bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapy of Falciparum Malaria in Sub-Saharan Africa: from Molecule to Policy
Authors: Winstanley Peter , Ward Stephen , Snow Robert , Breckenridge Alasdair 
Published: July 2004

SUMMARY
The burden of falciparum malaria remains as great as ever, and, as has probably always been the case, it is carried mainly by tropical Africa. Of the various means available for the control of malaria, the use of effective drugs remains the most important and is likely to remain so for a considerable time to come. Unfortunately, the extensive development of resistance by the parasite threatens the utility of most of the affordable classes of drug: the development of novel antimalarials has never been more urgently needed. Any attempt to understand the vast complexities of falciparum malaria in Africa requires an ability to think “from molecule to policy.” In consequence, the review ambitiously tries to examine the current pharmacopeia, the process by which new drugs are developed and the ways in which drugs are actually used, in both the formal and informal health sectors. The informal sector is particularly important in Africa, where around half of all antimalarial treatments are bought from informal outlets and taken at home without supervision by health care professionals: the potential impact of adherence on clinical outcome is discussed. Given that the full costs are carried by the patient in a large proportion of cases, the importance of drug affordability is explored. The review also discusses the splicing of new drugs into national policy. The various parameters that feed into deliberations on changes in drug policy are discussed.
Competency Assessment in the Clinical Microbiology Laboratory
Authors: Sharp Susan E. , Elder B. Laurel 
Published: July 2004

SUMMARY
The laboratory comprises an invaluable part of the total health care provided to patients. Competency assessment is one method by which we can verify that our employees are competent to perform laboratory testing and report accurate and timely results. To derive the greatest benefit from the inclusion of competency assessment in the laboratory, we must be sure that we are addressing areas where our efforts can be best utilized to optimize patient care. To be competent, an employee must know how to perform a test, must have the ability to perform the test, must be able to perform the test properly without supervision, and know when there is a problem with the test that must be solved. In some cases, competency assessment protocols may demonstrate areas of competence but can fail to disclose incompetence. For example, challenges of low-complexity tasks (such as reading the technical procedure manual) are inferior to challenges that measure understanding and execution of a protocol, and poorly designed competency challenges will probably not detect substandard laboratory performance. Thus, if we are to receive the greatest benefit from our competency assessment programs, which may be time-consuming for the supervisors and the staff as well, we must not only meet the letter of the law but also find a way to make these assessments meaningful, instructive, and able to detect areas of concern. As we address competency assessment in our laboratories, we must understand that when done properly, competency assessment will reward our organizations and assist us in providing the best possible care to our patients.
Ergonomic stressors and upper extremity musculoskeletal disorders in automobile manufacturing: a one year follow up study
Authors: Punnett L , Gold J , Katz J N , Gore R , Wegman D H 
Published: July 2004

Aims:To estimate the one year cumulative incidence and persistence of upper extremity (UE) soft tissue disorders, in a fixed cohort of automotive manufacturing workers, and to quantify their associations with ergonomic exposures.Methods:At baseline and at follow up, cases of UE musculoskeletal disorders were determined by interviewer administered questionnaire and standardised physical examination of the upper extremities. The interview obtained new data on psychosocial strain and updated the medical and work histories. An index of exposure to ergonomic stressors, obtained at baseline interview, was the primary independent variable. Cumulative incidence and persistence of UE disorders (defined both by symptoms and by physical examination plus symptoms) were analysed in relation to baseline ergonomic exposures, adjusting for other covariates. The incidence of new disorders was modelled using multivariate proportional hazards regression among workers who were not cases in the first year and the prevalence on both occasions was modelled by repeated measures analysis.Results:A total of 820 workers (69% of eligible cohort members) was examined. Follow up varied slightly by department group but not by baseline exposure level or other characteristics. Among the non-cases at baseline, the cumulative incidence of UE disorders was 14% by symptoms and 12% by symptoms plus examination findings. These rates increased with index of physical exposures primarily among subjects who had the same jobs at follow up as at baseline. Increased exposure during follow up increased risk of incidence. The persistence of UE disorders from baseline to follow up examination was nearly 60% and somewhat associated with baseline exposure score.Conclusions:These longitudinal results confirm the previous cross sectional associations of UE musculoskeletal disorders with exposure to combined ergonomic stressors. The exposure-response relation was similar for incident cases defined by symptoms alone and those confirmed by physical examination.
Lung function changes in coke oven workers during 12 years of follow up
Authors: Wu J , Griffiths D , Kreis I A , Darling C 
Published: July 2004

