bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of the Haemodialysis Procedure on Platelets, Coagulation and Fibrinolysis
Authors: Sabovic Mišo , Salobir Barbara , Preloznik Zupan Irena , Bratina Petra , Bojec Vida , Buturovic Ponikvar Jadranka
Published: June 2006

In end-stage renal disease, in particularly when treated with haemodialysis, the function of platelets, coagulation and fibrinolytic systems can be disturbed, thus contributing to either thrombotic or bleeding complications. It is important to know whether the currently used haemodialysis procedure itself (by biocompatible membranes and better anticoagulation with nandroparin) affects platelets, coagulation or fibrinolysis. In 15 patients who had been treated with chronic haemodialysis, we measured and compared platelet aggregation (induced by adenosine diphosphate, collagen and epinephrine), the markers of coagulation and fibrinolysis activation (thrombin-antithrombin complexes, thrombin fragments F1+2, D-dimer), and fibrinolytic parameters, i.e. fibrinogen, plasminogen, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 antigen and activity, before and immediately after the regular haemodialysis sessions. We did not find differences between pre- and post-haemodialysis platelet aggregation induced with all agents. Markers of coagulation and fibrinolysis activation remained unchanged during the process of haemodialysis. However, in post-haemodialysis samples, t-PA activity was significantly increased. Other fibrinolytic parameters remained unchanged. In conclusion, our results showed that the current technique of haemodialysis procedure does not affect platelet aggregation or activate coagulation, and therefore, does not contribute to a thrombotic tendency. However, it does directly affect fibrinolysis through activation of t-PA, which might be clinically relevant since this could increase the bleeding tendency in some haemodialysis patients.
Influence of Factor V HR2 on Thrombin Generation and Clinical Manifestation in Rare Bleeding Disorders
Authors: Strey Rüdiger F. , Siegemund Annelie , Siegemund Thomas , Schubert Christine , Schuster Gudrun , Wulff Karin , Herrmann Falko H.
Published: June 2006

In this study we investigated the influence of the presence of the factor V HR2 haplotype, defined by the factor V gene mutation H1299R (FVHR2), on thrombin generation. Measurements were performed in platelet-poor plasma of individuals with factor VHR2 or factor VLeiden in comparison to a control group carrying none of these mutations. Coagulation was triggered by low concentrations of recombinant tissue factor in the presence of activated protein C. Thrombin generation was monitored by a fluorogenic substrate. The endogenous thrombin potential was calculated from the obtained curves. As a result we observed an increased thrombin generation both for individuals heterozygous and homozygous for FVHR2. The level of endogenous thrombin potential is in the same range as in samples of patients heterozygous or homozygous for FVLeiden. The results indicate that FVHR2 plays a role as a risk factor for venous thrombosis in homozygous patients through an increased thrombin generation. The association between different clinical manifestations in individuals with FVII deficiency and endogenous thrombin potential and the presence of FVHR2 was studied.
Needle Electromyographic Findings in 98 Patients with Myositis
Authors: Blijham Paul J. , Hengstman Gerald J.D. , Hama-Amin Ako Dara , van Engelen Baziel G.M. , Zwarts Machiel J.
Published: June 2006

Background/Aims: Little is known about the distribution of electromyographic (EMG) abnormalities in myositis even though this is relevant in daily practice. Methods: A retrospective semiquantitative analysis of needle EMG findings was performed in a group of 98 patients with myositis. The frequency, type, and distribution of abnormalities were studied. The influence of the use of corticosteroids and the stage of the disease were evaluated. Results: In most patients, a myopathic pattern with spontaneous activity was found, although several clinically relevant exceptions were noted. Long-duration motor unit potentials were found in all three diagnostic groups and were not associated with disease duration. In the lower extremity a distal to proximal gradient was present, adding to the diagnostic confusion with neurogenic diseases, and spontaneous activity was absent in a relatively large group although none of the patients in the acute stage of the disease had a normal EMG. The use of corticosteroids reduced the number of abnormal findings in dermatomyositis and polymyositis, but not in inclusion body myositis. Conclusion: A myopathic pattern with spontaneous activity was most frequently found, although several clinically relevant exceptions were noted. These results illustrate the spectrum of EMG findings in myositis, and may aid the clinician in the interpretation of the EMG in these patients.
A Study of Potential Interactive Genetic Factors in Huntington’s Disease
Authors: Panegyres Peter K. , Beilby John , Bulsara Max , Toufexis Katina , Wong Cathy
Published: June 2006

Aim: To assess the role of genetic factors, other than the CAG repeat length, on the development of Huntington’s disease (HD) in an isolated Caucasian population in the south-west of Western Australia. Methods: 114 patients with symptomatic HD according to the Unified HD Rating Scale research criteria were examined along with 51 control patients. The length of the CAG repeat sequence in the IT15 gene and the adjacent CCG and Δ2642 polymorphisms were determined by polymerase chain reaction along with common genotypes of the angiotensin-converting enzyme (ACE) and apolipoprotein E (APOE) genes. Results: The CAG expansion was associated with age of onset and the development of neurological dysfunction. We found no effect of the expanded CCG allele on age of onset, neurological dysfunction or the size of the CAG expansion. We observed a twofold increase in the Δ2642 polymorphism and the risk of developing symptomatic HD which was not significant (OR 2.06; 95% CI 0.60–7.07). The presence of an APOE Ε4 allele was associated with an increased risk of HD which was not significant either (OR 1.04–1.73; 95% CI 0.10–10.68). ACE genotypes showed no association with risk factors for the disease. Conclusion: In our study of a geographically isolated Caucasian HD population in the south-west of Western Australia we have not observed that the expanded CCG allele, the Δ2642 polymorphism, the APOE Ε4 allele and ACE genotypes are associated with an increased risk for the development of symptomatic HD.
Evaluation of Efficacy, Tolerability, and Treatment Satisfaction with Almotriptan in 3 Consecutive Migraine Attacks
Authors: Massiou Hélène , Pradalier Andre , Donnet Anne , Lanteri-Minet Michel , Allaf Bashar
Published: June 2006

