bluuebunny/crossref_metadata_2025 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

Glioblastoma 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

Activation 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

Neuroglobin (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

Biomarkers 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

The 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

RasGRF1 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

Purpose:  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.
Poverty, Deprivation and Consistent Poverty*
Authors: SAUNDERS PETER , NAIDOO YUVISTHI
Published: May 2009

Controversy over the setting of poverty lines and its narrow focus on income has undermined the influence of poverty research on policy. The deprivation approach overcomes these limitations by identifying deprivation as an inability to afford items that receive majority support for being essential. This paper estimates the incidence of deprivation and compares the results with those produced using a conventional poverty framework. The results confirm overseas findings by showing that the groups most deprived differ from those with the highest poverty rates and that there is a low degree of overlap between income poverty and deprivation. Older people show up as faring better under the deprivation approach, while working‐age individuals and families fare worse and the relative position of the most highly disadvantaged groups are worse in terms of deprivation than in terms of poverty. Deprivation also provides a clearer differentiation between those who can and cannot afford specific necessities than a classification based on low income, and is also shown to vary systematically with several indicators of subjective well‐being. Estimates of consistent poverty that combine low income with deprivation are shown to differ from conventional (income‐based) poverty rates, and provide the basis for future poverty measures.
IGF‐1 derived small neuropeptides and analogues: a novel strategy for the development of pharmaceuticals for neurological conditions
Authors: Guan Jian , Gluckman Peter D
Published: May 2009

Insulin‐like growth factor‐1 (IGF‐1) is neuroprotective and improves long‐term function after brain injury. However, its clinical application to neurological disorders is limited by its large molecular size, poor central uptake and mitogenic potential. Glycine‐proline‐glutamate (GPE) is naturally cleaved from the IGF‐1 N‐terminal and it is also neuroprotective after ischemic injury, which provided a novel strategy of drug discovery for neurological disorders. GPE is not enzymatically stable, thus intravenous infusion of GPE becomes necessary for stable and potent neuroprotection. The broad effective dose range and treatment window of 3–7 h after the lesion suggest its potential for treating acute brain injuries. G‐2meth‐PE, a GPE analogue designed to be more enzymatic resistant, has a prolonged plasma half‐life and is more potent in neuroprotection. Neuroprotection by GPE and its analogue may involve modulation of inflammation, promotion of astrocytosis, inhibition of apoptosis and vascular remodelling. Acute administration of GPE also prevents 6‐OHDA‐induced nigrostrial dopamine depletion. Delayed treatment with GPE does not prevent dopamine loss, but improves long‐term function. Cyclo‐glycyl‐proline (cyclic Gly‐Pro) is an endogenous DKP that may be derived from GPE. Cyclic Gly‐Pro and its analogue cyclo‐L‐glycyl‐L‐2‐allylproline (NNZ 2591) are both neuroprotective after ischaemic injury. NNZ2591 is highly enzymatic resistant and centrally accessible. Its peripheral administration improves somatosensory‐motor function and long‐term histological outcome after brain injury. Our research suggests that small neuropeptides have advantages over growth factors in the treatment of brain injury, and that modified neuropeptides designed to overcome the limitations of their endogenous counterparts represent a novel strategy of pharmaceutical discovery for neurological disorders.
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

Purpose:  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.
Washing platelets in neutral, calcium‐free, Ringer's acetate
Authors: Kelley Walter E. , Edelman Bennett B. , Drachenberg Cinthia B. , Hess John R.
Published: May 2009

BACKGROUND: Washed platelets (PLTs) are occasionally requested for patients with histories of allergic or anaphylactic reactions. Washing methods and conditions result in the loss of PLT number and function. Short postwash storage times occasionally conflict with other patient activities and result in the wastage of washed products. Better washing procedures are a start to longer postwash hold times.

