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1.  Islet β-cell mass in diabetes and how it relates to function, birth, and death 
In type 1 diabetes (T1D) β-cell mass is markedly reduced by autoimmunity. Type 2 diabetes (T2D) results from inadequate β-cell mass and function that can no longer compensate for insulin resistance. The reduction of β-cell mass in T2D may result from increased cell death and/or inadequate birth through replication and neogenesis. Reduction in mass allows glucose levels to rise, which places β cells in an unfamiliar hyperglycemic environment, leading to marked changes in their phenotype and a dramatic loss of glucose-stimulated insulin secretion (GSIS), which worsens as glucose levels climb. Toxic effects of glucose on β cells (glucotoxicity) appear to be the culprit. This dysfunctional insulin secretion can be reversed when glucose levels are lowered by treatment, a finding with therapeutic significance. Restoration of β-cell mass in both types of diabetes could be accomplished by either β-cell regeneration or transplantation. Learning more about the relationships between β-cell mass, turnover, and function and finding ways to restore β-cell mass are among the most urgent priorities for diabetes research.
doi:10.1111/nyas.12031
PMCID: PMC3618572  PMID: 23363033
beta-cell; islets; diabetes; neogenesis; insulin secretion
2.  Predicting response to bevacizumab in ovarian cancer: a panel of potential biomarkers informing treatment selection 
Purpose
The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial.
Experimental design
ICON7 was a phase III international trial in EOC which demonstrated a modest but statistically significant benefit in progression-free survival with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (5 responders, 5 non-responders) were analysed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial).
Results
Three candidate biomarkers were identified, mesothelin, fms-like tyrosine kinase-4 (FLT4) and α1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high risk status in initial (p<0.02) and combined (p<0.01) validation cohorts. In cohort I individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (p=0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared to standard arm.
Conclusions
This study demonstrates a discriminatory signature comprising mesothelin, FLT4, AGP and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts.
doi:10.1158/1078-0432.CCR-13-0489
PMCID: PMC3780518  PMID: 23935036
biomarkers; proteomics; bevacizumab; serum; predictive; ICON7
3.  Breast Cancer in Systemic Lupus Erythematosus 
Oncology  2013;85(2):117-121.
Objective
Evidence points to a decreased breast cancer risk in systemic lupus erythematosus (SLE). We analyzed data from a large multisite SLE cohort, linked to cancer registries.
Methods
Information on age, SLE duration, cancer date, and histology was available. We analyzed information on histological type and performed multivariate logistic regression analyses of histological types according to age, SLE duration, and calendar year.
Results
We studied 180 breast cancers in the SLE cohort. Of the 155 cases with histology information, 11 were referred to simply as ‘carcinoma not otherwise specified’. In the remaining 144 breast cancers, the most common histological type was ductal carcinoma (n = 95; 66%) followed by lobular adenocarcinoma (n = 11; 8%), 15 cancers were of mixed histology, and the remaining ones were special types. In our regression analyses, the independent risk factors for lobular versus ductal carcinoma was age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01–1.14] and for the ‘special’ subtypes it was age (OR 1.06, 95% CI 1.01–1.10) and SLE duration (OR 1.05, 95% CI 1.00–1.11).
Conclusions
Generally, up to 80% of breast cancers are ductal carcinomas. Though our results are not definitive, in the breast cancers that occur in SLE, there may be a slight decrease in the ductal histological type. In our analyses, age and SLE duration were independent predictors of histological status.
doi:10.1159/000353138
PMCID: PMC3934367  PMID: 23887245
Breast cancer; Systemic lupus erythematosus; Histopathology; Epidemiology
4.  U.S. Mental Health Policy: Addressing the Neglect of Asian Americans 
Although Asian Americans are proportionally the fastest-growing ethnic group in the United States, federal mental health policies have neglected their special needs. U.S. federal mental health policy has shifted in the past 50 years from an emphasis on increasing accessibility to treatment to improving the quality of care and focusing on the brain as the basis of mental illness. However, the mental health needs of Asian Americans have been a relatively low priority. Myths about Asian Americans that have led to the general neglect of their mental health needs are that they: (a) are a small group; (b) are a successful group and do not experience problems; and (c) do not experience mental health disparities. Nevertheless, Asian Americans are a significant proportion of the population which experiences acculturative stress and discrimination that are often associated with psychopathology. However, Asian Americans who experience psychopathology are less likely than other groups to use mental health services. Political efforts must be made to get Asian Americans into positions of leadership and power in which they can make decisions about mental health policy priorities.
