bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential
Authors: Araki Hiroto , Yoshinaga Kazumi , Boccuni Piernicola , Zhao Yan , Hoffman Ronald , Mahmud Nadim 
Published: December 2006

Abstract
Human hematopoietic stem cells (HSCs) exposed to cytokines in vitro rapidly divide and lose their characteristic functional properties presumably due to the alteration of a genetic program that determines the properties of an HSC. We have attempted to reverse the silencing of this HSC genetic program by the sequential treatment of human cord blood CD34+ cells with the chromatin-modifying agents, 5-aza-2′-deoxycytidine (5azaD) and trichostatin A (TSA). We determined that all CD34+CD90+ cells treated with 5azaD/TSA and cytokines after 9 days of incubation divide, but to a lesser degree than cells exposed to only cytokines. When CD34+CD90+ cells that have undergone extensive number of cell divisions (5-10) in the presence of cytokines alone were transplanted into immunodeficient mice, donor cell chimerism was not detectable. By contrast, 5azaD/TSA-treated cells that have undergone similar numbers of cell divisions retained their marrow repopulating potential. The expression of several genes and their products previously implicated in HSC self-renewal were up-regulated in the cells treated with 5azaD/TSA as compared to cells exposed to cytokines alone. These data indicate that HSC treated with chromatin-modifying agents are capable of undergoing repeated cell divisions in vitro while retaining their marrow-repopulating potential.
Molecular basis of glutathione reductase deficiency in human blood cells
Authors: Kamerbeek Nanne M. , van Zwieten Rob , de Boer Martin , Morren Gert , Vuil Herma , Bannink Natalja , Lincke Carsten , Dolman Koert M. , Becker Katja , Heiner Schirmer R. , Gromer Stephan , Roos Dirk 
Published: December 2006

Abstract
Hereditary glutathione reductase (GR) deficiency was found in only 2 cases when testing more than 15 000 blood samples. We have investigated the blood cells of 2 patients (1a and 1b) in a previously described family suffering from favism and cataract and of a novel patient (2) presenting with severe neonatal jaundice. Red blood cells and leukocytes of the patients in family 1 did not contain any GR activity, and the GR protein was undetectable by Western blotting. Owing to a 2246-bp deletion in the patients' DNA, translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme. The red blood cells from patient 2 did not exhibit GR activity either, but the patient's leukocytes contained some residual activity that correlated with a weak protein expression. Patient 2 was found to be a compound heterozygote, with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the superfamily of NAD(P)H-dependent disulfide reductases, into alanine on the other allele. Studies on recombinant GR G330A revealed a drastically impaired thermostability of the protein. This is the first identification of mutations in the GR gene causing clinical GR deficiency.
Induced hypertension for the treatment of acute MCA occlusion beyond the thrombolysis window: case report
Authors: Bogoslovsky Tanya , Häppölä Olli , Salonen Oili , Lindsberg Perttu J 
Published: December 2006

Abstract

Background
A minority of stroke patients is eligible for thrombolytic therapy. Small pilot case series have hinted that elevation of incident arterial blood pressure might be associated with a favorable prognosis either in acute or subacute stroke. However, these patients were not considered for thrombolytic therapy and were not followed – up systematically. We used pharmacologically induced hypertension in a stroke patient with middle cerebral artery (MCA) occlusion ineligible for thrombolysis that was followed-up by radiological, clinical and functional outcome assessment.

Case presentation
A patient with acute embolic MCA occlusion producing a large, ischemic penumbra confirmed by perfusion CT was treated by induced hypertension with phenylephrine started within 4 h of admission. Increase in the mean arterial pressure by 20% led to a reduction of neurological deficit by 3 points on the National Institute of Stroke Scale. MRI and CT scans performed during phenylephrine infusion showed the presence of limited subcortical and cortical infarct changes that were clearly less extensive than the perfusion deficit in the brain perfusion CT at baseline, found in the absence of MCA patency. No complications due to induced hypertension therapy occurred. Moderate functional improvement up to modified Rankin scale 2 at follow up took place.