The objective of the open-label, multicenter Migraine – Satisfaction with Treatment: Reality with Almogran® study was to assess efficacy, tolerability, and satisfaction with almotriptan 12.5 mg among migraineurs who were not achieving adequate results with their current acute therapy. Data from 434 patients (342 evaluable), were obtained for 929 attacks by 154 neurologists in France. Using a questionnaire developed by the National Agency for Accreditation and Evaluation in Health (ANAES), almotriptan was associated with an increased proportion of patients experiencing significant relief at 2 h (69.3 vs. 26.6%), tolerating the medication well (91.2 vs. 76.0%), able to resume activities (70.5 vs. 24.9%), and taking only 1 dose (59.4 vs. 28.1%) compared with previous therapies. At 2 h, headache pain had disappeared in 33.4% of attacks and was mild in 26.9%. Recurrence rate was 28.4% and rescue analgesics were used in 20.9% of attacks. The rate of adverse event-related discontinuations was 2.6%. The proportion of patients who were very satisfied/satisfied overall with almotriptan treatment was 69%. Almotriptan 12.5 mg was effective, well-tolerated and associated with a high rate of treatment satisfaction in patients whose previous acute migraine therapy was inadequate according to the ANAES recommendations.
Serum Levels of Matrix Metalloproteinases-2 and -9 and Their Tissue Inhibitors in Inflammatory Neuromuscular Disorders
Authors: Hurnaus S. , Mueller-Felber W. , Pongratz D. , Schoser B.G.H.
Published: June 2006

We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG) therapy in 33 patients with chronic immune-mediated neuropathies and myopathies and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9 and TIMP-1 serum levels higher in all patients compared to age-matched controls. Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels increased, while MMP-9 serum levels decreased, indicating tissue repair. After 60 days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1 and TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue damage. Comparing the MMP/TIMP results with the clinical courses, IVIG treatment tended to change MMP/TIMP levels in a way that paralleled clinical improvement and relapse. In sum, during a distinct time period, IVIG therapy seems to be able to modulate MMP-mediated tissue repair.
EEG Findings after a Cerebral Territorial Infarct in Patients Who Develop Early- and Late-Onset Seizures
Authors: De Reuck J. , Goethals M. , Claeys I. , Van Maele G. , De Clerck M.
Published: June 2006

Background: EEG findings are generally not considered to be very helpful for the diagnosis of poststroke seizures. Purpose: This retrospective study investigates the EEG characteristics in patients who develop seizures after a cerebral territorial infarct. Patients and Methods: The study population consisted of 110 patients with seizures after a cerebral territorial infarct (12 with early- and 98 with late-onset seizures) and 275 without. All 110 patients had an interictal EEG after their first seizure. The EEG patterns after the stroke were compared between those available from 69 patients who developed seizures and those from 275 who did not. Also the EEG patterns after the seizure (n = 110) were compared to those in the poststroke group without subsequent seizures. Results: Periodic lateralized epileptic discharges (PLEDs) on the EEG after stroke were only found in 5.8% of the patients with early- and late-onset seizures. They were absent in the stroke group without seizures. Frontal intermittent rhythmic delta activities (FIRDAs) were observed in 24.6% of the seizure group, compared to 1.1% in the control group. Diffuse slowing occurred also significantly more often in the former (21.7%) compared to the latter group (5.1%). Normal EEG findings were seen in 53.8% of the stroke patients without seizures, compared to 8.5% in those with seizures. The incidence of focal slowing was the same in both groups. Similar findings were observed when comparing the EEG patterns of the patients after the first poststroke seizure to those of the stroke group without subsequent seizures. In patients with early-onset seizures, PLEDs or FIRDAs were present in 25% each. FIRDAs and diffuse slowing were significantly more frequently observed on the poststroke EEGs of patients who developed late-onset seizures. Conclusions: FIRDAs, PLEDs and diffuse slowing are the most frequent EEG findings in patients with early-onset seizures. Patients with FIRDAs and diffuse slowing on the poststroke EEG have a high risk to develop late-onset seizures, while the chance is reduced in those with normal EEG findings.
Effect of Erythropoietin on Urinary Liver-Type Fatty-Acid-Binding Protein in Patients with Chronic Renal Failure and Anemia
Authors: Nakamura Tsukasa , Sugaya Takeshi , Kawagoe Yasuhiro , Suzuki Tsukasa , Ueda Yoshihiko , Koide Hikaru
Published: June 2006

