bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paracetamol use and risk of ovarian cancer: a meta‐analysis
Authors: Bonovas Stefanos , Filioussi Kalitsa , Sitaras Nikolaos M. 
Published: October 2005

AimOvarian cancer remains the most fatal gynaecological malignancy. Several observational studies have examined paracetamol as a potential chemopreventive agent. The nonconclusive nature of the epidemiological evidence prompted us to conduct a detailed meta‐analysis of the studies published on the subject in peer‐reviewed literature.MethodsA comprehensive search for articles published up to 2004 was performed, reviews of each study were conducted and data were abstracted. Prior to meta‐analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated using the random and the fixed‐effects models.ResultsEight studies (four case–control and four cohort studies), published between 1998 and 2004, were included. We found no evidence of publication bias or heterogeneity among the studies. The analysis revealed an inverse association between paracetamol use and ovarian cancer risk. This association was marginally significant assuming a random‐effects model (RR = 0.84, 95% CI 0.70, 1.00), but not statistically significant assuming a fixed‐effects model (RR = 0.90, 95% CI 0.80, 1.01). When the analysis was stratified into subgroups according to study design, the association was inverse in both case–control and cohort studies, but only in the former was it statistically significant. The sensitivity analysis strengthened our confidence in the validity of this association. Furthermore, our results provided evidence for a dose effect; ‘regular use’ was associated with a statistically significant 30% reduction in the risk of developing ovarian cancer compared with non‐use (RR = 0.70, 95% CI 0.51, 0.95).ConclusionsOur meta‐analysis supports a protective association between paracetamol use and ovarian cancer, and provides evidence for a dose effect. However, the question of paracetamol’s potential association with ovarian cancer deserves further verification, since proof of chemoprevention would represent a major public health advance.
Limited predictability of amikacin clearance in extreme premature neonates at birth
Authors: Allegaert Karel , Anderson Brian J. , Cossey Veerle , Holford Nicholas H. G. 
Published: October 2005

AimIdentify and quantify factors describing variability of amikacin clearance in preterm neonates at birth.MethodsPopulation pharmacokinetics of amikacin were estimated in a cohort of 205 extreme preterm neonates [post conception age (PCA) 27.8, SD 1.8, range 24–30 weeks; weight 1.07, SD 0.34, range 0.45–1.98 kg, postnatal age < 72 h]. Covariate analysis included weight, PCA, Apgar score, prophylactic administration of a nonsteroidal anti‐inflammatory drug (NSAID) to the neonate, maternal indomethacin and betamethasone administration, and chorioamnionitis.ResultsA one‐compartment linear disposition model with zero order input (0.3 h i.v. infusion) and first‐order elimination was used. The population parameter estimate for volume of distribution (V) was 40.2 l per 70 kg. Clearance (CL) increased from 0.486 l h−1 per 70 kg at 24 weeks PCA to 0.940 l h−1 per 70 kg by 30 weeks PCA. The population parameter variability (PPV) for CL and V was 0.336 and 0.451. The use of a NSAID (either aspirin or ibuprofen) in the first day of life reduced amikacin clearance by 22%. Overall 65% of the variability of CL was predictable. Weight explained 48%, PCA 15% and NSAIDs 2%.ConclusionsSize and post‐conception age are the major contributors to clearance variability in extreme premature neonates (<31 weeks PCA). The large (35% of total) unexplained variability in clearance reinforces the need for target concentration intervention to reduce variability in exposure to a safe and effective range.
Erythropoiesis and red cell function in vertebrate embryos
Authors: Baumann R. , Dragon S. 
Published: October 2005

AbstractAll vertebrate embryos produce a specific erythroid cell population – primitive erythrocytes – early in development. These cells are characterized by expression of the specific embryonic haemoglobins. Many aspects of primitive erythropoiesis and the physiological function of primitive red cells are still enigmatic. Nevertheless, recent years have seen intensive efforts to characterize in greater detail the molecular events underlying the initiation of erythropoiesis in vertebrate embryos. Several key genes have been identified that are necessary for primitive and the subsequent definitive erythropoiesis, which differs in several aspect from primitive erythropoiesis. This review gives in its first part a short overview dealing with comparative aspects of primitive and early definitive erythropoiesis in higher and lower vertebrates and in the second part we discuss the physiological function of primitive red cells based mainly on results from mammalian and avian embryos.
Regulation of erythropoietin production
Authors: Eckardt K.‐U. , Kurtz A. 
Published: October 2005