doi:10.1037/a0029950
PMCID: PMC3905325  PMID: 24490000
Asian Americans; mental health policy; acculturative stress; discrimination; ethnic identity
5.  Solution structures of the Bacillus cereus metallo-β-lactamase BcII and its complex with the broad spectrum inhibitor R-thiomandelic acid 
Biochemical Journal  2013;456(Pt 3):397-407.
Metallo-β-lactamases, enzymes which inactivate β-lactam antibiotics, are of increasing biological and clinical significance as a source of antibiotic resistance in pathogenic bacteria. In the present study we describe the high-resolution solution NMR structures of the Bacillus cereus metallo-β-lactamase BcII and of its complex with R-thiomandelic acid, a broad-spectrum inhibitor of metallo-β-lactamases. This is the first reported solution structure of any metallo-β-lactamase. There are differences between the solution structure of the free enzyme and previously reported crystal structures in the loops flanking the active site, which are important for substrate and inhibitor binding and catalysis. The binding of R-thiomandelic acid and the roles of active-site residues are defined in detail. Changes in the enzyme structure upon inhibitor binding clarify the role of the mobile β3–β4 loop. Comparisons with other metallo-β-lactamases highlight the roles of individual amino-acid residues in the active site and the β3–β4 loop in inhibitor binding and provide information on the basis of structure–activity relationships among metallo-β-lactamase inhibitors.
Metallo-β-lactamases are important in antibiotic resistance in micro-organisms. We report the first solution structure of a metallo-β-lactamase and its complex with an inhibitor, allowing the key flexible loops flanking the active site and their role in inhibitor binding to be properly defined.
doi:10.1042/BJ20131003
PMCID: PMC3898119  PMID: 24059435
antibiotic resistance; enzyme structure; inhibitor binding; metallo-β-lactamase; NMR spectroscopy; zinc enzyme; HSQC, heteronuclear single-quantum coherence; MBL, metallo-β-lactamase; NOE, nuclear Overhauser effect
6.  Sustained NF-κB Activation and Inhibition in β-Cells Have Minimal Effects on Function and Islet Transplant Outcomes 
PLoS ONE  2013;8(10):e77452.
The activation of the transcription factor NF-κB leads to changes in expression of many genes in pancreatic β-cells. However, the role of NF-κB activation in islet transplantation has not been fully elucidated. The aim of the present study was to investigate whether the state of NF-κB activation would influence the outcome of islet transplantation. Transgenic mice expressing a dominant active IKKβ (constitutively active) or a non-degradable form of IκBα (constitutive inhibition) under control of the rat insulin promoter were generated. Islets from these mice were transplanted into streptozotocin diabetic mice in suboptimal numbers. Further, the effects of salicylate (an inhibitor of NF-κB) treatment of normal islets prior to transplantation, and the effects of salicylate administration to mice prior to and after islet implantation were evaluated. Transplantation outcomes were not affected using islets expressing a non-degradable form of IκBα when compared to wild type controls. However, the transplantation outcomes using islets isolated from mice expressing a constitutively active mutant of NF-κB were marginally worse, although no aberrations of islet function in vitro could be detected. Salicylate treatment of normal islets or mice had no effect on transplantation outcome. The current study draws attention to the complexities of NF-κB in pancreatic beta cells by suggesting that they can adapt with normal or near normal function to both chronic activation and inhibition of this important transcription factor.
doi:10.1371/journal.pone.0077452
PMCID: PMC3799630  PMID: 24204831
7.  SF-36 summary and subscale scores are reliable outcomes of neuropsychiatric events in systemic lupus erythematosus 
Annals of the rheumatic diseases  2011;70(6):961-967.
