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1.  Gender specific patterns of age-related decline in aortic stiffness: a cardiovascular magnetic resonance study including normal ranges 
Background
Young females exhibit lower cardiovascular event rates that young men, a pattern which is lost, or even reversed with advancing age. As aortic stiffness is a powerful risk factor for cardiovascular events, a gender difference with advancing age could provide a plausible explanation for this pattern.
Methods
777 subjects (♀n = 408, ♂n = 369) across a wide range of age (21–85 years) underwent cardiovascular magnetic resonance to assess aortic pulse wave velocity (PWV) and, in addition, aortic distensibility at three levels; 1) ascending aorta (Ao) and 2) proximal descending aorta (PDA) at the level of the pulmonary artery and 3) the abdominal aorta (DDA).
Results
There was a strong negative correlation between increasing age and regional aortic distensibility (Ao♀R-0.84, ♂R-0.80, PDA♀R-0.82, ♂R-0.77, DDA♀R-0.80, ♂R-0.71 all p < 0.001) and a strong positive correlation with PWV, (♀R0.53, ♂R 0.63 both p < 0.001). Even after adjustment for mean arterial pressure, body mass index, heart rate, smoking and diabetes, females exhibited a steeper decrease in all distensibility measures in response to increasing age (Ao♀-1.3 vs ♂-1.1 mmHg-1, PDA ♀-1.2 vs ♂-1.0 mmHg, DDA ♀-1.8 vs ♂-1.4 mmHg-1 per 10 years increase in age all p < 0.001). No gender difference in PWV increase with age was observed (p = 0.11).
Conclusion
Although advancing age is accompanied by increased aortic stiffness in both males and females, a significant sex difference in the rate of change exists, with females showing a steeper decline in aortic elasticity. As aortic stiffness is strongly related to cardiovascular events our observations may explain the increase in cardiovascular event rates that accompanies the menopausal age in women.
doi:10.1186/s12968-015-0126-0
PMCID: PMC4332729
Aorta; Cardiovascular magnetic resonance; Age
2.  High expression of the stem cell marker nestin is an adverse prognostic factor in WHO grade II-III astrocytomas and oligoastrocytomas 
Journal of neuro-oncology  2014;117(1):183-189.
Infiltrating astrocytomas and oligoastrocytomas of low to anaplastic grade (WHO grades II and III), in spite of being associated with a wide range of clinical outcomes, can be difficult to subclassify and grade by the current histopathologic criteria. Unlike oligodendrogliomas and anaplastic oligodendrogliomas that can be identified by the 1p/19q codeletion and the more malignant glioblastomas (WHO grade IV astrocytomas) that can be diagnosed solely based on objective features on routine hematoxylin and eosin sections, no such objective criteria exist for the subclassification of grade II-III astrocytomas and oligoastrocytomas (A+OA II-III). In this study, we evaluated the prognostic and predictive value of the stem cell marker nestin in adult A+OA II-III (n=50) using immunohistochemistry and computer-assisted analysis on tissue microarrays. In addition, the correlation between nestin mRNA level and total survival was analyzed in the NCI Rembrandt database. The results showed that high nestin expression is a strong adverse prognostic factor for total survival (p=0.0004). The strength of the correlation was comparable to but independent of the isocitrate dehydrogenase 1/2 (IDH 1/2) mutation status. Histopathological grading and subclassification did not correlate significantly with outcome, although the interpretation of this finding is limited by the fact that grade III tumors were treated more aggressively than grade II tumors. These results suggest that nestin level and IDH 1/2 mutation status are strong prognostic features in A+OA II-III and possibly more helpful for treatment planning than routine histopathological variables such as oligodendroglial component (astrocytoma vs. oligoastrocytoma) and WHO grade (grade II vs. III).
doi:10.1007/s11060-014-1376-7
PMCID: PMC4326086  PMID: 24519516
mixed glioma; outcome; prognosis; progression-free survival; low-grade gliomas; anaplastic gliomas
3.  Effects of Five Ayurvedic Herbs on Locomotor Behaviour in a Drosophila melanogaster Parkinson’s Disease Model 
Phytotherapy research : PTR  2014;28(12):1789-1795.
Current conventional treatments for Parkinson’s disease (PD) are aimed at symptom management, as there is currently no known cure or treatment that can slow down its progression. Ayurveda, the ancient medical system of India, uses a combination of herbs to combat the disease. Herbs commonly used for this purpose are Zandopa (containing Mucuna pruriens), Withania somnifera, Centella asiatica, Sida cordifolia and Bacopa monnieri. In this study, these herbs were tested for their potential ability to improve climbing ability of a fruit fly (Drosophila melanogaster) PD model based on loss of function of phosphatase and tensin-induced putative kinase 1 (PINK1). Fruit flies were cultured on food containing individual herbs or herbal formulations, a combination of all five herbs, levodopa (positive control) or no treatment (negative control). Tests were performed in both PINK1 mutant flies and healthy wild-type (WT) flies. A significant improvement in climbing ability was observed in flies treated with B. monnieri compared with untreated PINK1 mutant flies. However, a significant decrease in climbing ability was observed in WT flies for the same herb. Centella asiatica also significantly decreased climbing ability in WT flies. No significant effects were observed with any of the other herbs in either PINK1 or WT flies compared with untreated flies.
doi:10.1002/ptr.5199
PMCID: PMC4310928  PMID: 25091506
Ayurveda; climbing ability; Drosophila melanogaster; Parkinson’s disease; PINK1
4.  Unbalanced Activation of Glutathione Metabolic Pathways Suggests Potential Involvement in Plant Defense against the Gall Midge Mayetiola destructor in Wheat 
Scientific Reports  2015;5:8092.