STUDY DESIGN AND METHODS: Twenty‐six units of just‐outdated 6‐ or 7‐day‐old apheresis PLT concentrates were sampled; washed in neutral, calcium‐free, Ringer's acetate (NRA); allowed to recover for 0.5 hour; and resampled. PLTs were counted, subjected to transmission electron microscopy, diluted with either equal‐volume NRA (prewash) or autologous plasma (postwash), and subjected to thromboelastography. Pre‐ and postwash products were compared.

RESULTS: PLT recovery was 71%. Plasma removal was 96%. Electron microscopy PLT morphology was unchanged by washing. Thromboelastography showed a mild decrease in final clot strength after washing that was not related to PLT concentration.

CONCLUSIONS: PLT washing in NRA allows good recovery of PLT numbers and good preservation of function in vitro as assessed by thromboelastography. If performed in a closed‐system cell washer, extension of the current 4‐hour storage time for washed PLTs should be possible.
Transfusion management of sickle cell patients during bone marrow transplantation with matched sibling donor
Authors: McPherson Marianne E. , Anderson Alan R. , Haight Ann E. , Jessup Paula , Castillejo Marta‐Inés , Hillyer Christopher D. , Josephson Cassandra D.
Published: May 2009

BACKGROUND: Sickle cell disease (SCD) patients have unique transfusion considerations during bone marrow transplantation (BMT), including prophylaxis against stroke and alloimmunization. Characterization of transfusion requirements is important for blood bank and clinician patient management.

STUDY DESIGN AND METHODS: A retrospective analysis of red blood cell (RBC) and platelet (PLT) transfusion of SCD patients during myeloablative matched sibling donor (MSD) BMT at one institution from 1993 to 2007 was performed. Patient characteristics (RBC blood group antibodies, ABO‐incompatible donor, BMT‐related morbidity) and transfusion practices (RBC phenotype matching, transfusion threshold, and blood age) were assessed for effect on total RBC transfusion volumes.

RESULTS: Twenty‐seven patients received MSD BMT with 96% survival and 0% rejection. Six alloimmunized patients received RBCs with extended phenotype matching (C, c, E, e, K, Fya, Jkb), 14 nonalloimmunized received limited matching (C, c, E, e, K), and 7 did not have phenotype matching. Among 26 survivors, a median seven RBC transfusions (range, 3‐15) and 13.5 PLT transfusions (range, 4‐48) per patient were administered, equivalent to 64 mL/kg RBCs (range, 22‐122 mL/kg) and 106 mL/kg PLTs (range, 26‐343 mL/kg). BMT‐related morbidity predicted increased RBC transfusions (p = 0.006). Venoocclusive disease was associated with greater RBC (p = 0.016) and PLT transfusion volumes (p = 0.016). Greater phenotype matching was associated with decreased RBC transfusions (p = 0.0247).

CONCLUSIONS: SCD patients have high transfusion support during MSD BMT. Communication of BMT complications to the blood bank is essential for transfusion inventory management. Phenotype matching decreased RBC transfusions in this cohort and warrants further investigation in SCD transfusion therapy.
“You Look, Thank God, Quite Good on the Outside”: Imitating the Ideal Self in a Jewish Ultra‐Orthodox Rehabilitation Site
Authors: Goodman Yehuda C.
Published: May 2009

Rather than viewing therapeutic interventions as either compliance or resistance to the social order, I analyze them as mimesis of cultural ideal selves. In particular, I examine the new mediations of the social order constituted in mimetic therapeutic practices and their entailed creativity and ambivalence. Drawing on participant observation in a Jewish ultra‐Orthodox (Haredi) rehabilitation site I explore how, given the ruptures brought about in mental disorders, caretakers offer their clients new ways to inhabit the normal self through its imitation. Specifically, caregivers construct replications of dominant selves by selectively deploying modern and neotraditional discourses of the self in diverse social contexts and in multiple registries like body, emotions, social relations, and ways of belonging to the community. I suggest that mimetic therapeutic work is carried out along emerging social distinctions that are associated with Haredim's complex relations with the secular society, and with cultural contestations within the community itself.
Outpatient Management of Primary Spontaneous Pneumothorax in the Emergency Department of a Community Hospital Using a Small‐bore Catheter and a Heimlich Valve
Authors: Hassani Behzad , Foote John , Borgundvaag Bjug
Published: May 2009