AbstractThe glycoprotein hormone erythropoietin (EPO) is an essential growth and survival factor for erythroid progenitor cells, and the rate of red blood cell production is normally determined by the serum EPO concentration. EPO production is inversely related to oxygen availability, so that an effective feedback loop is established, which controls erythropoiesis. Since recombinant EPO became available as an effective therapeutic agent, significant progress has also been made in understanding the basis of this feedback control. The main determinant of EPO synthesis is the transcriptional activity of its gene in liver and kidneys, which is related to local oxygen tensions. This control is achieved by hypoxia‐inducible transcription factors (HIF), consisting of a constitutive β‐subunit and one of two alternative oxygen‐regulated HIFα subunits (HIF‐1α and HIF‐2α). In the presence of oxygen (normoxia) the HIFα subunits are hydroxylated, which targets them for proteasomal degradation. Under hypoxia, because of the lack of molecular oxygen, HIF cannot be hydroxylated and is thereby stabilized. Although HIF‐1α was the first transcription factor identified through its ability to bind to an enhancer sequence of the EPO gene, more recent evidence suggests that HIF‐2α is responsible for the regulation of EPO. Although EPO is a prime example for an oxygen‐ regulated gene, the role of the HIF system goes far beyond the regulation of EPO, because it operates widely in almost all cells and controls a broad transcriptional response to hypoxia, including genes involved in cell metabolism, angiogenesis and vascular tone. Further evidence suggests that apart from its effect as an erythropoietic hormone EPO acts as a paracrine, tissue‐protective protein in the brain and possibly also in other organs.
Anaemia and the heart
Authors: Hörl W. H. , Ertl G. 
Published: October 2005

AbstractAnaemia is common in patients with congestive heart failure (CHF). Its prevalence increases with disease severity as a consequence of renal insufficiency, cytokine production, blood loss, iron deficiency, malnutrition and/or plasma volume overload. Anaemia can contribute to worsening of CHF. There is a nonlinear relationship (U‐shaped curve) between haemoglobin and survival. Prevalence of anaemia among elderly people with acute myocardial infarction is high and is associated with more frequent in‐hospital events, including death. Anaemia is also associated with higher in‐hospital mortality rate after coronary bypass surgery and with all‐cause and cardiac mortality after percutaneous coronary interventions. Patients with anaemia and cardiovascular disease have a higher mortality rate after cardiac/noncardiac surgery as compared to those with anaemia but without cardiovascular disease or those with cardiovascular disease but without anaemia. However, not all authors confirmed these findings. Therefore, multicentre trials to clarify this issue are urgently needed. Pleiotropic effects of recombinant human erythropoietin include reduction of myocardial and cerebral infarct size without an increase in haematocrit, neovascularization as well as mobilization of endothelial progenitor cells.
Anaemia in cancer patients: pathophysiology, incidence and treatment
Authors: Bokemeyer C. , Oechsle K. , Hartmann J.‐T. 
Published: October 2005

AbstractThis review focuses on the pathophysiology, incidence and treatment of anaemia in cancer patients. Causative factors such as different chemotherapy regimens and patient risk factors for the development of anaemia are discussed in order to identify the patient group that is most likely to receive red blood cell transfusions and would thus have the largest benefit from treatment with erythropoietic proteins. The data available with recombinant human erythropoietin alfa, recombinant human erythropoietin beta and darbepoetin alfa are described in more detail and the significant benefit of treating cancer anaemia by these molecules is outlined. Finally, differences in treatment approaches between these erythropoietic proteins are discussed in order to guide treatment decisions specific for the individual patients’ situation.
Intravenous iron therapy: well‐tolerated, yet not harmless
Authors: Sengölge G. , Hörl W. H. , Sunder‐Plassmann G. 
Published: October 2005

