bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estrogen receptor polymorphisms and the risk of endometrial cancer
Authors: Ashton KA , Proietto A , Otton G , Symonds I , McEvoy M , Attia J , Gilbert M , Hamann U , Scott RJ 
Published: May 2009

Objective  There is evidence that estrogens and some of their metabolites are involved in endometrial cancer pathogenesis. As estrogens mediate their effects via the estrogen receptors, ESR1 and ESR2, the objective of this investigation was to determine whether six single nucleotide polymorphisms (SNPs) in these two genes were over‐represented in a population of endometrial cancer patients compared with a healthy matched control population, thereby associating differences in these genes with endometrial cancer.Design  The study is a case–control investigation large enough to detect a two‐fold increased risk, assuming a dominant genetic model, with P = 0.05 and 80% power.Setting  The study and control populations were all from the Hunter‐New England region of New South Wales, Australia collected between the years 1992 and 2005.Population  The study consisted of 191 endometrial cancer patients and 291 healthy controls matched for gender and age.Methods  Two SNPs in ESR1 and four SNPs in ESR2 were genotyped using PCR‐based restriction fragment length polymorphism analysis and real‐time PCR. Odds ratios were calculated using unconditional logistic regression and SIMHAP was used for haplotype analysis, adjusting for potential endometrial cancer risk factors. Kaplan–Meier survival analysis, Cox regression and t tests were used to examine the patient’s age of diagnosis of endometrial cancer and genotype.Main outcome measures  Over‐representation of ESR1 and ESR2 polymorphisms in the endometrial cancer population compared with the control population indicates an involvement in the development and/or progression of disease.Results  Two ESR1 (rs2234693 and rs9340799) and two ESR2 (rs1255998 and rs944050) polymorphisms were associated with an increased risk of endometrial cancer. Following adjustment for risk factors, the association with the ESR1 and ESR2 polymorphisms (rs2234693, rs1255998 and rs944050) remained highly significant. Haplotype analysis revealed that carriers of the ESR1 haplotype (variant alleles; rs2234693 and rs9340799) and the ESR2 haplotype (variant allele; rs1255998 and wild‐type alleles; rs944050, rs4986938 and rs1256049) were at an increased risk (OR 1.862, P = 0.013 and OR 1.918, P = 0.046 respectively). This risk was even greater in women carrying both risk haplotypes (OR 5.041, P = 0.007).Conclusions  Our data suggest that the ESR1 (rs2234693 and rs9340799) and the ESR2 (rs1255998 and rs944050) polymorphisms may be associated with an increased risk of developing endometrial cancer.
A trend analysis in referrals during pregnancy and labour in Dutch midwifery care 1988–2004
Authors: Amelink‐Verburg MP , Rijnders MEB , Buitendijk SE 
Published: May 2009

Objective To assess the trends and patterns of referral from midwives to obstetricians within the Dutch maternity care system from 1988 to 2004, and the differences in referral patterns between nulliparous and parous women.Design A descriptive study.Setting The Dutch midwifery database (LVR1), which monitored 74% (1988) to 94% (2004) of all midwifery care in the Netherlands between 1988 and 2004.Population A total of 1 977 006 pregnancies, attended by a primary care level midwife.Methods The indications for referral from midwifery to obstetric care were classified into fifteen groups (eight antepartum, six intrapartum and one postpartum). The trends in referrals of these indications were analysed by general linear models.Main outcome measures Trends in the percentage of antepartum, intrapartum and postpartum referrals from midwifery care to obstetric care; trends in the specific indications for referral; contribution of different groups of the indications to the trend.Results From 1988 to 2004 an increase of 14.5% (from 36.9 to 51.4%) occurred in referrals from primary midwifery care to secondary obstetric care either during pregnancy, childbirth or in the postpartum period. The timing of the referrals was as follows: antepartum +9.0%, intrapartum +5.2% and postpartum +0.3%. In parous women, the increase in referrals was greater (+16.6%) than in nulliparous women (+12.3%) (P = 0.001). The commonest indications for referrals in nulliparous women were anticipated or evident complications due to ‘failure to progress in the first or second stage’ and ‘fetal distress’. Parous women were most commonly referred for anticipated or evident complications due to ‘medical history’ and ‘fetal distress’. In nulliparous women, 52% of the increase in referrals was related to the need of pain relief and occurrence of meconium‐stained amniotic fluid; in parous women, 54% of the increase in referrals was related to the general medical and obstetrical history of the women, particularly previous caesarean section, and the occurrence of meconium‐stained amniotic fluid.Conclusions During a 17‐year period, there was a continuous increase in the referral rate from midwives to obstetricians. Previous caesarean section, requirement for pain relief and the presence of meconium‐stained amniotic fluid were the main contributors to the changes in referral rates. Primary prevention of caesarean section and antenatal preparation for childbirth are important interventions in the maintenance of primary obstetric care for low‐risk pregnant women.
PPARγ and RXRγ ligands act synergistically as potent antineoplastic agents in vitro and in vivo glioma models
Authors: Papi Alessio , Tatenhorst Lars , Terwel Dick , Hermes Michael , Kummer Markus P. , Orlandi Marina , Heneka Michael T. 
Published: May 2009

