simplest fit of data suggested a 2:1 plasminogen:FXa33/13 stoichiometry for both, which were proportionately enhanced by Ca2+. Only Lys-Pg demonstrated significant Ca2+-independent binding to FXa33/13. In the presence of Ca2+, weak C-terminal lysine-independent binding could be detected, but only for Glu-Pg. The elastase-generated plasminogen fragment encompassing the angiostatin-like kringle domains 1 to 3 (K1–3) inhibited binding of FXa33/13 to Lys-Pg, whereas fragments corresponding to kringle 4- and kringle 5-protease domain had no effect. Immobilized K1–3 binding to FXa33/13 had both Ca2+-dependent and -independent components. The principal KMd for the interaction was 10-fold higher than Lys-Pg. In the presence of Ca2+, eACA inhibited FXa33/13 binding to K1–3 by 30%, but eliminated binding in the absence of Ca2+. These studies suggest that Ca2+-dependent and -independent binding of Lys-Pg to FXa33/13 are C-terminal lysine-dependent. The N-terminal 1–77 amino acids of Glu-Pg confer significant C-terminal lysine-independent binding, which may play a role during the initiating stages of plasminogen activation.
No interaction between factor V Leiden and hyperhomocysteinemia or MTHFR 677TT genotype in venous thrombosis
Authors: Keijzer Miranda B. A. J. , Borm George F. , Blom Henk J. , Bos Gerard M. J. , Rosendaal Frits R. , den Heijer Martin
Published: June 2007

Homocysteine may have a thrombogenic effect through inhibition of inactivation of factor Va by activated protein C. Because factor V Leiden also leads to resistance of factor V to activated protein C, it would be possible that both factors show interaction for the risk of venous thrombosis. This has been reported in some studies, but not in others. We performed a meta-analysis to investigate a possible interaction between factor V Leiden and hyperhomocysteinemia, including 825 subjects with venous thrombosis and 2,109 controls, for the risk of venous thrombosis. In addition, we assessed a possible interaction between factor V Leiden and MTHFR 677TT genotype (the most common genetic determinant of homocysteine levels), including 2,547 subjects with venous thrombosis and 4,327 controls. We also investigated the interaction effect of factor V Leiden and hyperhomocysteinemia in a large case-only study using data of the VITRO study, including 2,077 subjects with first-time venous thrombosis. The meta-analysis yielded no evidence for additive or multiplicative interaction between factor V Leiden and hyperhomocysteinemia [relative excess risk due to interaction (RERI) –1.77 (95%CI –8.61 to 5.08) and multiplicative interaction term 0.86 (95%CI 0.35 to 2.14)].The case-only study also showed no interaction effect [0.58 (95%CI 0.29 to 1.16)]. Also the metaanalysis on factor V Leiden and MTHFR 677TT yielded no evidence of interaction; RERI 0.13 (95%CI –3.60 to 3.86) and multiplicative interaction term 1.23 (95%CI 0.72 to 2.11). Both the meta-analyses of published studies and a large case-only study did not show evidence for interaction between factor V Leiden and hyperhomocysteinemia for risk of venous thrombosis.
Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and haemophilia A patients
Authors: Guo Delan , Key Nigel , Conti-Fine Bianca , Hu Genlin
Published: June 2007

HaemophiliaA patients treated with human factorVIII (fVIII) may develop antibody (Ab) inhibitors to fVIII. FVIII-specific CD4+ T cells are common in haemophilia A patients, but also in healthy subjects who do not have a sustained anti-fVIII Ab response. Here, we examined the fVIII-induced IFNγ -, IL-4- and TGF- β 1-producing CD4+ T blasts by culturing peripheral blood mononuclear cells (PBMC) from controls and patients with recombinant fVIII. FVIII exposure significantly increased IFNγ - and IL-4-, but not TGF-β 1-producing CD4+ T blasts in patients with inhibitors. Patients without inhibitors had fVIII-induced IFNγ - andTGF-β 1-,but not IL-4-producing CD4+ T blasts.Controls did not have IL-4-producing CD4+ T blasts. However, controls whose PMBC proliferated in response to fVIII had fVIII-induced CD4+ T blasts that produced IFN-γ, the number of which correlated with the intensity of the proliferative response to fVIII of their PMBC, whereas controls whose PMBC did not proliferate to fVIII had predominantly fVIII-induced CD4+ T blasts that producedTGF- β 1.The presence in controls and patients without inhibitors of fVIII-induced IFN-γ -producing CD4 + T cells, but not IL-4-producing CD4+ T cells, which are abundant in inhibitor patients, suggests a role of Th1 cells in initiating the immune response to fVIII, and of Th2 cells in the development of strong inhibitor production. The polarized high ratios of Th3/Th1 and Th3/Th2 in controls and patients without inhibitors suggest that a preponderance ofTh3 cells in the response to fVIII may help to maintain tolerance to fVIII.
Simple and safe exclusion of pulmonary embolism in outpatients using quantitative D-dimer and Wells’ simplified decision rule
Authors: Steeghs Neeltje , Niessen Rene W. L. M. , Jonkers Gé J. P. M. , Dik Hans , Castel Ad , Werker-van Gelder Lies , Vlasveld Tom L. , van Klink Rik C. J. , Planken Erwin V. , Huisman Menno V. , Goekoop Robbert J.
Published: June 2007

A safe and effective management strategy is pivotal in excluding pulmonary embolism (PE). The combination of Wells’ simplified dichotomous clinical decision rule and D-dimer test is non-invasive and could be highly efficient, though its safety has not been widely studied. We evaluated safety and efficiency of this combination in excluding PE. Wells clinical decision rule was performed in 941 consecutive patients with suspected PE and, if patients had a score ≤ 4.0 points, a VIDAS D-dimer test followed. Patients with a normal D-dimer concentration had no further tests, PE was considered excluded, and patients did not receive anticoagulant treatment. Patients, in whom PE was excluded, were followed up for three months. Four hundred fifty patients (51.2%) had a clinical decision score ≤ 4.0 points and a normal D-dimer concentration. In 45 of these patients, during the initial diagnostic period additional objective testing, although not indicated, was performed, and PE was established in two patients. During three months of follow up no venous thromboembolic events (VTE) occurred. Therefore, the overall VTE failure rate was two of 450 (0.4% [95%CI 0–1.1]); the overall prevalence of PE was 12.3%. The diagnostic protocol could be completed and allowed a decision to be made in 90% of the study patients. This study has prospectively established the safety of a combination of a dichotomized clinical decision rule and D-dimer test in ruling out PE. The strategy proved highly efficient, since more than 50% of patients could be managed without the need for more invasive and expensive tests.