Glutathione, γ-glutamylcysteinylglycine, exists abundantly in nearly all organisms. Glutathione participates in various physiological processes involved in redox reactions by serving as an electron donor/acceptor. We found that the abundance of total glutathione increased up to 60% in resistant wheat plants within 72 hours following attack by the gall midge Mayetiola destructor, the Hessian fly. The increase in total glutathione abundance, however, is coupled with an unbalanced activation of glutathione metabolic pathways. The activity and transcript abundance of glutathione peroxidases, which convert reduced glutathione (GSH) to oxidized glutathione (GSSG), increased in infested resistant plants. However, the enzymatic activity and transcript abundance of glutathione reductases, which convert GSSG back to GSH, did not change. This unbalanced regulation of the glutathione oxidation/reduction cycle indicates the existence of an alternative pathway to regenerate GSH from GSSG to maintain a stable GSSG/GSH ratio. Our data suggest the possibility that GSSG is transported from cytosol to apoplast to serve as an oxidant for class III peroxidases to generate reactive oxygen species for plant defense against Hessian fly larvae. Our results provide a foundation for elucidating the molecular processes involved in glutathione-mediated plant resistance to Hessian fly and potentially other pests as well.
doi:10.1038/srep08092
PMCID: PMC4308708  PMID: 25627558
5.  Targeted Disruption of an EH-domain Protein Endocytic Complex, Pan1-End3 
Traffic (Copenhagen, Denmark)  2013;15(1):10.1111/tra.12125.
Pan1 is a multi-domain scaffold that enables dynamic interactions with both structural and regulatory components of the endocytic pathway. Pan1 is composed of Eps15 Homology (EH) domains which interact with adaptor proteins, a central region that is responsible for its oligomerization and C-terminal binding sites for Arp2/3, F-actin, and type-I myosin motors. In this study, we have characterized the binding sites between Pan1 and its constitutive binding partner End3, another EH domain containing endocytic protein. The C-terminal End3 Repeats of End3 associate with the N-terminal part of Pan1’s central coiled-coil region. These repeats appear to act independently of one another as tandem, redundant binding sites for Pan1. The end3-1 allele was sequenced, and corresponds to a C-terminal truncation lacking the End3 Repeats. Mutations of the End3 Repeats highlight that those residues which are identical between these repeats serve as contact sites for the interaction with Pan1.
doi:10.1111/tra.12125
PMCID: PMC3855908  PMID: 24118836
Pan1; End3; Endocytosis; EH domain; Amphipathic helix; End3-1
6.  Perfluoroalkyl substances and lipid concentrations in plasma during pregnancy among women in the Norwegian Mother and Child Cohort Study 
Environment international  2013;62:10.1016/j.envint.2013.10.004.
Background
Perfluoroalkyl substances (PFASs) are widespread and persistent environmental pollutants. Previous studies, primarily among non-pregnant individuals, suggest positive associations between PFAS levels and certain blood lipids. If there is a causal link between PFAS concentrations and elevated lipids during pregnancy, this may suggest a mechanism by which PFAS exposure leads to certain adverse pregnancy outcomes, including preeclampsia.
Methods
This cross-sectional analysis included 891 pregnant women enrolled in the Norwegian Mother and Child (MoBa) Cohort Study in 2003–2004. Non-fasting plasma samples were obtained at mid-pregnancy and analyzed for nineteen PFASs. Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured in plasma. Linear regression was used to quantify associations between each PFAS exposure and each lipid outcome. A multiple PFAS model was also fitted.
Results
Seven PFASs were quantifiable in >50% of samples. Perfluorooctane sulfonate (PFOS) concentration was associated with total cholesterol, which increased 4.2 mg/dL per interquartile shift (95% CI=0.8, 7.7) in adjusted models. Five of the seven PFASs studied were positively associated with HDL cholesterol, and all seven had elevated HDL associated with the highest quartile of exposure. Perfluoroundecanoic acid showed the strongest association with HDL: HDL increased 3.7 mg/dL per interquartile shift (95% CI=2.5, 4.9).
Conclusion
Plasma concentrations of PFASs were positively associated with HDL cholesterol, and PFOS was positively associated with total cholesterol in this sample of pregnant Norwegian women. While elevated HDL is not an adverse outcome per se, elevated total cholesterol associated with PFASs during pregnancy could be of concern if causal.
doi:10.1016/j.envint.2013.10.004
PMCID: PMC3870471  PMID: 24189199
The Norwegian Mother and Child Cohort Study; MoBa; perfluoroalkyl substances; perfluorooctanoic acid; perfluorooctane sulfonate
7.  Feasibility and Acceptability of Utilizing a Smartphone Based Application to Monitor Outpatient Discharge Instruction Compliance in Cardiac Disease Patients around Discharge from Hospitalization 
The purpose of this study was to determine the feasibility and acceptability of utilizing a smartphone based application to monitor compliance in patients with cardiac disease around discharge. For 60 days after discharge, patients' medication compliance, physical activity, follow-up care, symptoms, and reading of education material were monitored daily with the application. 16 patients were enrolled in the study (12 males, 4 females, age 55 ± 18 years) during their hospital stay. Five participants were rehospitalized during the study and did not use the application once discharged. Seven participants completed 1–30 days and four patients completed >31 days. For those 11 patients, medication reminders were utilized 37% (1–30-day group) and 53% (>31-day group) of the time, education material was read 44% (1–30) and 53% (>31) of the time, and physical activity was reported 25% (1–30) and 42% (>31) of the time. Findings demonstrated that patients with stable health utilized the application, even if only minimally. Patients with decreased breath sounds by physical exam and who reported their health as fair to poor on the day of discharge were less likely to utilize the application. Acceptability of the application to report health status varied among the stable patients.