AbstractGlioblastoma represent the most common primary brain tumor in adults and are currently considered incurable. We investigated antiproliferative and anti‐invasive mechanisms of 6‐OH‐11‐O‐hydroxyfenantrene (IIF), a retinoid X receptor ligand, and pioglitazone (PGZ), a peroxisome proliferator‐activated receptor γ activator, in three different glioblastoma cell lines. A dose‐dependent reduction of tumor invasion and strong decrease of matrix metalloproteinases 2 and 9 expression was observed, especially when a combination therapy of IIF and PGZ was administered. Combined treatment also markedly reduced proliferation and induced apoptosis in all glioma cell lines tested. This was in particular accompanied by decrease of antiapoptotic proteins Bcl2 and p53, while simultaneously pro‐apoptotic cytochrome c, cleaved caspase 3, Bax and Bad levels increased. These in vitro findings were further substantiated in a murine glioma model in vivo, where oral administration of PGZ and IIF resulted in significantly reduced tumor volume and proliferation. Of note, treatment with nuclear receptor ligands was not only effective when the treatment was initiated shortly after the intraparenchymal seeding of the glioma cells, but even when initiated in the last third of the observation period. Collectively, our results demonstrate the effectiveness of a combined treatment of ligands of proliferator‐activated receptor and retinoid X receptor against glioblastoma.
Activation of p38 MAPK in the substantia nigra leads to nuclear translocation of NF‐κB in MPTP‐treated mice: implication in Parkinson’s disease
Authors: Karunakaran S. , Ravindranath V. 
Published: May 2009

AbstractActivation and translocation of the transcription factor nuclear factor kappa B (NF‐κB) from cytoplasm to the nucleus has been reported in models of Parkinson’s disease (PD). Our focus was to discern the upstream events which ultimately lead to NF‐κB nuclear translocation using animal model of PD. We demonstrate that p38 activation results in downstream phosphorylation of NF‐κB and accumulation of p65 subunit of NF‐κB selectively in ventral midbrain but not in striatum. Treatment with p38 inhibitor, SB239063, prevented downstream phosphorylation of IκBα and p65 translocation to the nucleus in the ventral midbrain. Phosphorylation of anti‐apoptotic Bcl2, an NF‐κB target gene by p38 to inactive pBcl2ser87 was also attenuated by SB239063. Increased staining of p65 in the nuclei of cells in the substantia nigra but not in the ventral tegmental area of MPTP‐treated mice further suggests a role for NF‐κB in PD. In agreement with the above, sustained caspase activation is seen in the ventral midbrain but not in striatum. We demonstrate the region specific p38‐mediated activation of NF‐κB following MPTP treatment demonstrating the role of p38/NF‐κB signaling in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression.
Role of neuroglobin in regulating reactive oxygen species in the brain of the anoxia‐tolerant turtle Trachemys scripta
Authors: Nayak Gauri , Prentice Howard M. , Milton Sarah L. 
Published: May 2009