Background/Aim: The urinary liver-type fatty-acid-binding protein (L-FABP) level reflects the clinical progression of chronic kidney disease. We conducted a study to determine whether administration of erythropoietin (EPO), which is produced in response to hypoxic stress, affects urinary protein excretion and L-FABP levels in patients with chronic renal failure (CRF) and anemia. Methods: The study was an interventional trial that included 20 anemic CRF patients (median serum creatinine level 2.0 mg/dl, range 1.3–2.9 mg/dl; median hemoglobin concentration 9.2 g/dl, range 8.2–9.8 g/dl; median estimated glomerular filtration rate 20.5 ml/min, range 15.0–28.0 ml/min; group A). Recombinant EPO (12,000 U twice/month) was given to these patients for 6 months. Urinary protein, L-FABP, 8-hydroxy-2′-deoxyguanosine, and hemoglobin levels were measured before and 3 and 6 months after treatment. Twenty nonanemic CRF patients were enrolled as controls (group B). Results: After 6 months, the hemoglobin level was increased as compared with the baseline level in group A treated with EPO (median 11.3 g/dl, range 9.3–13.8 g/dl, vs. median 9.2 g/dl, range 8.2–9.8 g/dl; p < 0.01) but not in the untreated group B (median 11.8 g/dl, range 10.2–13.0 g/dl, vs. median 12.1 g/dl, range 10.8–13.4 g/dl; not significant). The urinary protein excretion was decreased as compared with the baseline level in group A (median 1.2 g/day, range 0.6–1.9 g/day, vs. median 1.9 g/day, range 1.1–2.6 g/day; p < 0.01) but not in group B (median 1.4 g/day, range 0.7–2.2 g/day, vs. median 1.6 g/day, range 0.7–2.3 g/day; not significant). The urinary L-FABP level was also decreased as compared with the baseline level in group A (median 50.0 µg/g creatinine, range 7.5–90.0 µg/g creatinine, vs. median 115.0 µg/g creatinine, range 20.0–225.0 µg/g creatinine; p < 0.01) but not in group B (median 82.0 µg/g creatinine, range 15.5–158.0 µg/g creatinine, vs. median 76.0 µg/g creatinine, range 25.0–138.5 µg/g creatinine; not significant). The glomerular filtration rate changed little throughout the study period in either group. The urinary 8-hydroxy-2′-deoxyguanosine level was decreased as compared with the baseline level in group A (median 22.0 ng/mg creatinine, range 8.0–30.0 ng/mg creatinine, vs. median 38.5 ng/mg creatinine, range 14.0–68.0 ng/mg creatinine; p < 0.01) but not in group B (median 33.0 ng/mg creatinine, range 9.0–56.0 ng/mg creatinine, vs. median 30.0 ng/mg creatinine, range 10.0–54.0 ng/mg creatinine; not significant). Conclusion: EPO supplementation may ameliorate renal tubular damage, in part, due to a reduction of oxidative stress in CRF patients with anemia.
Neutrophil-Gelatinase-Associated Lipocalin and Renal Function after Percutaneous Coronary Interventions
Authors: Bachorzewska-Gajewska H. , Malyszko J. , Sitniewska E. , Malyszko J.S. , Dobrzycki S.
Published: June 2006

Background/Aims: The value of neutrophil-gelatinase-associated lipocalin (NGAL), a novel biomarker in the detection of acute renal failure in children after cardiac surgery, has been highlighted in previous studies. The incidence of percutaneous coronary intervention (PCI) increases, which may possibly result in increased incidences of contrast nephropathy, its potentially serious complication. Therefore, the aim of our study was to assess prospectively NGAL in patients undergoing elective PCI in relation to serum creatinine. Methods: NGAL was assessed in the serum and urine using commercially available kits. Results: We measured urinary and serum NGAL before, and 2, 4, 12, 24 and 48 h after PCI. We found a significant rise in serum NGAL 2 and 4 h after PCI, and a rise in urinary NGAL 4 and 12 h after PCI. Before PCI, serum NGAL was significantly associated with serum creatinine, urea, urinary NGAL, hemoglobin, hematocrit, albumin, age and presence of diabetes. In multivariate analysis, serum creatinine was the only predictor of serum NGAL. Serum NGAL 2 h after PCI correlated with serum creatinine, duration of PCI, HbA1c, hematocrit, hemoglobin and urinary NGAL. In multivariate analysis, the only predictors of serum NGAL 2 h after PCI were serum creatinine, time of PCI and HbA1c. Serum NGAL before PCI was significantly higher in diabetics than in non-diabetics. Conclusions: NGAL may represent a sensitive early biomarker of renal impairment after PCI. Serum creatinine, duration of PCI, but not type and amount of contrast agent, and appropriate treatment of diabetes, reflected by HbA1c, predict a rise in serum NGAL and kidney function following PCI.
Who serves the underserved? Predictors of physician care to medically indigent patients
Authors: Chirayath Heidi Taylor
Published: June 2006

Using a national sample of 466 doctors, this work is the first to determine how sociodemographic characteristics, family lives, educational experiences and work environments combine over the life course to shape physician attitudes and behaviors toward serving the medically indigent. Survey data reveal that most physicians have positive experiences with indigent patients, and feel responsible for providing care for the needy. On average, one-quarter of doctors’ patients are medically indigent, and physicians provide six hours of charity care per week.