Aims:To investigate the effect of exposure to coke oven emissions on the lung function of coke oven workers.Methods:The study population, followed from 1978 and 1990, was 580 male workers with at least two sets of lung function measurements (FVC, FEV1, FEV1/FVC, and FEF25–75%). An annual rate of change (time slope) for age and height adjusted lung function index was estimated for each subject. This “time slope” was then treated as the response variable in a weighted multiple regression analysis with selected predictors.Results:For all 580 subjects, each year of working in the “operation” group (the most exposed) was found to increase the FVC decline by around 0.7 ml/year (95% CI 0.1 to 1.3 ml/year). After the exclusion of 111 subjects without detailed work history, the above finding was confirmed and each year of exposure in “operation” was also found to increase the FEV1decline by around 0.8 ml/year (95% CI 0.1 to 1.4 ml/year).Conclusions:These findings are consistent with the results of previous cross-sectional studies. Work duration in the most exposed position in the coke ovens was associated with increased annual decline for FVC and FEV1. The estimated effect of one year of work exposure in “operation” is equivalent, in terms of the reduction in lung function, to an estimated 2.1 pack-years of smoking for FVC and 1.2 pack-years of smoking for FEV1.
The association between occupational factors and adverse health outcomes in chronic obstructive pulmonary disease
Authors: Blanc P D , Eisner M D , Trupin L , Yelin E H , Katz P P , Balmes J R 
Published: July 2004

Background and Aims:Despite recognition that occupational exposures may make a substantive contribution to the aetiology of COPD, little is known about the potential role of work related factors in COPD related health outcomes.Methods:Prospective cohort study using structured telephone interviews among a random sample of adults aged 55–75 reporting a COPD condition (emphysema, chronic bronchitis, or COPD). Using multivariate models adjusting for smoking and demographic factors, the separate and combined associations were estimated between occupational exposure to vapours, gas, dust, or fumes (VGDF) and leaving work due to lung disease (respiratory related work disability) with health outcomes and utilisation ascertained at one year follow up.Results:Of 234 subjects, 128 (55%) reported exposure to VGDF on their longest held jobs, 58 (25%) reported respiratory related work disability, and 38 (16%) subjects reported both. Combined exposure to VGDF and respiratory related work disability (rather than either factor alone) was associated with the greatest risk at follow up of frequent (everyday) restricted activity days attributed to a breathing or lung condition (OR 3.8; 95% CI 1.4 to 10.1), emergency department (ED) visit (OR 3.9; 95% CI 1.4 to 10.5), and hospitalisation (OR 7.6; 95% CI 1.8 to 32).Conclusions:Among persons with COPD, past occupational exposures and work disability attributed to lung disease, particularly in combination, appear to be risk factors for adverse health related outcomes.
Targeted retroviral transduction of c-kit+ hematopoietic cells using novel ligand display technology
Authors: Chandrashekran Anil , Gordon Myrtle Y. , Casimir Colin 
Published: July 2004

AbstractGene therapy for a wide variety of disorders would be greatly enhanced by the development of vectors that could be targeted for gene delivery to specific populations of cells. We describe here high-efficiency targeted transduction based on a novel targeting strategy that exploits the ability of retroviruses to incorporate host cell proteins into the surface of the viral particle as they bud through the plasma membrane. Ecotropic retroviral particles produced in cells engineered to express the membrane-bound form of stem cell factor (mbSCF) transduce both human cell lines and primary cells with high efficiency in a strictly c-kit (SCF receptor)-dependent fashion. The availability of efficient targeted vectors provides a platform for the development of a new generation of therapies using in vivo gene delivery. (Blood. 2004;104: 2697-2703)
Combination of retinoic acid and tumor necrosis factor overcomes the maturation block in a variety of retinoic acid-resistant acute promyelocytic leukemia cells
Authors: Witcher Michael , Shiu Hoi Ying , Guo Qi , Miller Wilson H. 
Published: July 2004