AbstractNeuroglobin (Ngb) is an oxygen binding heme protein found in nervous tissue with a yet unclear physiological and protective role in the hypoxia‐sensitive mammalian brain. Here we utilized in vivo and in vitro studies to examine the role of Ngb in anoxic and post‐anoxic neuronal survival in the freshwater turtle. We employed semiquantitative RT‐PCR and western blotting to analyze Ngb mRNA and protein levels in turtle brain and neuronally enriched cultures. Ngb expression is strongly up‐regulated by hypoxia and post‐anoxia reoxygenation but increases only modestly in anoxia. The potential neuroprotective role of Ngb in this species was analyzed by knocking down Ngb using specific small interfering RNA. Ngb knockdown in neuronally enriched cell cultures resulted in significant increases in H2O2 release compared to controls but no change in cell death. Cell survival may be linked to activation of other protective responses such as the extracellular regulated kinase transduction pathway, as phosphorylated extracellular regulated kinase levels in anoxia were significantly higher in Ngb knockdown cultures compared to controls. The greater expression of Ngb when reactive oxygen species are likely to be high, and the increased susceptibility of neurons to H2O2 release and external oxidative stress in knockdown cultures, suggests a role for Ngb in reducing reactive oxygen species production or in detoxification, though it does not appear to be of primary importance in the anoxia tolerant turtle in the presence of compensatory survival mechanisms.
Dkk‐3 is elevated in CSF and plasma of Alzheimer’s disease patients
Authors: Zenzmaier Christoph , Marksteiner Josef , Kiefer Andreas , Berger Peter , Humpel Christian 
Published: May 2009

AbstractBiomarkers in CSF can offer improved diagnostic accuracy for Alzheimer’s disease (AD). The present study investigated whether the glycoprotein and putative tumor suppressor Dickkopf homolog 3 (Dkk‐3) is secreted into CSF and evaluated its applicability as a diagnostic marker for AD. Using our highly specific immunoenzymometric assay, Dkk‐3 levels were measured in plasma and/or CSF of patients suffering from depression, mild cognitive impairment (MCI), or AD and compared with healthy subjects. Dkk‐3 identity was verified by western blot and matrix‐assisted laser desorption/ionization time‐of‐flight (MALDI‐TOF) mass spectrometry (MS)/MS. High concentrations of Dkk‐3 were detected in CSF compared with plasma (28.2 ± 1.3 vs. 1.22 ± 0.04 nmol/L, respectively). Consistently Dkk‐3 expression was demonstrated in neurons of the cortex and epithelial cells of the choroid plexus, the major source of CSF. Significantly increased Dkk‐3 levels in plasma and CSF were observed for AD patients compared with healthy subjects but not patients suffering from MCI or depression. In summary, our data indicate that elevated Dkk‐3 levels are specifically associated with AD and might serve as a potential non‐invasive AD biomarker in plasma.
Heme oxygenase‐1 and neurodegeneration: expanding frontiers of engagement
Authors: Schipper Hyman M. , Song Wei , Zukor Hillel , Hascalovici Jacob R. , Zeligman David 
Published: May 2009

AbstractThe heme oxygenases (HOs), responsible for the degradation of heme to biliverdin/bilirubin, free iron and CO, have been heavily implicated in mammalian CNS aging and disease. In normal brain, the expression of HO‐2 is constitutive, abundant and fairly ubiquitous, whereas HO‐1 mRNA and protein are confined to small populations of scattered neurons and neuroglia. In contradistinction to HO‐2, the ho‐1 gene (Hmox1) is exquisitely sensitive to induction by a wide range of pro‐oxidant and other stressors. In Alzheimer disease and mild cognitive impairment, immunoreactive HO‐1 protein is over‐expressed in neurons and astrocytes of the cerebral cortex and hippocampus relative to age‐matched, cognitively intact controls and co‐localizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO‐1 is markedly over‐expressed in astrocytes of the substantia nigra and decorates Lewy bodies in affected dopaminergic neurons. HMOX1 is also up‐regulated in glial cells surrounding human cerebral infarcts, hemorrhages and contusions, within multiple sclerosis plaques, and in other degenerative and inflammatory human CNS disorders. Heme‐derived free ferrous iron, CO, and biliverdin/bilirubin are biologically active substances that have been shown to either ameliorate or exacerbate neural injury contingent upon specific disease models employed, the intensity and duration of HO‐1 expression and the nature of the prevailing redox microenvironment. In ‘stressed’ astroglia, HO‐1 hyperactivity promotes mitochondrial sequestration of non‐transferrin iron and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in Alzheimer disease, Parkinson disease and other aging‐related neurodegenerative disorders. Glial HO‐1 expression may also impact cell survival and neuroplasticity in these conditions by modulating brain sterol metabolism and proteosomal degradation of neurotoxic protein aggregates.
RasGRF1 disruption causes retinal photoreception defects and associated transcriptomic alterations
Authors: Fernández‐Medarde Alberto , Barhoum Rima , Riquelme Raquel , Porteros Angel , Núñez Alejandro , De Luis Alberto , De Las Rivas Javier , De La Villa Pedro , Varela‐Nieto Isabel , Santos Eugenio 
Published: May 2009