Objectives:  The objective was to assess the effectiveness of a small‐bore catheter (8F) connected to a one‐way Heimlich valve in the emergency department (ED)‐based outpatient management of primary spontaneous pneumothorax (PSP).

Methods:  The authors conducted a structured chart audit in a retrospective case series of patients with PSP who were treated with a small‐bore (8F) catheter and a Heimlich valve who were seen in the ED of a community hospital between April 2000 and March 2005. To be eligible, patients had to be available for a telephone interview. Main outcomes were success of treatment (sustained, complete lung reexpansion), admission, and surgical intervention rates. Secondary outcomes included number of chest x‐rays (CXRs), number of visits to the ED, treatment duration, complications, and recurrence rates.

Results:  The authors identified 62 discrete episodes of PSP in 50 patients, with a mean (±standard deviation [SD]) age of 25.5 ± 10.5 years (range = 14–53 years). In 50 of 62 episodes (81%, 95% confidence interval [CI] = 70.8% to 90.5%), patients were discharged directly from the ED. Patients were admitted to the hospital at some point for treatment in 27/62 episodes (43.5%, 95% CI = 31.2% to 55.9%). Surgery was performed for acute treatment failure in 17 episodes. Ultimately, 19 patients, who accounted for 21 of 62 episodes (33.9%, 95% CI = 22.1% to 45.6%), had surgery at some point in the study. Mean (±SD) time to admission for those patients initially discharged from the ED was 2.9 (±2.01) days (95% CI = 1.9 to 3.8 days). There were no serious complications from treatment; the minor complication rate (misplacement or dislodging of the chest tube) was 22.6% (95% CI = 12.2% to 33.0%). No association was found between the size of pneumothorax and treatment failure.

Conclusions:  This study suggests that the initial management of PSP with a small‐bore catheter and Heimlich valve can easily be performed by emergency physicians in the community hospital setting and appears safe. A larger study systematically comparing this approach with alternative therapies is needed.
Multicenter Validation of the Philadelphia EMS Admission Rule (PEAR) to Predict Hospital Admission in Adult Patients Using Out‐of‐hospital Data
Authors: Meisel Zachary F. , Mathew Rex , Wydro Gerald C. , Crawford Mechem C. , Pollack Charles V. , Katzer Robert , Prabhu Anjeli , Ozumba Adora , Pines Jesse M.
Published: May 2009

Objectives:  The objective was to validate a previously derived prediction rule for hospital admission using routinely collected out‐of‐hospital information.

Methods:  The authors performed a multicenter retrospective cohort study of 1,500 randomly selected, adult patients transported to six separate emergency departments (EDs; three community and three academic hospitals in three separate health systems) by a city‐run emergency medical services (EMS) system over a 1‐year period. Patients younger than 18 years or who bypassed the ED to be evaluated by trauma, obstetric, or psychiatric teams were excluded. The score consisted of six weighted elements that generated a total score (0–14): age ≥ 60 years (3 points); chest pain (3); shortness of breath (3); dizzy, weakness, or syncope (2); history of cancer (2); and history of diabetes (1). Receiver operator characteristic (ROC) curves for the decision rule and admission rates were calculated among individual hospitals and for the entire cohort.

Results:  A total of 1,102 patients met inclusion criteria. The admission rate for the entire cohort was 40%, and individual hospital admission rates ranged from 28% to 57%. Overall, 34% had a score of ≥4, and 29% had a score of ≥5. Area under the ROC curve (AUC) for the combined cohort was 0.83 for all admissions and 0.72 for intensive care unit (ICU) admissions; AUCs at individual hospitals ranged from 0.72 to 0.85. The admission rate for a score of ≥4 was 77%; for a score of ≥5 the admission rate was 80%.