AbstractIn the majority of patients with chronic renal failure, it is essential to substitute erythropoietic agents and iron to maintain a haemoglobin level above 11 g dL−1. Intravenous iron is more effective than oral iron. Substitution of intravenous iron is mainly performed using iron(III)‐hydroxide–sucrose complex (iron sucrose) and iron(III)–sodium‐gluconate in sucrose (iron gluconate), and is, in general, well‐tolerated. Nonetheless, intravenous iron therapy has effects on endothelial cells, polymorphonuclear leucocytes and cytokines which are most likely related to non‐transferrin bound labile iron. These effects suggest a role of iron in infection or atherosclerosis. Yet, not all available data support the association of iron with infection and atherosclerosis. A recent trial showed that iron sucrose is safe when given as treatment for iron deficiency or for maintenance of iron stores. Nevertheless, iron therapy should be handled with cautiousness but its use should not be feared whenever indicated.
Sex, haemoglobin and kidney disease: new perspectives
Authors: Duncan J. A. , Levin A. 
Published: October 2005

AbstractAnaemia is recognized as a common complication of chronic kidney disease with significant associated morbidity and mortality. Published data document the negative impact of anaemia on cardiovascular disease outcomes, progression of chronic kidney disease (CKD), hospitalizations, rehabilitation and quality of life, among others. Gender differences have been identified in many of these areas as well as, and importantly, in cardiovascular and chronic kidney disease outcomes. Female gender is associated with lower risk of cardiovascular morbidity and mortality as well as slower progression of chronic kidney disease. Interestingly, there are some well‐described physiological adaptations to anaemia in women, which include shifting of the haemoglobin oxygen dissociation curve to reduce oxygen affinity secondary to higher levels of 2,3‐diphosphoglycerate. However, the complex physiology underlying the impact of anaemia or gender on patients with chronic kidney disease is not well‐characterized to date. Furthermore, there has been little examination of the potential interaction between anaemia and gender on cardiac or kidney outcomes.In this paper, we review the documented impact of anaemia and gender on outcomes, and explore the interaction of anaemia and gender in patients with CKD. We also present data that describe the potential importance of considering gender when targeting specific levels of haemoglobin. The value of a new perspective on haemoglobin and gender in kidney disease is important from both a physiological and an economical perspective.
The epidemiology and control of anaemia among pre‐ESRD patients with chronic kidney disease
Authors: McClellan W. M. , Jurkovitz C. , Abramson J. 
Published: October 2005

AbstractAnaemia is a common condition among pre‐end‐stage renal disease (pre‐ESRD) patients with chronic kidney disease (CKD). Indeed, data from clinical studies indicate that anaemia may be present in as many as two‐thirds of such patients. Use of recombinant human erythropoietin (EPO) provides an effective means of correcting anaemia in CKD patients and helps to reduce the risk of renal disease progression and related problems. Unfortunately, EPO therapy is underutilized in these persons. Consequently, anaemia remains a major problem in the pre‐ESRD CKD population. Evidence suggests that anaemia in the presence of CKD can lead to an increased risk of a number of adverse outcomes, including mortality, progression of kidney disease, coronary heart disease, stroke, hospitalization, and decreases in quality of life. Anaemia's association with these adverse outcomes suggests that effective treatment of anaemia in pre‐ESRD CKD patients is of great importance and that substantial efforts should be made to ensure that these patients receive appropriate therapy to correct anaemia.
Hormonal adjuvants for the treatment of renal anaemia
Authors: Deicher R. , Hörl W. H. 
Published: October 2005