doi:10.1155/2014/415868
PMCID: PMC4276693  PMID: 25574165
8.  The Complex I Subunit NDUFA10 Selectively Rescues Drosophila pink1 Mutants through a Mechanism Independent of Mitophagy 
PLoS Genetics  2014;10(11):e1004815.
Mutations in PINK1, a mitochondrially targeted serine/threonine kinase, cause autosomal recessive Parkinson's disease (PD). Substantial evidence indicates that PINK1 acts with another PD gene, parkin, to regulate mitochondrial morphology and mitophagy. However, loss of PINK1 also causes complex I (CI) deficiency, and has recently been suggested to regulate CI through phosphorylation of NDUFA10/ND42 subunit. To further explore the mechanisms by which PINK1 and Parkin influence mitochondrial integrity, we conducted a screen in Drosophila cells for genes that either phenocopy or suppress mitochondrial hyperfusion caused by pink1 RNAi. Among the genes recovered from this screen was ND42. In Drosophila pink1 mutants, transgenic overexpression of ND42 or its co-chaperone sicily was sufficient to restore CI activity and partially rescue several phenotypes including flight and climbing deficits and mitochondrial disruption in flight muscles. Here, the restoration of CI activity and partial rescue of locomotion does not appear to have a specific requirement for phosphorylation of ND42 at Ser-250. In contrast to pink1 mutants, overexpression of ND42 or sicily failed to rescue any Drosophila parkin mutant phenotypes. We also find that knockdown of the human homologue, NDUFA10, only minimally affecting CCCP-induced mitophagy, and overexpression of NDUFA10 fails to restore Parkin mitochondrial-translocation upon PINK1 loss. These results indicate that the in vivo rescue is due to restoring CI activity rather than promoting mitophagy. Our findings support the emerging view that PINK1 plays a role in regulating CI activity separate from its role with Parkin in mitophagy.
Author Summary
Two genes linked to heritable forms of the neurodegenerative movement disorder Parkinson's disease (PD), PINK1 and parkin, play important roles in mitochondrial homeostasis through mechanisms which include the degradation of dysfunctional mitochondria, termed mitophagy, and the maintenance of complex I (CI) activity. Here we report the findings of an RNAi based screen in Drosophila cells for genes that may regulate the PINK1-Parkin pathway which identified NDUFA10 (ND42 in Drosophila), a subunit of CI. Using a well-established cellular system and in vivo Drosophila genetics, we demonstrate that while NDUFA10/ND42 only plays a minimal role in mitophagy, restoration of CI activity through overexpression of either ND42 or its co-chaperone sicily is able to substantially rescue behavioral deficits in pink1 mutants but not parkin mutants. Moreover, while parkin overexpression is known to rescue pink1 mutants, it apparently achieves this without restoring CI activity. These results suggest that increasing CI activity or promoting mitophagy can be beneficial in pink1 mutants, and further highlights separable functions of PINK1 and Parkin.
doi:10.1371/journal.pgen.1004815
PMCID: PMC4238976  PMID: 25412178
9.  Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations 
Nature Communications  2014;5:5245.
Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson’s disease. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson’s disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson’s disease.
Mutations in the kinase LRRK2 are associated with Parkinson’s disease. Godena et al. find that disease-associated LRRK2 mutations promote its binding to deacetylated microtubules, and cause defects in axonal transport and Drosophila locomotor behaviour that can be reversed by enhancing tubulin acetylation.
doi:10.1038/ncomms6245
PMCID: PMC4208097  PMID: 25316291
10.  Support for All in the UK Work Programme? Differential Payments, Same Old Problem 
Social Policy & Administration  2014;48(2):221-239.
The UK has been a high profile policy innovator in welfare-to-work provision which has led in the Coalition government's Work Programme to a fully outsourced, ‘black box’ model with payments based overwhelmingly on job outcome results. A perennial fear in such programmes is providers' incentives to ‘cream’ and ‘park’ claimants, and the Department for Work and Pensions has sought to mitigate such provider behaviours through Work Programme design, particularly via the use of claimant groups and differential pricing. In this article, we draw on a qualitative study of providers in the programme alongside quantitative analysis of published performance data to explore evidence around creaming and parking. The combination of the quantitative and qualitative evidence suggest that creaming and parking are widespread, seem systematically embedded within the Work Programme, and are driven by a combination of intense cost-pressures and extremely ambitious performance targets alongside overly diverse claimant groups and inadequately calibrated differentiated payment levels.
doi:10.1111/spol.12058
PMCID: PMC4211436  PMID: 25411516
Welfare-to-work; Employment services; Creaming and parking; Conditionality; Work Programme; Payment by results
11.  How could Parkin-mediated ubiquitination of mitofusin promote mitophagy? 
Autophagy  2010;6(5):660-662.
doi:10.4161/auto.6.5.12242
PMCID: PMC4196639  PMID: 20484985
Parkinson disease; neurodegeneration; Parkin; PINK1; Mfn; mitochondrial dynamics; ubiquitination; Drosophila
12.  Routine pre-pregnancy health promotion for improving pregnancy outcomes 
Background
A number of potentially modifiable risk factors are known to be associated with poor pregnancy outcomes. These include smoking, drinking excess alcohol, and poor nutrition. Routine health promotion (encompassing education, advice and general health assessment) in the pre-pregnancy period has been proposed for improving pregnancy outcomes by encouraging behavioural change, or allowing early identification of risk factors. While results from observational studies have been encouraging, this review examines evidence from randomised controlled trials of preconception health promotion.