Conclusion
Induced hypertension in acute ischemic stroke seems clinically feasible and may be beneficial in selected normo- or hypotensive stroke patients not eligible for thrombolytic recanalization therapy.
The role of sexually transmitted infections in male circumcision effectiveness against HIV – insights from clinical trial simulation
Authors: Desai Kamal , Boily Marie-Claude , Garnett Geoff P , Mâsse Benoît R , Moses Stephen , Bailey Robert C 
Published: December 2006

Abstract
Background
A landmark randomised trial of male circumcision (MC) in Orange Farm, South Africa recently showed a large and significant reduction in risk of HIV infection, reporting MC effectiveness of 61% (95% CI: 34%–77%). Additionally, two further randomised trials of MC in Kisumu, Kenya and Rakai, Uganda were recently stopped early to report 53% and 48% effectiveness, respectively. Since MC may protect against both HIV and certain sexually transmitted infections (STI), which are themselves cofactors of HIV infection, an important question is the extent to which this estimated effectiveness against HIV is mediated by the protective effect of circumcision against STI. The answer lies in the trial data if the appropriate statistical analyses can be identified to estimate the separate efficacies against HIV and STI, which combine to determine overall effectiveness.

Objectives and Methods
Focusing on the MC trial in Kisumu, we used a stochastic prevention trial simulator (1) to determine whether statistical analyses can validly estimate efficacy, (2) to determine whether MC efficacy against STI alone can produce large effectiveness against HIV and (3) to estimate the fraction of all HIV infections prevented that are attributable to efficacy against STI when both efficacies combine.

Results
Valid estimation of separate efficacies against HIV and STI as well as MC effectiveness is feasible with available STI and HIV trial data, under Kisumu trial conditions. Under our parameter assumptions, high overall effectiveness of MC against HIV was observed only with a high MC efficacy against HIV and was not possible on the basis of MC efficacy against STI alone. The fraction of all HIV infections prevented which were attributable to MC efficacy against STI was small, except when efficacy of MC specifically against HIV was very low. In the three MC trials which reported between 48% and 61% effectiveness (combining STI and HIV efficacies), the fraction of HIV infections prevented in circumcised males which were attributable to STI was unlikely to be more than 10% to 20%.

Conclusion
Estimation of efficacy, attributable fraction and effectiveness leads to improved understanding of trial results, gives trial results greater external validity and is essential to determine the broader public health impact of circumcision to men and women.
The role of cholesterol and sphingolipids in chemokine receptor function and HIV-1 envelope glycoprotein-mediated fusion
Authors: Ablan Sherimay , Rawat Satinder S , Viard Mathias , Wang Ji Ming , Puri Anu , Blumenthal Robert 
Published: December 2006

Abstract

Background
HIV-1 entry into cells is a multifaceted process involving target cell CD4 and the chemokine receptors, CXCR4 or CCR5. The lipid composition of the host cell plays a significant role in the HIV fusion process as it orchestrates the appropriate disposition of CD4 and co-receptors required for HIV-1 envelope glycoprotein (Env)-mediated fusion. The cell membrane is primarily composed of sphingolipids and cholesterol. The effects of lipid modulation on CD4 disposition in the membrane and their role in HIV-1 entry have extensively been studied. To focus on the role of lipid composition on chemokine receptor function, we have by-passed the CD4 requirement for HIV-1 Env-mediated fusion by using a CD4-independent strain of HIV-1 Env.

Results
Cell fusion mediated by a CD4-independent strain of HIV-1 Env was monitored by observing dye transfer between Env-expressing cells and NIH3T3 cells bearing CXCR4 or CCR5 in the presence or absence of CD4. Chemokine receptor signaling was assessed by monitoring changes in intracellular [Ca2+] mobilization induced by CCR5 or CXCR4 ligand. To modulate target membrane cholesterol or sphingolipids we used Methyl-β-cyclodextrin (MβCD) or 1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP), respectively. Treatment of the target cells with these agents did not change the levels of CD4 or CXCR4, but reduced levels of CCR5 on the cell surface. Chemokine receptor signalling was inhibited by cholesterol removal but not by treatment with PPMP. HIV-1 Env mediated fusion was inhibited by >50% by cholesterol removal. Overall, PPMP treatment appeared to slow down the rates of CD4-independent HIV-1 Env-mediated Fusion. However, in the case of CXCR4-dependent fusion, the differences between untreated and PPMP-treated cells did not appear to be significant.