AbstractHormonal adjuvants, besides being erythropoietic agents, broaden the spectrum of therapeutic options for the treatment of the anaemia of chronic kidney disease (CKD). Lowering elevated parathyroid hormone levels by oral calcium supplementation and phosphate restriction, by varying dialysate calcium concentrations, by administration of vitamin D3 derivatives and, in the near future, by treatment with calcimimetics may prove efficient in some patients to fight extensive requirements of erythropoietic agents. Clinical evidence for a principal role of secondary hyperparathyroidism in resistance to erythropoietin, however, is lacking. Active vitamin D3 derivatives, in addition to their beneficial effects on secondary hyperparathyroidism, appear to exert a direct, stimulatory action on erythroid precursor cells and possibly also an inhibitory action on collagen synthesis by bone marrow stromal cells. Growth hormone (GH) induces insulin‐like growth factor (IGF)‐1, which in turn counteracts apoptosis similarly to erythropoietin, and fosters proliferation of burst‐ and colony‐forming units‐erythroid (BFU‐E, CFU‐E). If erythropoietic agents improve survival of CKD patients, a similar benefit should apply for strategies that increase synthesis and bioavailabilty of IGF‐1. The latter appears to be reduced in CKD patients, and zinc supplementation potentially enhances it via an increase in free IGF‐1. Finally, androgens also exert anti‐anaemic effects. Nandrolone decanoate constitutes the only androgen currently applicable for selected male dialysis patients over the age of 50 years. It should not be given to women, however, because of serious side effects. Collectively, hormonal interventions offer the potential to reduce requirements of erythropoietic agents, and some may also improve physical performance.
Anaemia after renal transplantation
Authors: Lorenz M. , Winkelmayer W. C. , Hörl W. H. , Sunder‐Plassmann G. 
Published: October 2005

AbstractAnaemia is a frequent complication among long‐term renal transplant recipients. A prevalence of approximately 40% has been reported in several studies. If renal function declines to stage 5 kidney disease, the prevalence of anaemia in kidney transplants is even higher. A positive correlation between haemoglobin concentration and creatinine clearance has been reported, which is a function of endogenous erythropoietin production by the functioning graft. Inflammation related to a retained kidney graft may cause hypo‐responsiveness to erythropoietic agents once kidney transplant recipients return to dialysis. Furthermore, the use of azathioprine, mycophenolate mofetil and sirolimus may be associated with post‐transplant anaemia. Along with erythropoietin deficiency, depletion of iron stores is one of the major reasons for anaemia in the kidney transplant population. The proportion of hypochromic red blood cells appears to be a useful parameter to measure iron supply and utilization as well as to estimate mortality risks in kidney transplant recipients. While anaemia is an important cardiovascular risk‐factor after transplantation, our data suggest that anaemia is not associated with mortality and graft loss. Nevertheless, inadequate attention is paid so far to the management of anaemia after renal transplantation. A promising future aspect for risk reduction of cardiovascular disease includes the effect of erythropoietic agents on endothelial progenitor cells.
Erythropoietin‐induced, antibody‐mediated pure red cell aplasia*
Authors:   The Pure Red Cell Aplasia Global Scientific Advisory Board (GSAB)
Published: October 2005

AbstractPure red cell aplasia (PRCA) is a rare haematological condition that is characterized by severe aregenerative anaemia due to an almost complete cessation of red blood cell production. While antibody‐mediated PRCA was extremely rare before 1998, the incidence of this disorder increased sharply after 1998 in patients receiving subcutaneous epoetin alfa produced by Ortho‐Biotech and marketed outside the USA. The diagnosis of antibody‐mediated PRCA relies mostly on the results of bone marrow biopsy or aspirate, which shows an absence of erythroid precursors and/or red cell maturation arrest while counts of white cell and platelet precursors are normal, and on the identification of circulating anti‐erythropoietin antibodies. Retrospective analysis of PRCA cases has shown that immunosuppressive therapy can induce a disappearance of anti‐erythropoietin antibodies in most patients.
VEGF‐A, VEGF‐D and VEGF‐DΔNΔC induced intimal hyperplasia in carotid arteries
Authors: Bhardwaj S. , Roy H. , Heikura T. , Ylä‐Herttuala S. 
Published: October 2005