Objectives
To assess the effectiveness of routine pre-pregnancy health promotion for improving pregnancy outcomes when compared with no pre-pregnancy care or usual care.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (February 2009).
Selection criteria
Randomised and quasi-randomised trials examining health promotion interventions which aim to identify and modify risk factors before pregnancy. The review focuses on all women of childbearing age rather than those in high-risk groups. We have excluded trials where interventions are aimed specifically at women with established medical, obstetric or genetic risks or already receiving treatment as part of programmes for high-risk groups.
Data collection and analysis
Two review authors independently assessed eligibility and carried out data extraction.
Main results
Four trials (2300 women) are included. The interventions ranged from brief advice through to education on health and lifestyle over several sessions. For most outcomes, data were only available from individual studies. Only one study followed up through pregnancy and there was no strong evidence of a difference between groups for preterm birth, congenital anomalies or weight for gestational age; only one finding (mean birthweight) reached statistical significance (mean difference −97.00, 95% confidence interval (CI) −168.05 to −25.95). This finding needs to be interpreted with caution as pregnancy outcome data were available for only half of the women randomised. There was some evidence that health promotion interventions were associated with positive maternal behavioural change including lower rates of binge drinking (risk ratio 1.24, 95% CI 1.06 to 1.44). Overall, there has been little research in this area and there is a lack of evidence on the effects of pre-pregnancy health promotion on pregnancy outcomes.
Authors’ conclusions
There is little evidence on the effects of pre-pregnancy health promotion and much more research is needed in this area. There is currently insufficient evidence to recommend the widespread implementation of routine pre-pregnancy health promotion for women of childbearing age, either in the general population or between pregnancies.
doi:10.1002/14651858.CD007536.pub2
PMCID: PMC4164828  PMID: 19821424
*Pregnancy Outcome; Health Behavior; Health Education [methods]; Health Promotion [*methods]; Maternal Behavior; Preconception Care [*methods]; Randomized Controlled Trials as Topic; Risk Factors; Adult; Female; Humans; Pregnancy; Young Adult
13.  Chemosensitivity Predicted by BluePrint 80-Gene Functional Subtype and MammaPrint in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST) 
Annals of Surgical Oncology  2014;21(10):3261-3267.
Purpose
The purpose of the NBRST study is to compare a multigene classifier to conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping to predict chemosensitivity as defined by pathological complete response (pCR) or endocrine sensitivity as defined by partial response.
Methods
The study includes women with histologically proven breast cancer, who will receive neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2, and Basal.
Results
A total of 426 patients had definitive surgery. Thirty-seven of 211 (18 %) IHC/FISH hormone receptor (HR)+/HER2− patients were reclassified by Blueprint as Basal (n = 35) or HER2 (n = 2). Fifty-three of 123 (43 %) IHC/FISH HER2+ patients were reclassified as Luminal (n = 36) or Basal (n = 17). Four of 92 (4 %) IHC/FISH triple-negative (TN) patients were reclassified as Luminal (n = 2) or HER2 (n = 2). NCT pCR rates were 2 % in Luminal A and 7 % Luminal B patients versus 10 % pCR in IHC/FISH HR+/HER2− patients. The NCT pCR rate was 53 % in BluePrint HER2 patients. This is significantly superior (p = 0.047) to the pCR rate in IHC/FISH HER2+ patients (38 %). The pCR rate of 36 of 75 IHC/FISH HER2+/HR+ patients reclassified as BPLuminal is 3 %. NCT pCR for BluePrint Basal patients was 49 of 140 (35 %), comparable to the 34 of 92 pCR rate (37 %) in IHC/FISH TN patients.
Conclusions
BluePrint molecular subtyping reclassifies 22 % (94/426) of tumors, reassigning more responsive patients to the HER2 and Basal categories while reassigning less responsive patients to the Luminal category. These findings suggest that compared with IHC/FISH, BluePrint more accurately identifies patients likely to respond (or not respond) to NCT.
doi:10.1245/s10434-014-3908-y
PMCID: PMC4161926  PMID: 25099655
14.  TRAP1 rescues PINK1 loss-of-function phenotypes 
Human Molecular Genetics  2013;22(14):2829-2841.