Conclusion
Although modulation of cholesterol and sphingolipids has similar effects on CD4 -dependent HIV-1 Env-mediated fusion, sphingolipid modulation had little effect on CD4-independent HIV-1 Env-mediated fusion. Chemokine receptor function remained intact following treatment of cells with PPMP. Therefore such treatment may be considered a more suitable agent to inhibit CD4 dependent HIV-1 infection.
Breastfeeding duration in mothers who express breast milk: a cohort study
Authors: Win Nwet N , Binns Colin W , Zhao Yun , Scott Jane A , Oddy Wendy H 
Published: December 2006

Abstract

Background
The expression of breast milk allows a mother to be away intermittently from her infant while continuing to breastfeed. The aim of this study was to investigate the association between expression of breast milk and breastfeeding duration

Methods
A cohort study of 12 months duration. The mothers were recruited from two public maternity hospitals in Perth, Australia between mid-September 2002 and mid-July 2003. While in hospital, participating mothers completed a questionnaire that included questions on how they were feeding their newborn. Telephone interviews conducted at regular periods monitored changes in infant feeding practices, including expression of breast milk. Multivariate Cox regression analysis was used to explore the association between breast milk expression and the duration of any breastfeeding.

Results
A total of 587 mothers, or 55% of those eligible, participated in the study. Of these 93.5% were breastfeeding at discharge from hospital. Mothers who expressed breast milk (at one or more time periods) were less likely to discontinue any breastfeeding before six months (Relative Risk 0.71, 95% CI 0.52, 0.98) than those who had never expressed milk.

Conclusion
This study found that mothers who express breast milk are more likely to breastfeed to six months (any breastfeeding). While further research is required in different cultures to confirm these results, the appropriate use of expressed breast milk may be a means to help mothers to achieve six months of full breastfeeding while giving more lifestyle options.
CyberKnife® radiosurgery in the treatment of complex skull base tumors: analysis of treatment planning parameters
Authors: Collins Sean P , Coppa Nicholas D , Zhang Ying , Collins Brian T , McRae Donald A , Jean Walter C 
Published: December 2006

Abstract

Background
Tumors of the skull base pose unique challenges to radiosurgical treatment because of their irregular shapes, proximity to critical structures and variable tumor volumes. In this study, we investigate whether acceptable treatment plans with excellent conformity and homogeneity can be generated for complex skull base tumors using the Cyberknife® radiosurgical system.

Methods
At Georgetown University Hospital from March 2002 through May 2005, the CyberKnife® was used to treat 80 patients with 82 base of skull lesions. Tumors were classified as simple or complex based on their proximity to adjacent critical structures. All planning and treatments were performed by the same radiosurgery team with the goal of minimizing dosage to adjacent critical structures and maximizing target coverage. Treatments were fractionated to allow for safer delivery of radiation to both large tumors and tumors in close proximity to critical structures.

Results
The CyberKnife® treatment planning system was capable of generating highly conformal and homogeneous plans for complex skull base tumors. The treatment planning parameters did not significantly vary between spherical and non-spherical target volumes. The treatment parameters obtained from the plans of the complex base of skull group, including new conformity index, homogeneity index and percentage tumor coverage, were not significantly different from those of the simple group.

Conclusion
Our data indicate that CyberKnife® treatment plans with excellent homogeneity, conformity and percent target coverage can be obtained for complex skull base tumors. Longer follow-up will be required to determine the safety and efficacy of fractionated treatment of these lesions with this radiosurgical system.
The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis
Authors: Bondeson Jan , Wainwright Shane D , Lauder Sarah , Amos Nick , Hughes Clare E 
Published: December 2006