AbstractRetinoic acid (RA) overcomes the maturation block in t(15:17) acute promyelocytic leukemia (APL), leading to granulocytic differentiation. Patients receiving RA alone invariably develop RA resistance. RA-resistant cells can serve as useful models for the development of treatments for both APL and other leukemias. Previously, we showed that RA and tumor necrosis factor (TNF) promote monocytic differentiation of the APL cell line NB4 and U937 monoblastic cells. Here, we report that combining TNF with RA leads to maturation of several RA-resistant APL cells along a monocytic pathway, whereas UF-1, a patient-derived RA-resistant cell line, showed characteristics of granulocytic differentiation. We found distinct differences in gene regulation between UF-1 cells and cells showing monocytic differentiation. Although IRF-7 was up-regulated by TNF and RA in all cells tested, expression of c-jun and PU.1 correlated with monocytic differentiation. Furthermore, synergistic induction of PU.1 DNA binding and macrophage colony-stimulating factor receptor (m-CSF-1R) mRNA was observed only in cells differentiating into monocytes. Using neutralizing antibodies against m-CSF-1R or its ligand, we found that inhibiting this pathway strongly reduced CD14 expression in response to RA and TNF, suggesting that this pathway is essential for their synergy in RA-resistant leukemia cells. (Blood. 2004;104:3335-3342)
Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance
Authors: St. Pierre Timothy G. , Clark Paul R. , Chua-anusorn Wanida , Fleming Adam J. , Jeffrey Gary P. , Olynyk John K. , Pootrakul Pensri , Robins Erin , Lindeman Robert 
Published: July 2004

AbstractMeasurement of liver iron concentration (LIC) is necessary for a range of iron-loading disorders such as hereditary hemochromatosis, thalassemia, sickle cell disease, aplastic anemia, and myelodysplasia. Currently, chemical analysis of needle biopsy specimens is the most common accepted method of measurement. This study presents a readily available noninvasive method of measuring and imaging LICs in vivo using clinical 1.5-T magnetic resonance imaging units. Mean liver proton transverse relaxation rates (R2) were measured for 105 humans. A value for the LIC for each subject was obtained by chemical assay of a needle biopsy specimen. High degrees of sensitivity and specificity of R2 to biopsy LICs were found at the clinically significant LIC thresholds of 1.8, 3.2, 7.0, and 15.0 mg Fe/g dry tissue. A calibration curve relating liver R2 to LIC has been deduced from the data covering the range of LICs from 0.3 to 42.7 mg Fe/g dry tissue. Proton transverse relaxation rates in aqueous paramagnetic solutions were also measured on each magnetic resonance imaging unit to ensure instrument-independent results. Measurements of proton transverse relaxivity of aqueous MnCl2 phantoms on 13 different magnetic resonance imaging units using the method yielded a coefficient of variation of 2.1%.
Atypical marginal zone hyperplasia of mucosa-associated lymphoid tissue: a reactive condition of childhood showing immunoglobulin lambda light-chain restriction
Authors: Attygalle Ayoma D. , Liu Hongxiang , Shirali Sima , Diss Timothy C. , Loddenkemper Christoph , Stein Harald , Dogan Ahmet , Du Ming-Qing , Isaacson Peter G. 
Published: July 2004

Abstract
Mucosa-associated lymphoid tissue (MALT) lymphomas usually arise at sites of acquired MALT and are uncommon in native MALT (eg, Peyer patches and tonsil). Malignancy in these low-grade lymphomas is often inferred by immunoglobulin light-chain restriction and expression of CD43; molecular genetic evidence is sought only if these are in doubt. We report 6 cases (4 tonsils, 2 appendixes) of marginal zone (MZ) hyperplasia in children aged 3 to 11 years that, despite histologic and immunophenotypic features indicative of lymphoma, were polyclonal by molecular analysis. No lymphoma-directed therapy was given and patients remain alive and well (5 cases, median follow-up 35.3 months). The involved tonsil and appendix showed florid MZ hyperplasia with prominent intraepithelial B cells (IEBCs). The MZ B cells and IEBCs showed a high-proliferation fraction and a CD20+, CD21+, CD27-, immunoglobulin (Ig) superfamily receptor translocation-associated 1-positive (IRTA-1+), CD43+, multiple myeloma oncogene 1 (MUM-1), IgM+D+ phenotype. Polymerase chain reaction (PCR), cloning, and sequencing of rearranged IgH and Igλ genes (whole tissue sections [6 cases]; microdissected cells [2 cases]) showed that the MZ B cells and IEBCs were polyclonal and the IgH genes nonmutated. In contrast, MZ (intraepithelial) B cells of 6 control tonsils had a similar immunophenotype, except for expression of CD27 and polytypic light chains, whereas molecular studies showed that they were polyclonal with mutated Ig genes. (Blood. 2004;104:3343-3348)
Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML
Authors: O'Hare Thomas , Pollock Roy , Stoffregen Eric P. , Keats Jeffrey A. , Abdullah Omar M. , Moseson Erika M. , Rivera Victor M. , Tang Hao , Metcalf Chester A. , Bohacek Regine S. , Wang Yihan , Sundaramoorthi Raji , Shakespeare William C. , Dalgarno David , Clackson Tim , Sawyer Tomi K. , Deininger Michael W. , Druker Brian J. 
Published: July 2004