Conclusions:  The ability of this EMS rule to predict the likelihood of hospital admission appears valid in this multicenter cohort. Further studies are needed to measure the impact and feasibility of using this rule to guide decision‐making.
Temporal and contextual orchestration of cardiac fate by WNT‐BMP synergy and threshold
Authors: Verma Mahesh K. , Lenka Nibedita
Published: May 2009

Cardiomyogenic development proceeds with a cascade of intricate signalling events that operate in a temporo‐spatial fashion to specify cardiac cell fate during early embryogenesis. In fact, conflicting reports exist regarding the role of Wnt/β‐catenin signalling during cardiomyogenesis. Here, we describe a dose‐dependent and temporal effect of Wnt/β‐catenin signalling on in vitro cardiomyogenesis using embryonic stem cells (ESCs) as a model system. We could demonstrate that canonical Wnt activation during early stage of differentiation either through ligand or by GSK3β inhibition helped in maintaining Oct4 and Nanog expressions, and in parallel, it promoted mesoderm and endoderm inductions. In contrast, it led to attenuation in cardiomyogenesis that was reversed by moderate concentration of DKK1, but not soluble Fz8. However, higher DKK1 could also block cardiomyogenesis, suggesting thereby governance of a particular signalling threshold underlying this developmental event. Interestingly, Wnt signalling activation at early stage modulated BMP4 expression in a stage‐specific manner. Wnt activation, synchronized with BMP4 and brachyury up‐regulation at early stage, correlated well with mesoderm induction. Conversely, Wnt activation led to BMP4 and Wnt5a down‐regulation at late stage culminating in cardiomyogenic attenuation. Our findings suggested the existence of precise regulatory machinery with context‐dependent role of Wnt for fine tuning mesoderm induction and its derivatives, through establishment of Wnt gradient during ESCs’ differentiation. Moreover, contrary to mere activation/inhibition, a specific threshold of Wnt and BMP and their synergy seemed necessary for providing the guiding cues in orchestrating mesoderm induction and subsequent cardiomyogenesis.
Mitochondrial accumulation of polyubiquitinated proteins and differential regulation of apoptosis by polyubiquitination sites Lys‐48 and ‐63
Authors: Sun Faneng , Kanthasamy Arthi , Anantharam Vellareddy , Kanthasamy Anumantha G.
Published: May 2009

Proteins tagged with lysine (Lys, K) 48 polyubiquitins chains are destined for degradation by the 26S proteasomal system. Impairment of the ubiquitin proteasome system (UPS) function culminates in the accumulation of polyubiquitinated proteins in many neurodegenerative conditions including Parkinson’s disease (PD). Nevertheless, the cellular mechanisms underlying cell death induced by an impaired UPS are still not clear. Intriguingly, recent studies indicate that several proteins associated with familial PD are capable of promoting the assembly of Lys‐63 polyubiquitin chains. Therefore, the objective of this study was to examine the role of K48 and K63 ubiquitination in mitochondria‐mediated apoptosis in in vitro models of dopaminergic degeneration. Exposure of the widely used proteasome inhibitor MG‐132 to dopaminergic neuronal cell line (N27) induced a rapid accumulation of polyubiquitinated proteins in the mitochondria. This appears to result in the preferential association of ubiquitin conjugates in the outer membrane and polyubiquitination of outer membrane proteins. Interestingly, the ubiquitinK48R mutant effectively rescued cells from MG‐132‐induced mitochondrial apoptosis without altering the antioxidant status of cells; whereas the ubiqutinK63R mutant augmented the proapoptotic effect of MG‐132. Herein, we report a novel conclusion that polyubiquitinated proteins, otherwise subjected to proteasomal degradation, preferentially accumulate in the mitochondria during proteolytic stress; and that polyubiquitination of Lys‐48 and Lys‐63 are key determinants of mitochondria‐mediated cell death during proteasomal dysfunction. Together, these findings yield novel insights into a crosstalk between the UPS and mitochondria in dopaminergic neuronal cells.
DR5‐mediated DISC controls caspase‐8 cleavage and initiation of apoptosis in human glioblastomas
Authors: Bellail Anita C. , Tse Margaret C. L. , Song Jin H. , Phuphanich Surasak , Olson Jeffrey J. , Sun Shi Yong , Hao Chunhai
Published: May 2009