Multivariate regression and path analyses indicate that disparate social forces predict humanitarian attitudes and behaviors of physicians. Physician attitudes toward the indigent are shaped largely by socializing forces, including medical education and relationships with mentors. In contrast, care of indigent patients is driven by physician attitudes and by characteristics of medical practice such as specialty and practice setting. Implications for scholarship and for medical education, practice and health policy are discussed.
Gender accommodation in online cancer support groups
Authors: Seale Clive
Published: June 2006

The postings made to Internet forums by relatives and friends of people with breast and prostate cancer are described. Women post very frequently on the prostate cancer forum and assume a communication style that is similar to women elsewhere, prioritizing emotional forms of communication over the informational forms preferred by men and showing only mild signs of accommodation to a male style. Men on the breast cancer forum are in a minority and are often responding to the current or anticipated loss of a partner. Their communication behaviour is radically different from that required by dominant conceptions of masculinity. They prioritize emotional communication and the emotional welfare of family members. They experience this new form of communication as unsettling to their conceptions of traditional masculinity. Internet cancer support groups thus favour a form and content of communication generally associated with women’s culture
Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinations
Authors: Bradeen Heather A. , Eide Christopher A. , O'Hare Thomas , Johnson Kara J. , Willis Stephanie G. , Lee Francis Y. , Druker Brian J. , Deininger Michael W.
Published: June 2006

BMS-354825 (dasatinib) and AMN107 (nilotinib) are potent alternate Abl inhibitors with activity against many imatinib mesylate–resistant BCR-ABL kinase domain (KD) mutants, except T315I. We used N-ethyl-N-nitrosourea (ENU)–exposed Ba/F3-p210BCR-ABL cells to compare incidence and types of KD mutants emerging in the presence of imatinib mesylate, dasatinib, and nilotinib, alone and in dual combinations. Although ENU is expected to induce mutations in multiple proteins, resistant clones were almost exclusively BCR-ABL KD mutant at relevant concentrations of nilotinib and dasatinib, consistent with a central role of KD mutations for resistance to these drugs. Twenty different mutations were identified with imatinib mesylate, 10 with nilotinib (including only 1 novel mutation, E292V) and 9 with dasatinib. At intermediate drug levels the spectrum narrowed to F317V and T315I for dasatinib and Y253H, E255V, and T315I for nilotinib. Thus, cross-resistance is limited to T315I, which is also the only mutant isolated at drug concentrations equivalent to maximal achievable plasma trough levels. With drug combinations maximal suppression of resistant clone outgrowth was achieved at lower concentrations compared with single agents, suggesting that such combinations may be equipotent to higher-dose single agents. However, sequencing uniformly revealed T315I, consistent with the need for a T315I inhibitor, to completely block resistance.
Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury
Authors: Khan Samina Yasmin , Kelher Marguerite R. , Heal Joanna M. , Blumberg Neil , Boshkov Lynn K. , Phipps Richard , Gettings Kelly F. , McLaughlin Nathan J. , Silliman Christopher C.
Published: June 2006

Transfusion-related acute lung injury (TRALI) is a form of posttransfusion acute pulmonary insufficiency that has been linked to the infusion of biologic response modifiers (BRMs), including antileukocyte antibodies and lipids. Soluble CD40 ligand (sCD40L) is a platelet-derived proinflammatory mediator that accumulates during platelet storage. We hypothesized that human polymorpho-nuclear leukocytes (PMNs) express CD40, CD40 ligation rapidly primes PMNs, and sCD40L induces PMN-mediated cytotoxicity of human pulmonary microvascular endothelial cells (HMVECs). Levels of sCD40L were measured in blood components and in platelet concentrates (PCs) implicated in TRALI or control PCs that did not elicit a transfusion reaction. All blood components contained higher levels of sCD40L than fresh plasma, with apheresis PCs evidencing the highest concentration of sCD40L followed by PCs from whole blood, whole blood, and packed red blood cells (PRBCs). PCs implicated in TRALI reactions contained significantly higher sCD40L levels than control PCs. PMNs express functional CD40 on the plasma membrane, and recombinant sCD40L (10 ng/mL-1 μg/mL) rapidly (5 minutes) primed the PMN oxidase. Soluble CD40L promoted PMN-mediated cytotoxicity of HMVECs as the second event in a 2-event in vitro model of TRALI. We concluded that sCD40L, which accumulates during blood component storage, has the capacity to activate adherent PMNs, causing endothelial damage and possibly TRALI in predisposed patients.
In-vivo coronary flow profiling based on biplane angiograms: influence of geometric simplifications on the three-dimensional reconstruction and wall shear stress calculation
Authors: Wellnhofer Ernst , Goubergrits Leonid , Kertzscher Ulrich , Affeld Klaus
Published: June 2006

Background

Clinical studies suggest that local wall shear stress (WSS) patterns modulate the site and the progression of atherosclerotic lesions. Computational fluid dynamics (CFD) methods based on in-vivo three-dimensional vessel reconstructions have recently been shown to provide prognostically relevant WSS data. This approach is, however, complex and time-consuming. Methodological simplifications are desirable in porting this approach from bench to bedside. The impact of such simplifications on the accuracy of geometry and wall shear stress calculations has to be investigated.

Methods

We investigated the influence of two methods of lumen reconstruction, assuming circular versus elliptical cross-sections and using different resolutions for the cross-section reconstructions along the vessel axis. Three right coronary arteries were used, of which one represented a normal coronary artery, one with "obstructive", and one with "dilated" coronary atherosclerosis. The vessel volume reconstruction was performed with three-dimensional (3D) data from a previously validated 3D angiographic reconstruction of vessel cross-sections and vessel axis.