Abstract
The deregulated, oncogenic tyrosine kinase Bcr-Abl causes chronic myeloid leukemia (CML). Imatinib mesylate (Gleevec, STI571), a Bcr-Abl kinase inhibitor, selectively inhibits proliferation and promotes apoptosis of CML cells. Despite the success of imatinib mesylate in the treatment of CML, resistance is observed, particularly in advanced disease. The most common imatinib mesylate resistance mechanism involves Bcr-Abl kinase domain mutations that impart varying degrees of drug insensitivity. AP23464, a potent adenosine 5′-triphosphate (ATP)–based inhibitor of Src and Abl kinases, displays antiproliferative activity against a human CML cell line and Bcr-Abl–transduced Ba/F3 cells (IC50 = 14 nM; imatinib mesylate IC50 = 350 nM). AP23464 ablates Bcr-Abl tyrosine phosphorylation, blocks cell cycle progression, and promotes apoptosis of Bcr-Abl–expressing cells. Biochemical assays with purified glutathione S transferase (GST)–Abl kinase domain confirmed that AP23464 directly inhibits Abl activity. Importantly, the low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate–resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P. AP23464 was ineffective against mutant T315I, an imatinib mesylate contact residue. The potency of AP23464 against imatinib mesylate–refractory Bcr-Abl and its distinct binding mode relative to imatinib mesylate warrant further investigation of AP23464 for the treatment of CML.
Effects of positive end-expiratory pressure on gastric mucosal perfusion in acute respiratory distress syndrome
Authors: Bruhn Alejandro , Hernandez Glenn , Bugedo Guillermo , Castillo Luis 
Published: July 2004

Abstract
Introduction
Positive end-expiratory pressure (PEEP) improves oxygenation and can prevent ventilator-induced lung injury in patients with acute respiratory distress syndrome (ARDS). Nevertheless, PEEP can also induce detrimental effects by its influence on the cardiovascular system. The purpose of this study was to assess the effects of PEEP on gastric mucosal perfusion while applying a protective ventilatory strategy in patients with ARDS.

Methods
Eight patients were included. A pressure–volume curve was traced and ideal PEEP, defined as lower inflection point + 2 cmH2O, was determined. Gastric tonometry was measured continuously (Tonocap). After baseline measurements, 10, 15 and 20 cmH2O PEEP and ideal PEEP were applied for 30 min each. By the end of each period, hemodynamic, CO2 gap (gastric minus arterial partial pressures), and ventilatory measurements were performed.

Results
PEEP had no effect on CO2 gap (median [range], baseline: 19 [2–30] mmHg; PEEP 10: 19 [0–40] mmHg; PEEP 15: 18 [0–39] mmHg; PEEP 20: 17 [4–39] mmHg; ideal PEEP: 19 [9–39] mmHg; P = 0.18). Cardiac index also remained unchanged (baseline: 4.6 [2.5–6.3] l min-1 m-2; PEEP 10: 4.5 [2.5–6.9] l min-1 m-2; PEEP 15: 4.3 [2–6.8] l min-1 m-2; PEEP 20: 4.7 [2.4–6.2] l min-1 m-2; ideal PEEP: 5.1 [2.1–6.3] l min-1 m-2; P = 0.08). One patient did not complete the protocol because of hypotension.