PTEN-induced kinase 1 (PINK1) is a serine/threonine kinase that is localized to mitochondria. It protects cells from oxidative stress by suppressing mitochondrial cytochrome c release, thereby preventing cell death. Mutations in Pink1 cause early-onset Parkinson's disease (PD). Consistently, mitochondrial function is impaired in Pink1-linked PD patients and model systems. Previously, in vitro analysis implied that the protective effects of PINK1 depend on phosphorylation of the downstream factor, TNF receptor-associated protein 1 (TRAP1). Furthermore, TRAP1 has been shown to mitigate α-Synuclein-induced toxicity, linking α-Synuclein directly to mitochondrial dysfunction. These data suggest that TRAP1 seems to mediate protective effects on mitochondrial function in pathways that are affected in PD. Here we investigated the potential of TRAP1 to rescue dysfunction induced by either PINK1 or Parkin deficiency in vivo and in vitro. We show that overexpression of human TRAP1 is able to mitigate Pink1 but not parkin loss-of-function phenotypes in Drosophila. In addition, detrimental effects observed after RNAi-mediated silencing of complex I subunits were rescued by TRAP1 in Drosophila. Moreover, TRAP1 was able to rescue mitochondrial fragmentation and dysfunction upon siRNA-induced silencing of Pink1 but not parkin in human neuronal SH-SY5Y cells. Thus, our data suggest a functional role of TRAP1 in maintaining mitochondrial integrity downstream of PINK1 and complex I deficits but parallel to or upstream of Parkin.
doi:10.1093/hmg/ddt132
PMCID: PMC3690968  PMID: 23525905
15.  Specialised antenatal clinics for women with a pregnancy at high risk of preterm birth (excluding multiple pregnancy) to improve maternal and infant outcomes 
Background
Amongst the risk factors for preterm birth, previous preterm delivery is a strong predictor. Specialised clinics for women with a history of spontaneous preterm delivery have been advocated as a way of improving outcomes for women and their infants.
Objectives
To assess using the best available evidence, the value of specialised antenatal clinics for women with a pregnancy at high risk of preterm delivery when compared with ‘standard’ antenatal clinics.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 June 2011).
Selection criteria
All published, unpublished, and ongoing randomised controlled trials (including cluster-randomised trials) examining specialised compared with standard antenatal clinic care for women with a singleton pregnancy considered at high risk of preterm labour.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data.
Main results
We included three trials with 3400 women, all carried out in the USA. All focused on specialised clinics for women at high risk of preterm birth. Gestational age at delivery, preterm delivery, or both were primary outcomes in all studies. The interventions in the three trials differed.
Overall there was very little data on our prespecified outcomes. For most outcomes a single study provided data, hence there was not the statistical power to detect any possible differences between groups. There was no clear evidence that specialised antenatal clinics reduce the number of preterm births.
Authors’ conclusions
Specialised antenatal clinics are now an accepted part of care in many settings, and carrying out further randomised trials may not be possible. Any future research in this area should include psychological outcomes and should focus on which aspects of service provision are preferred by women. Such research could underpin further service development in this area.
doi:10.1002/14651858.CD006760.pub2
PMCID: PMC4084921  PMID: 21901705
16.  Ultrasound for fetal assessment in early pregnancy 
Background
Diagnostic ultrasound is a sophisticated electronic technology, which utilises pulses of high frequency sound to produce an image. Diagnostic ultrasound examination may be employed in a variety of specific circumstances during pregnancy such as after clinical complications, or where there are concerns about fetal growth. Because adverse outcomes may also occur in pregnancies without clear risk factors, assumptions have been made that routine ultrasound in all pregnancies will prove beneficial by enabling earlier detection and improved management of pregnancy complications. Routine screening may be planned for early pregnancy, late gestation, or both. The focus of this review is routine early pregnancy ultrasound.
Objectives
To assess whether routine early pregnancy ultrasound for fetal assessment (i.e. its use as a screening technique) influences the diagnosis of fetal malformations, multiple pregnancies, the rate of clinical interventions, and the incidence of adverse fetal outcome when compared with the selective use of early pregnancy ultrasound (for specific indications).
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (September 2009).
Selection criteria
Published, unpublished, and ongoing randomised controlled trials that compared outcomes in women who experienced routine versus selective early pregnancy ultrasound (i.e. less than 24 weeks’ gestation). We have included quasi-randomised trials.
Data collection and analysis
Two review authors independently extracted data for each included study. We used the Review Manager software to enter and analyse data.
Main results
Routine/revealed ultrasound versus selective ultrasound/concealed: 11 trials including 37505 women. Ultrasound for fetal assessment in early pregnancy reduces the failure to detect multiple pregnancy by 24 weeks’ gestation (risk ratio (RR) 0.07, 95% confidence interval (CI) 0.03 to 0.17). Routine scan is associated with a reduction in inductions of labour for ‘post term’ pregnancy (RR 0.59, 95% CI 0.42 to 0.83). Routine scans do not seem to be associated with reductions in adverse outcomes for babies or in health service use by mothers and babies. Long-term follow up of children exposed to scan in utero does not indicate that scans have a detrimental effect on children’s physical or cognitive development.
Authors’ conclusions
Early ultrasound improves the early detection of multiple pregnancies and improved gestational dating may result in fewer inductions for post maturity. Caution needs to be exercised in interpreting the results of aspects of this review in view of the fact that there is considerable variability in both the timing and the number of scans women received.
doi:10.1002/14651858.CD007058.pub2
PMCID: PMC4084925  PMID: 20393955
Congenital Abnormalities [ultrasonography]; Fetal Monitoring [methods]; Gestational Age; Perinatal Mortality; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy, Multiple; Ultrasonography, Prenatal [methods]; Female; Humans; Pregnancy
17.  The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells 
Gynecologic oncology  2011;125(1):226-230.