Results

The difference between the two vessel volumes calculated using the two evaluated methods is less than 1 %. The difference, of the calculated pressure loss, was between 2.5% and 8.5% for the evaluated methods. The distributions of the WSS histograms were nearly identical and strongly cross-correlated (0.91–0.95). The good agreement of the results was confirmed by a Chi-square test.

Conclusion

A simplified approach to the reconstruction of coronary vessel lumina, using circular cross-sections and a reduced axial resolution of about 0.8 mm along the vessel axis, yields sufficiently accurate calculations of WSS.
Combined IL-21 and Low-Dose IL-2 therapy induces anti-tumor immunity and long-term curative effects in a murine melanoma tumor model
Authors: He Hong , Wisner Preya , Yang Guojun , Hu Hong-Ming , Haley Dan , Miller William , O'Hara Aisling , Alvord W Gregory , Clegg Christopher H , Fox Bernard A , Urba Walter J , Walker Edwin B
Published: June 2006

Background

In vivo studies have recently demonstrated that interleukin 21 (IL-21) enhances the anti-tumor function of T-cells and NK cells in murine tumor models, and the combined use of IL-21 and IL-15 has resulted in prolonged tumor regression and survival in mice with previously established tumors. However, the combined anti-tumor effects of IL-21 and low dose IL-2 have not been studied even though IL-2 has been approved for human use, and, at low dose administration, stimulates the proliferation of memory T cells, and does not significantly increase antigen-induced apoptosis or regulatory T cell (Treg) expansion. This study examined whether recombinant IL-21 alone or in combination with low-dose IL-2 could improve the in vivo anti-tumor function of naïve, tumor-antigen specific CD8+T cells in a gp10025–33T cell receptor transgenic pmel murine melanoma model.

Methods

Congenic C57BL/6 (Ly5.2) mice bearing subcutaneous B16F10 melanoma tumors were sublethally irradiated to induce lymphopenia. After irradiation naive pmel splenocytes were adoptively transferred, and mice were immunized with bone marrow-derived dendritic cells pulsed with human gp10025–33(hgp10025–33). Seven days after vaccination groups of mice received 5 consecutive days of intraperitoneal administration of IL-2 alone (20 × 103IU), IL-21 alone (20 μg) or IL-21 and IL-2. Control animals received no cytokine therapy.

Results

IL-21 alone and IL-2 alone both delayed tumor progression, but only IL-21 significantly augmented long-term survival (20%) compared to the control group. However, combination therapy with IL-21 and IL-2 resulted in the highest long-term (>150 days) tumor-free survival frequency of 46%. Animals that were tumor-free for > 150 days demonstrated tumor-specific protection after rechallenge with B16F10 melanoma cells. At peak expansion (21 days post vaccination), the combination of IL-21 plus IL-2 resulted in a 2- to 3-fold higher absolute number of circulating tumor antigen-specific pmel CD8+T cells than was stimulated by IL-2 or IL-21 alone. Pmel CD8+T cells were predominantly partitioned into central memory (CD62L+/CD127+) or effector-memory (CD62L-/CD127+) phenotypes by day 28-post vaccination in IL-21 + IL-2 treated mice.

Conclusion

These observations support the potential use of IL-21 and low-dose IL-2 therapy in combination with a tumor-antigen vaccine and lymphopenic conditioning in future cancer clinical trials to maintain high numbers of anti-tumor memory CD8+T cells with the potential to sustain long term tumor regression and survival.
Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts
Authors: Connor Alison M , Berger Stuart , Narendran Aru , Keystone Edward C
Published: June 2006

Statins, competitive inhibitors of hydroxymethylglutaryl-CoA reductase, have recently been shown to have a therapeutic effect in rheumatoid arthritis (RA). In RA, synovial fibroblasts in the synovial lining, are believed to be particularly important in the pathogenesis of disease because they recruit leukocytes into the synovium and secrete angiogenesis-promoting molecules and proteases that degrade extracellular matrix. In this study, we show a marked reduction in RA synovial fibroblast survival through the induction of apoptosis when the cells were cultured with statins. Simvastatin was more effective in RA synovial fibroblasts than atorvastatin, and both statins were more potent on tumor necrosis factor-α-induced cells. In contrast, in osteoarthritis synovial fibroblasts, neither the statin nor the activation state of the cell contributed to the efficacy of apoptosis induction. Viability of statin-treated cells could be rescued by geranylgeraniol but not by farnesol, suggesting a requirement for a geranylgeranylated protein for synovial fibroblast survival. Phase partitioning experiments confirmed that in the presence of statin, geranylgeranylated proteins are redistributed to the cytoplasm. siRNA experiments demonstrated a role for Rac1 in synovial fibroblast survival. Western blotting showed that the activated phosphorylated form of Akt, a protein previously implicated in RA synovial fibroblast survival, was decreased by about 75%. The results presented in this study lend further support to the importance of elevated pAkt levels to RA synovial fibroblast survival and suggest that statins might have a beneficial role in reducing the aberrant pAkt levels in patients with RA. The results may also partly explain the therapeutic effect of atorvastatin in patients with RA.
Space-cohort Bayesian models in ecological studies
Authors: Catelan Dolores , Biggeri Annibale , Dreassi Emanuela , Lagazio Corrado
Published: June 2006