AbstractThere is an increasing body of evidence that synovitis plays a role in the progression of osteoarthritis and that overproduction of cytokines and growth factors from the inflamed synovium can influence the production of degradative enzymes and the destruction of cartilage. In this study, we investigate the role of synovial macrophages and their main proinflammatory cytokines, interleukin (IL)-1 and tumour necrosis factor-alpha (TNF-α), in driving osteoarthritis synovitis and influencing the production of other pro- and anti-inflammatory cytokines, production of matrix metalloproteinases, and expression of aggrecanases in the osteoarthritis synovium. We established a model of cultures of synovial cells from digested osteoarthritis synovium derived from patients undergoing knee or hip arthroplasties. By means of anti-CD14-conjugated magnetic beads, specific depletion of osteoarthritis synovial macrophages from these cultures could be achieved. The CD14+-depleted cultures no longer produced significant amounts of macrophage-derived cytokines like IL-1 and TNF-α. Interestingly, there was also significant downregulation of several cytokines, such as IL-6 and IL-8 (p < 0.001) and matrix metalloproteinases 1 and 3 (p < 0.01), produced chiefly by synovial fibroblasts. To investigate the mechanisms involved, we went on to use specific downregulation of IL-1 and/or TNF-α in these osteoarthritis cultures of synovial cells. The results indicated that neutralisation of both IL-1 and TNF-α was needed to achieve a degree of cytokine (IL-6, IL-8, and monocyte chemoattractant protein-1) and matrix metalloproteinase (1, 3, 9, and 13) inhibition, as assessed by enzyme-linked immunosorbent assay and by reverse transcription-polymerase chain reaction (RT-PCR), similar to that observed in CD14+-depleted cultures. Another interesting observation was that in these osteoarthritis cultures of synovial cells, IL-1β production was independent of TNF-α, in contrast to the situation in rheumatoid arthritis. Using RT-PCR, we also demonstrated that whereas the ADAMTS4 (a disintegrin and metalloprotease with thrombospondin motifs 4) aggrecanase was driven mainly by TNF-α, ADAMTS5 was not affected by neutralisation of IL-1 and/or TNF-α. These results suggest that, in the osteoarthritis synovium, both inflammatory and destructive responses are dependent largely on macrophages and that these effects are cytokine-driven through a combination of IL-1 and TNF-α.
Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins
Authors: Piccard Helene , Van den Steen Philippe E , Opdenakker Ghislain 
Published: December 2006

AbstractThe heme-binding hemopexin consists of two, four-bladed propeller domains connected by a linker region. Hemopexin domains are found in different species on the phylogenetic tree and in the human species represented in hemopexin, matrix metalloproteinases (MMPs), vitronectin, and products of the proteoglycan 4 gene. Hemopexin and hemopexin domains of human proteins fulfill functions in activation of MMPs, inhibition of MMPs, dimerization, binding of substrates or ligands, cleavage of substrates, and endocytosis by low-density lipoprotein receptor-related protein-1 (LRP-1; CD91) and LRP-2 (megalin, GP330). Insights into the structures and functions of hemopexin (domains) form the basis for positive or negative interference with the formation of molecular complexes and hence, might be exploited therapeutically in inflammation, cancer, and wound healing.
Cost Consequences of Implementing an Electronic Decision Support System for Ordering Laboratory Tests in Primary Care: Evidence from a Controlled Prospective Study in The Netherlands
Authors: Poley Marten J , Edelenbos Kyra I , Mosseveld Mees , van Wijk Marc AM , de Bakker Dinny H , van der Lei Johan , Rutten-van Mölken Maureen PMH 
Published: December 2006