Objective
Retinoids are important modulators of cell growth, differentiation, and proliferation. 9cUAB30, 9cUAB124, and 9cUAB130 are three novel retinoid compounds that show cytotoxic effects in other malignancies. We evaluated these novel retinoids in combination with chemotherapy against ovarian cancer stem cells (CSCs) in vitro and in an ex vivo model.
Methods
A2780 cells were plated in 96-well plates and treated with retinoid, carboplatin, or combination therapy. Cell viability was evaluated using ATPLite assay. The A2780 cell line was also analyzed for CSCs by evaluating ALDH activity using flow cytometry. A2780 cells treated ex vivo with retinoids and chemotherapy were injected into the flank of athymic nude mice in order to evaluate subsequent tumor initiating capacity.
Results
A2780 cells were sensitive to treatment with retinoids and carboplatin. The best treatment resulted from the combination of retinoid 9cUAB130 and carboplatin. Untreated A2780 cells demonstrated ALDH activity in 3.3% of the cell population. Carboplatin treatment enriched ALDH activity to 27.3%, while 9cUAB130±carboplatin maintained the ALDH positive levels similar to untreated controls (2.3% and 6.7%, respectively). Similar results were found in tumorsphere-forming conditions. Flank injections of ex vivo treated A2780 cells resulted in 4/4 mice developing tumors at 40 days in the untreated group, while 0/4 tumors developed in the 9cUAB130 and carboplatin treated group.
Conclusion
Combination treatment with carboplatin and retinoids reduced cell-viability, reduced CSC marker expression, and inhibited tumorigenicity, making it a more effective treatment when compared with carboplatin alone.
doi:10.1016/j.ygyno.2011.12.425
PMCID: PMC4049085  PMID: 22155260
Retinoid; Ovarian cancer; Stem cell
18.  Constructing a Novel Simple LEEP Training Model 
Background
Duty hour restrictions and enhanced focus on patient safety have prompted the development of new instruction models for practice of surgical techniques outside the operating room, including models for teaching loop electrosurgical excisional procedure (LEEP), a common procedure that gynecology residents perform to diagnose and manage cervical disease.
Objective
We sought to develop an inexpensive and reusable training model for guided practice opportunities that will improve gynecology residents' LEEP technique.
Methods
Polyvinyl chloride, foam, and a polish sausage are used to simulate the basic anatomy of the vagina and cervix. A 2-in-diameter polyvinyl chloride pipe and high-density foam are used to create a realistic representation with the sausage simulating the cervix. An electrosurgical pad is attached to the sausage and a standard operating room electrosurgical generator is used.
Results
After a brief lecture and demonstration of the LEEP procedure, gynecology residents are positioned at individual stations. Use of 2 to 3 instructors allows for the provision of directions and feedback to residents as they perform the simulated LEEP. During the last 6 years, this model has continued to improve residents' confidence and skills with the procedure.
Conclusions
An anatomically accurate LEEP model can not only improve resident knowledge, skills, and confidence, but also improve quality and patient safety. This training model allows residents to refine their surgical skills through guided practice and instructors to monitor performance before residents to perform the procedure on patients.
doi:10.4300/JGME-D-12-00061.1
PMCID: PMC3693702  PMID: 24404281
19.  Predictors of Plasma DDT and DDE Concentrations among Women Exposed to Indoor Residual Spraying for Malaria Control in the South African Study of Women and Babies (SOWB) 
Environmental Health Perspectives  2014;122(6):545-552.
Background: Few studies have examined predictors of DDT (dichlorodiphenyltrichloroethane) and DDE (dichlorodiphenyldichloroethylene) levels among residents in homes sprayed with DDT for malaria control with the aim of identifying exposure-reduction strategies.
Methods: The present analysis included 381 women enrolled in the Study of Women and Babies (SOWB) during 2010–2011, from eight South African villages in the Limpopo Province, South Africa. Indoor residual spraying (IRS) occurred in half of the villages. Questionnaires regarding various demographic and medical factors were administered and blood samples were obtained. We classified the women into three exposure groups by type of residence: unsprayed village (n = 175), IRS village in household with a low likelihood of DDT use (non-DDT IRS household, n = 106), IRS village in household with a high likelihood of DDT use (DDT IRS household, n = 100). We used multivariable models of natural log-transformed DDT plasma levels (in micrograms per liter) and DDE (in micrograms per liter) to identify predictors for each group.
Results: Median levels of DDT and DDE among women in unsprayed villages were 0.3 [interquartile range (IQR): 0.1–0.9] and 1.7 (IQR: 0.7–5.5), respectively. Median levels of DDT and DDE among women in DDT IRS households were 2.6 (IQR: 1.1–6.6) and 8.5 (IQR: 4.7–18.0), respectively. In unsprayed villages, women with water piped to the yard, rather than a public tap, had 73% lower DDT (95% CI: –83, –57%) and 61% lower DDE (95% CI: –74, –40%) levels. In DDT IRS households, women who reported taking more than six actions to prepare their home before IRS (e.g., covering water and food) had 40% lower DDT levels (95% CI: –63, –0.3%) than women who took fewer than four actions.
Conclusion: The predictors of DDT and DDE plasma levels identified in the present study may inform interventions aimed at decreasing exposure. Among households where DDT is likely to be used for IRS, education regarding home preparations may provide an interventional target.