AbstractRasGRF1 null mutant mice display impaired memory/learning and their hippocampus transcriptomic pattern includes a number of differentially expressed genes playing significant roles in sensory development and function. Odour avoidance and auditory brainstem response tests yielded normal results but electroretinographic analysis showed severe light perception impairment in the RasGRF1 knockouts. Whereas no structural alterations distinguished the retinas of wild‐type and knockout mice, microarray transcriptional analysis identified at least 44 differentially expressed genes in the retinas of these Knockout animals. Among these, Crb1, Pttg1, Folh1 and Myo7a have been previously related to syndromes involving retina degeneration. Interestingly, over‐expression of Folh1 would be expected to result in accumulation of its enzymatic product N‐acetyl‐aspartate, an event known to be linked to Canavan disease, a human cerebral degenerative syndrome often involving blindness and hearing loss. Consistently, in vivo brain nuclear magnetic resonance spectroscopy identified higher levels of N‐acetyl‐aspartate in our RasGRF1−/− mice and immunohistochemical analysis detected reduced levels of aspartoacylase, the enzyme which degrades N‐acetyl‐aspartate. These studies demonstrate for the first time the functional relevance of Ras signalling in mammalian photoreception and warrant further analysis of RasGRF1 Knockout mice as potential models to analyse molecular mechanisms underlying defective photoreception human diseases.
The distribution of anterior chamber depth in a Tehran population: the Tehran eye study
Authors: Hashemi Hassan , KhabazKhoob Mehdi , Mehravaran Shiva , Yazdani Kamran , Mohammad Kazem , Fotouhi Akbar 
Published: May 2009

AbstractPurpose: To determine the normal range of anterior chamber depth (ACD) in the population of Tehran by age and gender.Materials and methods: Four hundred and ten people (800 eyes) aged 14 years and over, residing in the first four municipality areas of Tehran were selected through a stratified random cluster sampling method. The measurements were all taken by a single skilled technician using Orbscan II, between 9:00 am and 7:00 pm. The ACD was defined as the distance between the corneal endothelium and the anterior lens surface. Considering the high correlation between the ACD readings of contralateral eyes (r = 0.82, p < 0.001), only data from right eyes were analysed.Results: In the participants, the mean age was 40.6 ± 16.8 years and 38.8% were male. The mean ACD was 2.79 mm [95% confidence interval (CI): 2.75–2.83]; 2.84 mm (95% CI: 2.79–2.90) in men and 2.75 mm (95% CI: 2.70–2.81) in women. Linear regression analysis revealed a mean ACD reduction of 0.013 mm per year of age (p < 0.001). The ACD decreased by 0.056 mm per diopter of spherical equivalent and 0.018 mm per mmHg of IOP (p < 0.001 and p = 0.030, respectively).Conclusions: We found the normal range of ACD in the population of Tehran which is slightly different from that reported from other geographical regions. The study also demonstrated the correlation of ACD with other factors; it decreases with age, and is slightly higher in men.
Pharmacokinetics of carisbamate (RWJ‐333369) in healthy Japanese and Western subjects
Authors: Zannikos Peter , Novak Gerald , Yao Caiping , Verhaeghe Tom , Franc Monique A. , Solanki Bhavna , Bialer Meir 
Published: May 2009