The ecological association between ‘low educational level′ and lung cancer mortality, both recorded at municipality level, is investigated. Six birth cohorts were retained from 1905 to 1940. Education data were derived from censuses of the period 1921-91. The education score was defined as prevalence of less educated people and was measured on a relative scale, defining a different threshold for ‘low educational level′ at each census. Four potentially relevant ages at first exposure were defined (20, 30, 40,50) to explore the temporal pattern of the disease. Thus, mortality in each cohort was matched to relative education at different periods corresponding to different ages at first exposure. The relevance of each age at first exposure and the degree of association between education and lung cancer mortality (males, Tuscany, 1971-99) were evaluated, defining a set of hierarchical Bayesian models, each corresponding to a different aetiologic hypothesis. Results show an inverse relationship between low education score and mortality for lung cancer, whose intensity decreases by cohort and becomes positive in the last one. This association was more evident for age at first exposure in the range 20-30 years. These results are consistent with the epidemiological transition of risk factors among socioeconomic classes and are coherent with the biological model of initiating carcinogen agents.
Estimation and filtering by reversible jump MCMC for a doubly stochastic Poisson model for ultra-high-frequency financial data
Authors: Centanni S , Minozzo M
Published: June 2006

We propose a modeling framework for ultra-high-frequency data on financial asset price movements. The models proposed belong to the class of the doubly stochastic Poisson processes with marks and allow an interpretation of the changes in price volatility and trading activity in terms of news or information arrival. Assuming that the intensity process underlying event arrivals is unobserved by market agents, we propose a signal extraction (filtering) method based on the reversible jump Markov chain Monte Carlo algorithm. Moreover, given a realization of the price process, inference on the parameters can be performed by appealing to stochastic versions of the expectation-maximization algorithm. The simulation methods proposed will be applied to the computation of hedging strategies and derivative prices.
Visceral Adiposity and Endothelial Lipase
Authors: Paradis Marie-Eve , Badellino Karen O. , Rader Daniel J. , Tchernof André , Richard Christian , Luu-The Van , Deshaies Yves , Bergeron Jean , Archer Wiedad R. , Couture Patrick , Bergeron Nathalie , Lamarche Benoı̂t
Published: June 2006

Context: Overexpression of endothelial lipase (EL) has been shown to reduce plasma high-density lipoprotein cholesterol levels in animal models. However, the extent to which EL contributes to modulate the deteriorated high-density lipoprotein profile observed in obesity in humans is less clear.

Objectives: The objectives of this study were to investigate the association between levels of obesity and visceral adiposity in particular and plasma EL concentrations.

Methods: Postheparin plasma EL concentrations were measured by ELISA and visceral adiposity by computed tomography in a sample of 80 sedentary men in good health. EL mRNA levels in abdominal sc and omental adipose tissues obtained during abdominal hysterectomies were measured in another sample of 14 women.

Results: Plasma EL levels were positively correlated with body mass index (R = 0.46, P < 0.0001), visceral adipose tissue accumulation (R = 0.44, P < 0.0001), and a proatherogenic lipid profile including increased plasma cholesterol and triglycerides. However, EL mRNA levels were similar in sc and omental AT and were 10,000-fold lower than lipoprotein lipase mRNA levels in those tissues.

Conclusions: Increased visceral adiposity is significantly correlated with elevated plasma EL levels, but this association is unlikely to be causal and may reflect other common metabolic alterations.
Integration of Prolactin and Glucocorticoid Signaling at the β-Casein Promoter and Enhancer by Ordered Recruitment of Specific Transcription Factors and Chromatin Modifiers
Authors: Kabotyanski Elena B. , Huetter Markus , Xian Wa , Rijnkels Monique , Rosen Jeffrey M.
Published: June 2006

Lactogenic hormone regulation of β-casein gene expression in mammary epithelial cells provides an excellent system in which to perform kinetic studies of chromatin remodeling and transcriptional activation. Using HC11 cells as a model, we have investigated the effects of prolactin (Prl) and glucocorticoids both singly and in combination at different time points after hormone treatment. Using chromatin immunoprecipitation analysis, we have determined the dynamics of assembly and disassembly of signal transducer and activator of transcription 5, glucocorticoid receptor, CCAAT enhancer binding protein β, and Ying Yang-1 at the hormonally activated β-casein proximal promoter as well as the distal mouse β-casein enhancer located approximately −6 kb upstream of the transcription start site. Prl alone resulted in a rapid recruitment of both signal transducer and activator of transcription 5 and histone deacetylase 1 to the β-casein promoter and enhancer, and reciprocally the dissociation of Ying Yang-1 from the proximal promoter. In addition, we have examined the recruitment of coactivator p300 and determined chromatin acetylation status as a function of hormonal treatment. Finally, we have established the time course of RNA polymerase II and phospho-RNA polymerase II accumulation at the β-casein promoter and enhancer after stimulation with hydrocortisone and Prl. Although glucocorticoids alone led to a rapid increase in histone H3 acetylation, treatment with both hormones was required for stable association of p300 and phospho-RNA polymerase II at both the promoter and enhancer. Collectively, these data suggest a model for the assembly of a multiprotein complex that helps to define how the signaling pathways controlled by these lactogenic hormones are integrated to regulate β-casein gene expression.
Microtubule plus-end loading of p150Glued is mediated by EB1 and CLIP-170 but is not required for intracellular membrane traffic in mammalian cells
Authors: Watson Peter , Stephens David J.
Published: June 2006