To explore the molecular mechanisms by which glioblastomas are resistant to tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL), we examined TRAIL signalling pathways in the tumours. TRAIL has four membrane‐anchored receptors, death receptor 4/5 (DR4/5) and decoy receptor 1/2 (DcR1/2). Of these receptors, only DR5 was expressed consistently in glioblastoma cell lines and tumour tissues, ruling out the role of DcR1/2 in TRAIL resistance. Upon TRAIL binding, DR5 was homotrimerized and recruited Fas‐associated death domain (FADD) and caspase‐8 for the assembly of death‐inducing signalling complex (DISC) in the lipid rafts of the plasma membrane. In the DISC, caspase‐8 was cleaved and initiated apoptosis by cleaving downstream caspases in TRAIL‐sensitive glioblastoma cells. In TRAIL‐resistant cells, however, DR5‐mediated DISC was modified by receptor‐interacting protein (RIP), cellular FADD‐like interleukin‐1β‐converting enzyme inhibitory protein (c‐FLIP) and phosphoprotein enriched in diabetes or in astrocyte‐15 (PED/PEA‐15). This DISC modification occurred in the non‐raft fractions of the plasma membrane and resulted in the inhibition of caspase‐8 cleavage and activation of nuclear factor‐κB (NF‐κB). Treatment of resistant cells with parthenolide, an inhibitor of inhibitor of κB (I‐κB), eliminated TRAIL‐induced NF‐κB activity but not TRAIL resistance. In contrast, however, targeting of RIP, c‐FLIP or PED/PEA‐15 with small interfering RNA (siRNA) led to the redistribution of the DISC from non‐rafts to lipid rafts and eliminated the inhibition of caspase‐8 cleavage and thereby TRAIL resistance. Taken together, this study indicates that the DISC modification by RIP, c‐FLIP and PED/PEA‐15 is the most upstream event in TRAIL resistance in glioblastomas.
Mechanical load modulates chondrogenesis of human mesenchymal stem cells through the TGF‐β pathway
Authors: Li Zhen , Kupcsik Laszlo , Yao Shan‐Jing , Alini Mauro , Stoddart Martin J.
Published: May 2009

This study investigated the effect of mechanical load on human mesenchymal stem cell (hMSC) differentiation under different exogenous transforming growth factor‐β1 (TGF‐β1) concentrations (0, 1 or 10 ng/ml).The role of the TGF‐β signalling pathway in this process was also studied. Human MSCs were seeded into fibrin‐biodegradable polyurethane scaffolds at a cell density of 5 × 106 cells per scaffold and stimulated using our bioreactor. One hour of surface motion superimposed on cyclic compression was applied once a day over seven consecutive days. Scaffolds were analysed for gene expression, DNA content and glycosaminoglycan amount. Addition of TGF‐β1 in the culture medium was sufficient to induce chondrogenesis of hMSCs. Depending on the TGF‐β1 concentration of the culture medium, mechanical load stimulated chondrogenesis of hMSCs compared to the unloaded scaffolds, with a much stronger effect on gene expression at lower TGF‐β1 concentrations. With TGF‐β1 absent in the culture medium, mechanical load stimulated gene transcripts and protein synthesis of TGF‐β1 and TGF‐β3. TGF‐β type I receptor inhibitor LY364947 blocked the up‐regulation on TGF‐β1 and TGF‐β3 production stimulated by mechanical load, and also blocked the chondrogenesis of hMSCs. Taken together, these findings suggest that mechanical load promotes chondrogenesis of hMSCs through TGF‐β pathway by up‐regulating TGF‐β gene expression and protein synthesis.
The rat as an animal model of Alzheimer's disease
Authors: Benedikz Eirikur , Kloskowska Ewa , Winblad Bengt
Published: May 2009