Citation: Whitworth KW, Bornman RM, Archer JI, Kudumu MO, Travlos GS, Wilson RE, Longnecker MP. 2014. Predictors of plasma DDT and DDE concentrations among women exposed to indoor residual spraying for malaria control in the South African Study of Women and Babies (SOWB). Environ Health Perspect 122:545–552; http://dx.doi.org/10.1289/ehp.1307025
doi:10.1289/ehp.1307025
PMCID: PMC4048257  PMID: 24577839
20.  Pyrosequencing Reveals the Predominance of Pseudomonadaceae in Gut Microbiome of a Gall Midge 
Pathogens  2014;3(2):459-472.
Gut microbes are known to play various roles in insects such as digestion of inaccessible nutrients, synthesis of deficient amino acids, and interaction with ecological environments, including host plants. Here, we analyzed the gut microbiome in Hessian fly, a serious pest of wheat. A total of 3,654 high quality sequences of the V3 hypervariable region of the 16S rRNA gene were obtained through 454-pyrosequencing. From these sequences, 311 operational taxonomic units (OTUs) were obtained at the ≥97% similarity cutoff. In the gut of 1st instar, otu01, a member of Pseudomonas, was predominant, representing 90.2% of total sequences. otu13, an unidentified genus in the Pseudomonadaceae family, represented 1.9% of total sequences. The remaining OTUs were each less than 1%. In the gut of the 2nd instar, otu01 and otu13 decreased to 85.5% and 1.5%, respectively. otu04, a member of Buttiauxella, represented 9.7% of total sequences. The remaining OTUs were each less than 1%. In the gut of the 3rd instar, otu01 and otu13 further decreased to 29.0% and 0%, respectively. otu06, otu08, and otu16, also three members of the Pseudomonadaceae family were 13.2%, 8.6%, and 2.3%, respectively. In addition, otu04 and otu14, two members of the Enterobacteriaceae family, were 4.7% and 2.5%; otu18 and otu20, two members of the Xanthomonadaceae family, were 1.3% and 1.2%, respectively; otu12, a member of Achromobacter, was 4.2%; otu19, a member of Undibacterium, was 1.4%; and otu9, otu10, and otu15, members of various families, were 6.1%, 6.3%, and 1.9%, respectively. The investigation into dynamics of Pseudomonas, the most abundant genera, revealed that its population level was at peak in freshly hatched or 1 day larvae as well as in later developmental stages, thus suggesting a prominent role for this bacterium in Hessian fly development and in its interaction with host plants. This study is the first comprehensive survey on bacteria associated with the gut of a gall midge, and provides a foundation for future studies to elucidate the roles of gut microbes in Hessian fly virulence and biology.
doi:10.3390/pathogens3020459
PMCID: PMC4243456  PMID: 25437809
Hessian fly; Mayetiola destructor; gut; microbe; symbiosis
21.  Dickkopf-Related Protein 1 Inhibits the WNT Signaling Pathway and Improves Pig Oocyte Maturation 
PLoS ONE  2014;9(4):e95114.
The ability to mature oocytes in vitro provides a tool for creating embryos by parthenogenesis, fertilization, and cloning. Unfortunately the quality of oocytes matured in vitro falls behind that of in vivo matured oocytes. To address this difference, transcriptional profiling by deep sequencing was conducted on pig oocytes that were either matured in vitro or in vivo. Alignment of over 18 million reads identified 1,316 transcripts that were differentially represented. One pathway that was overrepresented in the oocytes matured in vitro was for Wingless-type MMTV integration site (WNT) signaling. In an attempt to inhibit the WNT pathway, Dickkopf-related protein 1 was added to the in vitro maturation medium. Addition of Dickkopf-related protein 1 improved the percentage of oocytes that matured to the metaphase II stage, increased the number of nuclei in the resulting blastocyst stage embryos, and reduced the amount of disheveled segment polarity protein 1 protein in oocytes. It is concluded that transcriptional profiling is a powerful method for detecting differences between in vitro and in vivo matured oocytes, and that the WNT signaling pathway is important for proper oocyte maturation.
doi:10.1371/journal.pone.0095114
PMCID: PMC3989281  PMID: 24739947
22.  Determinants of plasma concentrations of perfluoroalkyl substances in pregnant Norwegian women 
Environment international  2013;54:74-84.
Background
Perfluoroalkyl substances (PFASs) are widespread pollutants that have been associated with adverse health effects although not on a consistent basis. Diet has been considered the main source of exposure. The aim of the present study was to identify determinants of four plasma PFASs in pregnant Norwegian women.
Methods
This study is based in the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. Our sample included 487 women who enrolled in MoBa from 2003–2004. A questionnaire regarding sociodemographic, medical, and reproductive history was completed at 17 weeks gestation and a dietary questionnaire was completed at 22 weeks gestation. Maternal plasma samples were obtained around 17 weeks of gestation. Plasma concentrations of four PFASs (perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA)) were examined in relation to demographic, lifestyle, dietary, and pregnancy-related covariates. Predictors were identified by optimizing multiple linear regression models using Akaike’s information criterion (AIC).
Results
Parity was the determinant with the largest influence on plasma PFAS concentrations, with r2 between 0.09 and 0.32 in simple regression models. In optimal multivariate models, when compared to nulliparous women, parous women had 46%, 70%, 19%, and 62% lower concentrations of PFOS, PFOA, PFHxS, and PFNA respectively (p<0.001 except for PFHxS, p<0.01). In all these models, duration of breastfeeding was associated with reduced PFAS levels. PFOA showed the largest reduction from breastfeeding, with a 2–3% reduction per month of breastfeeding in typical cases. Levels of PFOS, PFOA, and PFNA increased with time since most recent pregnancy. While pregnancy-related factors were the most important predictors, diet was a significant factor explaining up to 4% of the variance. One quartile increase in estimated dietary PFAS intake was associated with plasma PFOS, PFOA, PFHxS, and PFNA concentration increases of 7.2%, 3.3%, 5.8% and 9.8%, respectively, resulting in small, although non-trivial absolute changes in PFAS concentrations.