Microtubule dynamics and function are regulated, at least in part, by a family of proteins that localize to microtubule plus-ends, and include EB1, CLIP-170 and the dynactin component p150Glued. Plus-end pools of these proteins, notably dynactin, have been invoked in a number of `search-and-capture' mechanisms, including the attachment of microtubules to kinetochores during mitosis and to endomembranes prior to the initiation of intracellular transport. Here we show that, in mammalian cells, EB1 is required for the plus-end localization of CLIP-170, and that this is in turn required to localize p150Glued to plus-ends. Specific depletion of CLIP-170 results in defects in microtubule dynamics, cell polarization in response to scratch wounding and a loss of p150Glued from plus ends. By contrast, removal of p150Glued from plus-ends by depletion of either EB1 or CLIP-170 caused no defects in the localization of intracellular organelles, the dynamics of ER-to-Golgi transport, the efficiency of transferrin uptake or the motility of early endosomes or lysosomes. In addition to labelling microtubule plus-ends, we show that GFP-p150Glued becomes incorporated into the dynactin complex and labels small, highly dynamic, punctate structures that move along microtubules. A subset of these structures colocalizes with ER-Golgi transport intermediates. Together, these data show that the function of CLIP-170 and p150Glued in membrane trafficking is not associated with their plus-end localization.
Expression of disease-causing lamin A mutants impairs the formation of DNA repair foci
Authors: Manju Kaliyaperumal , Muralikrishna Bhattiprolu , Parnaik Veena K
Published: June 2006

A-type lamins are components of the nuclear lamina. Mutations in the gene encoding lamin A are associated with a range of highly degenerative diseases termed laminopathies. To evaluate sensitivity to DNA damage, GFP-tagged lamin A cDNAs with disease-causing mutations were expressed in HeLa cells. The inner nuclear membrane protein emerin was mislocalised upon expression of the muscular dystrophy mutants G232E, Q294P or R386K, which aberrantly assembled into nuclear aggregates, or upon expression of mutants causing progeria syndromes in vivo (lamin A del50, R471C, R527C and L530P). The ability of cells expressing these mutants to form DNA repair foci comprising phosphorylated H2AX in response to mild doses of cisplatin or UV irradiation was markedly diminished, unlike the nearly normal response of cells expressing wild-type GFP-lamin A or disease-causing H222P and R482L mutants. Interestingly, mutants that impaired the formation of DNA repair foci mislocalised ATR (for `ataxia telangiectasia-mutated and Rad3-related') kinase, which is a key sensor in the response to DNA damage. Our results suggest that a subset of lamin A mutants might hinder the response of components of the DNA repair machinery to DNA damage by altering interactions with chromatin.
Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism
Authors: Zhou Feng-Quan , Walzer Mark , Wu Yao-Hong , Zhou Jiang , Dedhar Shoukat , Snider William D.
Published: June 2006

Chondroitin sulfate proteoglycans (CSPGs) and myelin-based inhibitors are the most studied inhibitory molecules in the adult central nervous system. Unlike myelin-based inhibitors, few studies have reported ways to overcome the inhibitory effect of CSPGs. Here, by using regenerating adult dorsal root ganglion (DRG) neurons, we show that chondroitin sulfate proteoglycans inhibit axon assembly by a different mechanism from myelin-based inhibitors. Furthermore, we show that neither Rho inhibition nor cAMP elevation rescues extracellular factor-induced axon assembly inhibited by CSPGs. Instead, our data suggest that CSPGs block axon assembly by interfering with integrin signaling. Surprisingly, we find that nerve growth factor (NGF) promotes robust axon growth of regenerating DRG neurons over CSPGs. We have found that, unlike naive neurons that require simultaneous activation of neurotrophin and integrin pathways for axon assembly, either neurotrophin or integrin signaling alone is sufficient to induce axon assembly of regenerating neurons. Thus, our results suggest that the ability of NGF to overcome CSPG inhibition in regenerating neurons is probably due to the ability of regenerating neurons to assemble axons using an integrin-independent pathway. Finally, our data show that the GSK-3β-APC pathway, previously shown to mediate developing axon growth, is also necessary for axon regeneration.
Exact and heuristic algorithms for staged cutting problems
Authors: Cui Y , Wang Z , Li J
Published: June 2006

This paper presents exact and heuristic algorithms for unconstrained staged cutting problems. For a k-stage pattern, a group of parallel cuts at the final stage divide the sheet into several segments. For the k-stage pattern on the sheet to be optimal, the pattern on each segment must be an optimal ( k - 1)-stage pattern. Assume that the optimal ( k - 2)-stage patterns are known ( k 3); the exact algorithm solves one knapsack problem for each segment to obtain the optimal ( k - 1)-stage pattern on the segment and determines the optimal k-stage pattern on the sheet by solving one additional knapsack problem. The exact algorithm uses general strips, which consists of blanks of different sizes, whereas the heuristic algorithm uses uniform strips, each one of which contains only blanks of the same size. The computational results indicate that the algorithms are more efficient than other algorithms tested.
The isolated perfused rat liver: standardization of a time-honoured model
Authors: Bessems M , 't Hart N A , Tolba R , Doorschodt B M , Leuvenink H G D , Ploeg R J , Minor T , van Gulik T M
Published: June 2006

For many years, the isolated perfused rat liver (IPRL) model has been used to investigate the physiology and pathophysiology of the rat liver. This in vitro model provides the opportunity to assess cellular injury and liver function in an isolated setting. This review offers an update of recent developments regarding the IPRL set-up as well as the viability parameters that are used, with regards to liver preservation and ischaemia and reperfusion mechanisms.