Abstract
Background: The economic consequences of interventions to promote rational, evidence-based use of laboratory tests by physicians are not yet fully understood. We evaluated the cost consequences of a computer-based, guideline-driven decision-support system (CDSS) for ordering blood tests in primary care.
Methods: We installed the CDSS in 118 practices [159 general practitioners (GPs)] throughout The Netherlands and calculated the costs of the intervention in this group. During a period of 6 months before and 6 months after installation of the CDSS, the test-ordering behavior of 87 (109 GPs) of these 118 study practices was studied and the results were compared with those of a nonhistorical control group that did not receive the CDSS. In addition the costs of laboratory requests were calculated for both groups.
Results: Total intervention costs, comprising development costs and installation costs, amounted to €79 000 (€670 per practice). Whereas the introduction of the CDSS did not affect the number of order forms submitted to the laboratories, it did reduce the number of blood tests per order form. As a result, the CDSS yielded mean savings on the costs of laboratory requests of €847 per practice per 6 months.
Conclusions: This study demonstrates that providing electronic decision support for ordering blood tests in primary care represents an economically promising concept. Savings on laboratory costs are achievable and not offset by disproportionally high intervention costs.
Lateral Flow Immunoassay Using Europium (III) Chelate Microparticles and Time-Resolved Fluorescence for Eosinophils and Neutrophils in Whole Blood
Authors: Rundström Gerd , Jonsson Ann , Mårtensson Ola , Mendel-Hartvig Ib , Venge Per 
Published: December 2006

AbstractBackground: A simple point-of-care method for measuring leukocyte counts in a doctor’s office or emergency room could be of great importance. We developed a protocol for measuring cell count by disrupting the cell membrane and analyzing specific proteins within the cells and used it to analyze proteins from eosinophils and neutrophils.Methods: Lateral immunochromatographic (ICR) assays have been developed for eosinophil protein X (EPX) and human neutrophil lipocalin (HNL) as measures of the concentration of eosinophils and neutrophils. The correlation between the lateral ICR assays and cell counting of eosinophils and neutrophils was performed manually and with an automated cell counter. RIA assays measuring the same analytes were also compared with the results from cell counting and lateral ICR assays.Results: The optimized assays showed analytical detection limits below the clinical ranges of 3.36 μg/L and 2.05 μg/L for EPX and HNL, respectively. The recovery was 114.8%–122.8% for EPX and 94.5%–96.9% for HNL. The imprecision was 3%–17% CV for EPX over the whole range and 5%–16% CV for HNL. The correlation coefficients between manually counted cells and lateral ICR assays were 0.9 and 0.83 for EPX and HNL, respectively.Conclusion: The numbers of eosinophils and neutrophils in small amounts of blood can be estimated in the point-of-care setting by means of fast lateral ICR assays of EPX and HNL.
Circulating Concentrations of Growth-Differentiation Factor 15 in Apparently Healthy Elderly Individuals and Patients with Chronic Heart Failure as Assessed by a New Immunoradiometric Sandwich Assay
Authors: Kempf Tibor , Horn-Wichmann Rüdiger , Brabant Georg , Peter Timo , Allhoff Tim , Klein Gunnar , Drexler Helmut , Johnston Nina , Wallentin Lars , Wollert Kai C 
Published: December 2006

Abstract
Background: Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor β (TGF-β) cytokine superfamily. There has been increasing interest in using circulating GDF15 as a biomarker in patients, for example those with cardiovascular disease.
Methods: We developed an IRMA that uses a polyclonal, affinity chromatography–purified goat antihuman GDF15 IgG antibody, assessed the preanalytic characteristics of GDF15, and determined circulating GDF15 concentrations in 429 apparently healthy elderly individuals and 153 patients with chronic heart failure (CHF).
Results: The assay had a detection limit of 20 ng/L, an intraassay imprecision of ≤10.6%, and an interassay imprecision of ≤12.2%. Specificity was demonstrated with size-exclusion chromatography, parallel measurements with polyclonal and monoclonal anti-GDF15 antibody, and lack of cross-reactivity with TGF-β. The assay was not appreciably influenced by the anticoagulant matrix or unrelated biological substances. GDF15 was stable at room temperature for 48 h and resistant to 4 freeze-thaw cycles. Apparently healthy, elderly individuals presented with a median GDF15 concentration of 762 ng/L (25th–75th percentiles, 600–959 ng/L). GDF15 concentrations were associated with age and with cystatin C and C-reactive protein concentrations. CHF patients had increased GDF15 concentrations that were closely related to disease severity.
Conclusion: The IRMA can detect GDF15 in human serum and plasma with excellent sensitivity and specificity. The reference limits and confounding variables defined for apparently healthy elderly individuals and the favorable preanalytic characteristics of GDF15 are expected to facilitate future studies of GDF15 as a biomarker in various disease settings, including CHF.