Conclusion
The history of previous pregnancies and breastfeeding were the most important determinants of PFASs in this sample of pregnant women.
doi:10.1016/j.envint.2012.12.014
PMCID: PMC3605228  PMID: 23419425
Perfluoroalkyl substances; reproductive history; pregnancy; dietary exposure
23.  Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity 
Molecular Metabolism  2014;3(4):465-473.
A critical feature of obesity is enhanced insulin secretion from pancreatic β-cells, enabling the majority of individuals to maintain glycaemic control despite adiposity and insulin resistance. Surprisingly, the factors coordinating this adaptive β-cell response with adiposity have not been delineated. Here we show that fatty acid binding protein 4 (FABP4/aP2) is an adipokine released from adipocytes under obesogenic conditions, such as hypoxia, to augment insulin secretion. The insulinotropic action of FABP4 was identified using an in vitro system that recapitulates adipocyte to β-cell endocrine signalling, with glucose-stimulated insulin secretion (GSIS) as a functional readout, coupled with quantitative proteomics. Exogenous FABP4 potentiated GSIS in vitro and in vivo, and circulating FABP4 levels correlated with GSIS in humans. Insulin inhibited FABP4 release from adipocytes in vitro, in mice and in humans, consistent with feedback regulation. These data suggest that FABP4 and insulin form an endocrine loop coordinating the β-cell response to obesity.
Graphical abstract
doi:10.1016/j.molmet.2014.02.005
PMCID: PMC4060222  PMID: 24944906
Obesity; Adipokine; Adipocyte; Beta-cell; Insulin secretion; FABP4; T2D, type 2 diabetes; NEFA, non-esterified fatty acid; GSIS, glucose-stimulated insulin secretion; SILAC, stable-isotope labelling by amino acids in cell culture; ELISA, enzyme-linked immunosorbant assay; BMI, body mass index; cAMP, cyclic-AMP; IBMX, 3-Isobutyl-1-methylxanthine
24.  Tuberculin Skin Tests versus Interferon-Gamma Release Assays in Tuberculosis Screening among Immigrant Visa Applicants 
Objective. Use of tuberculin skin tests (TSTs) and interferon gamma release assays (IGRAs) as part of tuberculosis (TB) screening among immigrants from high TB-burden countries has not been fully evaluated. Methods. Prevalence of Mycobacterium tuberculosis infection (MTBI) based on TST, or the QuantiFERON-TB Gold test (QFT-G), was determined among immigrant applicants in Vietnam bound for the United States (US); factors associated with test results and discordance were assessed; predictive values of TST and QFT-G for identifying chest radiographs (CXRs) consistent with TB were calculated. Results. Of 1,246 immigrant visa applicants studied, 57.9% were TST positive, 28.3% were QFT-G positive, and test agreement was 59.4%. Increasing age was associated with positive TST results, positive QFT-G results, TST-positive but QFT-G-negative discordance, and abnormal CXRs consistent with TB. Positive predictive values of TST and QFT-G for an abnormal CXR were 25.9% and 25.6%, respectively. Conclusion. The estimated prevalence of MTBI among US-bound visa applicants in Vietnam based on TST was twice that based on QFT-G, and 14 times higher than a TST-based estimate of MTBI prevalence reported for the general US population in 2000. QFT-G was not better than TST at predicting abnormal CXRs consistent with TB.
doi:10.1155/2014/217969
PMCID: PMC3967820  PMID: 24738031
25.  An Intact Sialoadhesin (Sn/SIGLEC1/CD169) Is Not Required for Attachment/Internalization of the Porcine Reproductive and Respiratory Syndrome Virus 
Journal of Virology  2013;87(17):9538-9546.
Surface expression of SIGLEC1, also known as sialoadhesin or CD169, is considered a primary determinant of the permissiveness of porcine alveolar macrophages for infection by porcine reproductive and respiratory syndrome virus (PRRSV). In vitro, the attachment and internalization of PRRSV are dependent on the interaction between sialic acid on the virion surface and the sialic acid binding domain of the SIGLEC1 gene. To test the role of SIGLEC1 in PRRSV infection, a SIGLEC1 gene knockout pig was created by removing part of exon 1 and all of exons 2 and 3 of the SIGLEC1 gene. The resulting knockout ablated SIGLEC1 expression on the surface of alveolar macrophages but had no effect on the expression of CD163, a coreceptor for PRRSV. After infection, PRRSV viremia in SIGLEC1−/− pigs followed the same course as in SIGLEC1−/+ and SIGLEC1+/+ littermates. The absence of SIGLEC1 had no measurable effect on other aspects of PRRSV infection, including clinical disease course and histopathology. The results demonstrate that the expression of the SIGLEC1 gene is not required for infection of pigs with PRRSV and that the absence of SIGLEC1 does not contribute to the pathogenesis of acute disease.
doi:10.1128/JVI.00177-13
PMCID: PMC3754101  PMID: 23785195

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