A review of the literature was performed into studies regarding liver preservation or liver ischaemia and reperfusion. An overview of the literature is given with particular emphasis on perfusate type and volume, reperfusion pressure, flow, temperature, duration of perfusion, oxygenation and on applicable viability parameters (liver damage and function).

The choice of IPRL set-up depends on the question examined and on the parameters of interest. A standard technique is cannulation of the portal vein, bile duct and caval vein with pressure-controlled perfusion at 20 cm H2O (15 mmHg) to reach a perfusion flow of approximately 3 mL/min/g liver weight. The preferred perfusion solution is Krebs–Henseleit buffer, without albumin. The usual volume is 150–300 cm3, oxygenated to a pO2 of more than 500 mmHg. The temperature of the perfusate is maintained at 37°C. Standardized markers should be used to allow comparison with other experiments.
Laboratory environments and rodents' behavioural needs: a review
Authors: Balcombe J P
Published: June 2006

Laboratory housing conditions have significant physiological and psychological effects on rodents, raising both scientific and humane concerns. Published studies of rats, mice and other rodents were reviewed to document behavioural and psychological problems attributable to predominant laboratory housing conditions. Studies indicate that rats and mice value opportunities to take cover, build nests, explore, gain social contact, and exercise some control over their social milieu, and that the inability to satisfy these needs is physically and psychologically detrimental, leading to impaired brain development and behavioural anomalies (e.g. stereotypies). To the extent that space is a means to gain access to such resources, spatial confinement likely exacerbates these deficits. Adding environmental 'enrichments' to small cages reduces but does not eliminate these problems, and I argue that substantial changes in housing and husbandry conditions would be needed to further reduce them.
The effect of different doses of cisplatin on the pharmacokinetic parameters of cefepime in mice
Authors: Máthé András , Komka Kinga , Forczig Mónika , Szabó Dóra , Anderlik Piroska , Rozgonyi Ferenc
Published: June 2006

The simulation of human serum levels is essential in animal models to extrapolate the experimental results to clinical practice. Administration of a nephrotoxic drug such as cisplatin can be used to cause renal dysfunction as an approach to mimic human serum levels of renally excreted drugs. We aimed to determine the dose of cisplatin that did not affect the survival rate of mice and to achieve human-like serum concentrations of cefepime. Different doses of cisplatin (0, 10, 14, 18, 22 and 26 mg/kg) were given by intraperitoneal (i.p.) injection to mice three days prior to the i.p. administration of 80 mg/kg cefepime. With cisplatin doses of 18 and 22 mg/kg, the half-life of cefepime was significantly prolonged ( P<0.001) and all mice survived. The pretreatment with 26 mg/kg cisplatin significantly decreased survival ( P=0.001), but the half-life of cefepime was not significantly longer than of 18 mg/kg cisplatin. Serum levels of cefepime after the pretreatment with 18 mg/kg cisplatin were comparable to published human data. The administration of cisplatin appears to be a suitable method in mice for simulating human serum concentrations of renally excreted drugs.
Successful Treatment and Cerebrospinal Fluid Penetration of Oral Linezolid in a Patient with Coagulase-Negative Staphylococcus Ventriculitis
Authors: Boak Lauren M , Li Jian , Spelman Denis , du Cros Philipp , Nation Roger L , Rayner Craig R
Published: June 2006

Objective:

TO describe a case of coagulase-negative Staphylococcus ventriculitis successfully treated with oral linezolid, for which good cerebrospinal fluid (CSF) penetration was observed.

Case Summary:

A 69-year-old man had an extraventricular drain inserted following a right cerebellar infarct. On day 6, the CSF culture was positive for coagulase-negative staphylococci; intravenous vancomycin 1 g daily was initiated to treat ventriculitis. A ventriculoperitoneal shunt, inserted on day 35 to manage communicating hydrocephalus, was subsequently removed as symptoms suggesting infection presented. Coagulase-negative Staphylococcus was isolated from shunt reservoir aspirate, and intrathecal vancomycin 10 mg daily was added to the treatment regimen. On day 61, vancomycin was stopped and oral linezolid 600 mg twice daily was started. Linezolid was discontinued 22 days later, with no evidence of ongoing infection. Four blood samples were collected around the seventh dose of linezolid and 5 CSF samples were collected on separate days during treatment. Linezolid concentrations were measured in plasma and CSF by HPLC. Using an ADAPT II maximum a priori Bayesian estimator module, a 2 compartment pharmacokinetic model was fitted to the plasma linezolid concentration data and CSF:predicted plasma concentration ratios (ranging from 0.27 to 1.02) were derived. All CSF concentrations exceeded the reported 90% minimum inhibitory concentration of 2 mg/L for linezolid against coagulase-negative staphylococci.

Discussion:

Evidence of the effectiveness of linezolid against central nervous system infections is growing; however, limited data exist describing its CSF penetration. Oral linezolid exhibited good CSF penetration in this patient, which corresponded to positive clinical response.

Conclusions:

Oral linezolid may play a valuable role in the treatment of multiresistant gram-positive central nervous system infections.