Conclusion
PEEP of 10–20 cmH2O does not affect gastric mucosal perfusion and is hemodynamically well tolerated in most patients with ARDS, including those receiving adrenergic drugs.
Genetic Targeting of Relaxin and Insulin-Like Factor 3 Receptors in Mice
Authors: Kamat Aparna A. , Feng Shu , Bogatcheva Natalia V. , Truong Anne , Bishop Colin E. , Agoulnik Alexander I. 
Published: July 2004

Abstract
Relaxin (RLN) is a small peptide hormone that affects a variety of biological processes. Rln1 knockout mice exhibit abnormal nipple development, prolonged parturition, agerelated pulmonary fibrosis, and abnormalities in the testes and prostate. We describe here RLN receptor Lgr7-deficient mice. Mutant females have grossly underdeveloped nipples and are unable to feed their progeny. Some Lgr7−/− females were unable to deliver their pups. Histological analysis of Lgr7 mutant lung tissues demonstrates increased collagen accumulation and fibrosis surrounding the bronchioles and the vascular bundles, absent in wild-type animals. However, Lgr7-deficient males do not exhibit abnormalities in the testes or prostate as seen in Rln1 knockout mice. Lgr7-deficient females with additional deletion of Lgr8 (Great), another putative receptor for RLN, are fertile and have normal-sized litters. Double mutant males have normal-sized prostate and testes, suggesting that Lgr8 does not account for differences in Rln1−/− and Lgr7−/− phenotypes. Transgenic overexpression of Insl3, the cognate ligand for Lgr8, does not rescue the mutant phenotype of Lgr7-deficient female mice indicating nonoverlapping functions of the two receptors. Our data indicate that neither Insl3 nor Lgr8 contribute to the RLN signaling pathway. We conclude that the Insl3/Lgr8 and Rln1/Lgr7 actions do not overlap in vivo.
Estrogen Modulates Microglial Inflammatory Mediator Production via Interactions with Estrogen Receptor β
Authors: Baker Ann E. , Brautigam Vielska M. , Watters Jyoti J. 
Published: July 2004

AbstractEstrogens are well known to exert antiinflammatory effects outside the central nervous system (CNS). They have also been shown to exert neuroprotective effects in the CNS after several types of injury, including neurodegeneration. However, the molecular mechanisms by which these effects occur remain unclear. Because microglial hyperactivation and their production of neurotoxins is associated with many types of brain injury for which estrogens are beneficial, we sought to investigate the ability of estrogen to modulate microglial function. Furthermore, because little is known regarding the role of each of the two known estrogen receptors (ERs) in microglia, our studies were designed to test the hypothesis that 17β-estradiol (E2) exerts antiinflammatory effects in microglia, specifically via interactions with ERβ. We tested this hypothesis using the murine microglial cell line BV-2, which naturally expresses only ERβ. Our results indicate that not only does E2 decrease lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression, it also reduces the expression of cyclooxygenase-2, a target for estrogen that has not previously been reported for ERβ. We also observed that LPS-stimulated TNFα mRNA was increased by estrogen. E2 exerts these effects within 30 min compared with typical estrogen transcriptional responses. Tamoxifen and ICI 182,780 differentially blocked the inhibitory effects of E2 on LPS-stimulated iNOS and cyclooxygenase-2. In addition, we show that E2 alters LPS-stimulated MAPK pathway activation, supporting the idea that alterations in the MAPKs may be a potential mechanism by which ERβ mediates decreased microglial activation.
Identification of a Novel Apolipoprotein, ApoN, in Ovarian Follicular Fluid
Authors: O’Bryan Moira K. , Foulds Lynda M. , Cannon James F. , Winnall Wendy R. , Muir Julie A. , Sebire Kim , Smith A. Ian , Keah Hooi-Hong , Hearn Milton T. W. , de Kretser David M. , Hedger Mark P. 
Published: July 2004

AbstractA novel apolipoprotein, designated ApoN, has been identified in bovine ovarian follicular fluid using chromatographic purification methods, amino acid sequence analysis, molecular biology, and bioinformatics. The apolipoprotein is a hydrophobic 12-kDa protein processed from the C terminus of a 29-kDa precursor expressed in a number of tissues, including the ovary, testis, the anterior chamber of the eye, skeletal muscle, uterus, and liver. Bovine, porcine, and murine ApoN display significant homology at the amino acid level across the entire precursor sequence. Surprisingly, there appears to be no orthologous protein in the human, although an APON-like pseudogene is found on chromosome 12. The N-terminal fragment of the ApoN precursor shows significant homology with the N-terminal sequence of the precursor of the cholesterol transport regulatory protein ApoF, but the corresponding C-terminal sequences of ApoN and ApoF possess no homology. ApoN is present in the high-density lipoprotein fraction of bovine serum and both the high-density lipoprotein and low-density lipoprotein fractions of bovine follicular fluid and is found in several tissues that are associated with local immunological privilege. These data suggest that ApoN may play a role in steroidogenesis and/or immunoregulation in the gonads of nonhuman species, as well as similar roles in other tissues.