SummaryPurpose:  To compare the pharmacokinetics of carisbamate (RWJ‐333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations.Methods:  An open‐label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3‐day washout period; twice‐daily dosing of 250 mg carisbamate on days 5–8; subsequently, 500 mg on days 9–12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid‐chromatography‐mass‐spectrometry.Results:  Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80–125% limits, which are considered not to be of clinical significance. With dose–body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80–125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half‐life were similar in both groups, ranging from 35.1–41.4 ml/h/kg and 11.5–12.8 h.Discussion:  Carisbamate plasma exposure (AUC) and Cmax in Japanese subjects is ∼20–25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality.
First transmission of human immunodeficiency virus Type 1 by a cellular blood product after mandatory nucleic acid screening in Germany
Authors: Schmidt Michael , Korn Klaus , Nübling C. Micha , Chudy Michael , Kress Julia , Horst Heinz A. , Geusendam Geert , Hennig Holger , Sireis Walid , Rabenau Holger F. , Doerr Hans Wilhelm , Berger Annemarie , Hourfar Michael Kai , Gubbe Knut , Karl Andreas , Fickenscher Helmut , Tischer B. Karsten , Babiel Reiner , Seifried Erhard , Gürtler Lutz 
Published: May 2009

BACKGROUND: In February 2007, a 63‐year‐old man underwent surgery. Retrospective testing with nucleic acid testing (NAT) showed that the patient was human immunodeficiency virus Type 1 (HIV‐1) positive 10 days after transfusion. The transfusion‐transmitted infection had been identified by a donor‐related lookback started in April 2007 after anti‐HIV seroconversion.METHODS: Sequence analysis was performed in the gag‐pol region as well as in the V3 loop env region. Archived plasma from the transmitting donation was investigated for the individual‐donation NAT with the Roche COBAS AmpliPrep/COBAS TaqMan HIV‐1 test (Roche CAP/CTM HIV‐1 test) and for HIV antigen/antibody combination testing (Abbott Architect). Additional testing was done on the donor's follow‐up sample and on the recipient's sample.RESULTS: The Roche CAP/CTM HIV‐1 test failed to detect viral RNA by minipool NAT in the index donation (April 2007) as well as in the donation that caused the infection (January 2007). Phylogenetic analysis showed a very high genetic similarity among viral sequences from both donor and recipient, proving the HIV‐1 transmission by sequence data.CONCLUSION: This case represents the first documented HIV‐1 transmission by transfusion of red blood cells after mandatory introduction of HIV‐1 NAT for blood screening in Germany. Low viral load and mismatches in the primer/probe region might explain the detection failure of the NAT screening assay. A certain risk remains that new virus variants contain mutations at positions critical for amplification or detection of viral genomes. An option to reduce the risk of a detection failure by NAT is the simultaneous use of several conserved regions as amplification targets.
The association of preoperative anemia and perioperative allogeneic blood transfusion with the risk of surgical site infection
Authors: Weber Walter P. , Zwahlen Marcel , Reck Stefan , Misteli Heidi , Rosenthal Rachel , Buser Andreas S. , Kaufmann Mark , Oertli Daniel , Widmer Andreas F. , Marti Walter R. 
Published: May 2009

BACKGROUND: The purpose of the study was to investigate allogeneic blood transfusion (ABT) and preoperative anemia as risk factors for surgical site infection (SSI).STUDY DESIGN AND METHODS: A prospective, observational cohort of 5873 consecutive general surgical procedures at Basel University Hospital was analyzed to determine the relationship between perioperative ABT and preoperative anemia and the incidence of SSI. ABT was defined as transfusion of leukoreduced red blood cells during surgery and anemia as hemoglobin concentration of less than 120 g/L before surgery. Surgical wounds and resulting infections were assessed to Centers for Disease Control standards.RESULTS: The overall SSI rate was 4.8% (284 of 5873). In univariable logistic regression analyses, perioperative ABT (crude odds ratio [OR], 2.93; 95% confidence interval [CI], 2.1 to 4.0; p < 0.001) and preoperative anemia (crude OR, 1.32; 95% CI, 1.0 to 1.7; p = 0.037) were significantly associated with an increased odds of SSI. After adjusting for 13 characteristics of the patient and the procedure in multivariable analyses, associations were substantially reduced for ABT (OR, 1.25; 95% CI, 0.8 to 1.9; p = 0.310; OR, 1.07; 95% CI, 0.6 to 2.0; p = 0.817 for 1‐2 blood units and ≥3 blood units, respectively) and anemia (OR, 0.91; 95% CI, 0.7 to 1.2; p = 0.530). Duration of surgery was the main confounding variable.CONCLUSION: Our findings point to important confounding factors and strengthen existing doubts on leukoreduced ABT during general surgery and preoperative anemia as risk factors for SSIs.