AbstractBackground  The role of vascular endothelial growth factors (VEGFs) in intimal hyperplasia and atherogenesis remains unknown. Several studies have suggested that some members of the VEGF family reduce intimal hyperplasia, but others have proposed that VEGFs accelerate restenosis and atherosclerosis. This investigation conducted a comparative study with adenoviruses encoding different VEGFs in a rabbit carotid artery collar model of intimal hyperplasia in order to analyze the role of VEGFs in the formation of intimal hyperplasia.Materials and methods  Intimal hyperplasia was induced in the carotid arteries of cholesterol fed New Zealand White rabbits using a silastic collar. Adenoviral vectors encoding VEGF‐A, VEGF‐B, VEGF‐C, VEGF‐CΔNΔC, VEGF‐D and VEGF‐DΔNΔC were delivered to the adventitia using the collar as a gene delivery device. Adeno‐LacZ was used as a control.Results  A significant (P < 0·01) increase in the intima/media ratio was observed in the arteries transduced with VEGF‐A, VEGF‐D and VEGF‐DΔNΔC. There was a significant increase in the number of proliferating cells in the adventitia, media and intima of the VEGF‐A, VEGF‐D and the VEGF‐DΔNΔC transduced arteries. The majority of medial smooth muscle cells in these arteries had a synthetic phenotype. The presence of matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 in the VEGF‐A, VEGF‐D and the VEGF‐DΔNΔC transduced arteries was significantly increased. A significant positive correlation was observed between adventitial angiogenesis and intimal hyperplasia.Conclusions  Adventitial delivery of adenoviruses encoding VEGF‐A, VEGF‐D and VEGF‐DΔNΔC increased intimal hyperplasia in the rabbit collar model. Adventitial angiogenesis correlated positively with the intimal hyperplasia. These results indicated that efficient adventitial production of VEGF‐A, VEGF‐D and VEGF‐DΔNΔC can cause thickening of the inner layer of the artery in rabbits.
Erythrocyte transport efficacy of human blood: a rheological point of view
Authors: Bogar L. , Juricskay I. , Kesmarky G. , Kenyeres P. , Toth K. 
Published: October 2005

AbstractBackground  Large‐scale epidemiological studies have demonstrated that both anaemia and polycytaemia are independent cardiovascular risk factors. This was substantiated by the Framingham study, which demonstrated a U‐shaped relation between haemoglobin concentration and mortality. It was previously noted that delineating the corresponding haematocrit/blood viscosity ratios in the function of haematocrit provided a distribution of an inverted U‐shaped curve. The peak appeared physiologically important because it denotes a healthy balance between a relatively high oxygen binding capacity and a moderately low blood viscosity. It was the aim of this study to examine the mathematical relationship between the haematocrit and haematocrit/blood viscosity ratio.Methods  In a retrospective study, the haemorheological data of 32 healthy controls, 52 outpatients with hyperlipidaemia and 120 outpatients with Raynaud's disease were analyzed. Whole blood viscosity was measured with Hevimet 40 capillary viscometer at 37·0 °C and at shear rates of 10 s−1, 90 s−1 and 200 s−1.Results  Haematocrit/blood viscosity ratios in the function of haematocrit values showed a Gaussian association in the healthy subjects, hyperlipidaemic and Raynaud's disease outpatient groups. Peak values (i.e. the rheologically optimal haematocrit) were shear‐rate and group dependent and were found at 44·3%, 43·5% and 38·3% in controls, hyperlipidaemic and Raynaud's disease patients, respectively, at a shear rate of 90 s−1.Conclusions  This is one of the first reports in which a theoretically optimal haematocrit value was determined using the haematocrit/blood viscosity ratio. Further studies are needed to examine the potential clinical usefulness of this approach.
Severely impaired IL‐12/IL‐18/IFNγ axis in patients with hyper IgE syndrome
Authors: Netea M. G. , Kullberg B. J. , van Der Meer J. W. M. 
Published: October 2005

AbstractBackground  Hyperimmunoglobulin E syndrome (HIES) is an inborn disorder characterized by recurrent skin and respiratory tract infections, skeletal abnormalities, chronic eczema and elevated serum IgE. The nature of the host defence defect has yet to be established. The aim of this study was to investigate whether activation of the interleukin‐12/interleukin‐18/interferon‐γ axis, known to be crucial for the activation of cellular immune responses, is impaired in patients with HIES.Materials and methods  Cytokine production capacity of seven HIES patients and seven healthy controls was investigated in whole‐blood cultures stimulated with heat‐killed Staphylococcus aureus, Candida albicans, or a combination of interleukin (IL)‐12/IL‐18.Results  Interferon (IFN)γ production, in addition to IFNγ/IL‐10 ratios, was 10–30‐fold lower in the HIES patients compared with the healthy volunteers. In contrast TNF, IL‐1β and IL‐8 production was normal.Conclusions  These data revealed a severe dysbalance towards a Th2 phenotype in HIES patients which is likely to contribute to the specific pattern of infection susceptibility characteristic to HIES.