Introduction

The laboratory rat

Rat models of cholinergic‐clysfunction

Aβ‐based models of AD

Transgenic rats

Virally induced models of AD

Concluding remarks

As a disease model, the laboratory rat has contributed enormously to neuroscience research over the years. It has also been a popular animal model for Alzheimer's disease but its popularity has diminished during the last decade, as techniques for genetic manipulation in rats have lagged behind that of mice. In recent years, the rat has been making a comeback as an Alzheimer's disease model and the appearance of increasing numbers of transgenic rats will be a welcome and valuable complement to the existing mouse models. This review summarizes the contributions and current status of the rat as an animal model of Alzheimer's disease.
Cell‐penetrating peptide TAT‐mediated delivery of acidic FGF to retina and protection against ischemia–reperfusion injury in rats
Authors: Wang Yi , Lin Haihuan , Lin Shaoqiang , Qu Jia , Xiao Jian , Huang Yadong , Xiao Yechen , Fu Xiaobing , Yang Yongguang , Li Xiaokun
Published: May 2009

The development of non‐invasive ocular drug delivery systems is of practical importance in the treatment of retinal disease. In this study, we evaluated the efficacy of transactivator of transcription protein transduction domain (TAT‐PTD, TAT49–57) as a vehicle to deliver acidic FGF (aFGF) to retina in rats. TAT‐conjugated aFGF‐His (TAT‐aFGF‐His) exhibited efficient penetration into the retina following topical administration to the ocular surface. Immunochemical staining with anti‐His revealed that TAT‐aFGF‐His proteins were readily found in the retina (mainly in the ganglion cell layer) at 30 min. and remained detectable for at least 8 hrs after administration. In contrast, His+ proteins were undetectable in the retina after topical administration of aFGF‐His, indicating that aFGF‐His cannot penetrate the ocular barrier. Furthermore, TAT‐aFGF‐His, but not aFGF‐His, mediated significant protection against retinal ischemia–reperfusion (IR) injury. After IR injury, retina from TAT‐aFGF‐His‐treated rats showed better‐maintained inner retinal layer structure, reduced apoptosis of retinal ganglion cells and improved retinal function compared to those treated with aFGF‐His or PBS. These results indicate that conjugation of TAT to aFGF‐His can markedly improve the ability of aFGF‐His to penetrate the ocular barrier without impairing its biological function. Thus, TAT49–57 provides a potential vehicle for efficient drug delivery in the treatment of retinal disease.
Periodontitis as a potential risk factor for peri‐implantitis
Authors: Renvert Stefan , Persson G. Rutger
Published: May 2009

Objectives: To review the literature regarding the possible association between a previous history of periodontitis and peri‐implantitis.

Material and Methods: A search of MEDLINE as well as a manual search of articles were conducted. Publications and articles accepted for publication up to January 2008 were included.

Results: Out of 951 papers retrieved, a total of three papers were selected for the review. Thus, the available evidence for an association between periodontitis and peri‐implantitis is scarce.

Conclusions: Based on three studies with a limited number of patients and considerable variations in study design, different definitions of periodontitis, and confounding variables like smoking that not been accounted for, this systematic review indicates that subjects with a history of periodontitis may be at greater risk for peri‐implant infections. It should, however, be stressed that the data to support this conclusion are not very robust.