Objective
To examine change in health-related quality of life (HRQoL) in association with clinical outcomes of neuropsychiatric (NP) events in SLE.
Methods
An international study evaluated newly diagnosed SLE patients for NP events attributed to SLE and non-SLE causes. Outcome of events was determined by physician-completed 7-point scale and compared to patient-completed SF-36 questionnaires. Statistical analysis used linear mixed-effects regression models with patient specific random effects.
Results
274 patients (92% female; 68% Caucasian), from a cohort of 1400, had ≥ 1 NP event where the interval between assessments was 12.3 ± 2 months. The overall difference in change between visits in mental component summary (MCS) scores of the SF-36 was significant (p<0.0001) following adjustments for gender, ethnicity, center and previous score. A consistent improvement in NP status (N=295) was associated with an increase in the mean(SD) adjusted MCS score of 3.66(0.89) in SF-36 scores. Between paired visits where NP status consistently deteriorated (N=30), the adjusted MCS score decreased by 4.00(1.96). For the physical component summary (PCS) scores the corresponding changes were +1.73(0.71) and −0.62(1.58) (p<0.05) respectively. Changes in SF-36 subscales were in the same direction (p<0.05; with the exception of role physical). Sensitivity analyses confirmed these findings. Adjustment for age, education, medications, SLE disease activity, organ damage, disease duration, attribution and characteristics of NP events did not substantially alter the results.
Conclusion
Changes in SF-36 summary and subscale scores, in particular those related to mental health, are strongly associated with the clinical outcome of NP events in SLE patients.
doi:10.1136/ard.2010.138792
PMCID: PMC3795436  PMID: 21342917
Systemic lupus erythematosus; Neuropsychiatric; Inception cohort; Health related quality of life; SF-36
8.  The thermal effects of lavage on 57 ox femoral heads prepared for hip resurfacing arthroplasty 
Acta Orthopaedica  2013;84(5):448-452.
Background and purpose
Previously, we have documented surface temperatures recorded by thermography great enough to cause osteonecrosis of the femoral head during hip resurfacing. We now performed an in vitro investigation with 3 questions: (1) whether water irrigation reduced bone surface temperature, (2) whether external bone temperatures were similar to core temperatures, and (3) whether blunting of the reamer affected temperature generation.
Methods
Using an ox-bone model, 57 femoral heads were peripherally reamed. The surface temperatures of bone were measured using a thermal camera and internal bone temperatures were measured using 2 theromocouples. We measured the effects of cooling with water at room temperature and with ice-cooled water. Progressive blunting of reamers was assessed over the 57 experiments.
Results
Mean and maximum temperatures generated during peripheral reaming were greater when no irrigation was used. Ice-cold saline protected femoral heads from thermal damage. External bone temperatures were much greater than internal temperatures, which were not sufficiently elevated to cause osteonecrosis regardless of lavage. Blunting of the reamer was not found to have a statistically significant effect in this study.
Interpretation
Cooling with ice-cooled water is recommended. Internal bone temperatures are not elevated despite the high surface temperatures reached during femoral head resurfacing.
doi:10.3109/17453674.2013.845812
PMCID: PMC3822128  PMID: 24079554
9.  Prediction of Marginal Mass Required for Successful Islet Transplantation 
Islet quality assessment methods for predicting diabetes reversal (DR) following transplantation are needed. We investigated two islet parameters, oxygen consumption rate (OCR) and OCR per DNA content, to predict transplantation outcome and explored the impact of islet quality on marginal islet mass for DR. Outcomes in immunosuppressed diabetic mice were evaluated by transplanting mixtures of healthy and purposely damaged rat islets for systematic variation of OCR/DNA over a wide range. The probability of DR increased with increasing transplanted OCR and OCR/DNA. On coordinates of OCR versus OCR/DNA, data fell into regions in which DR occurred in all, some, or none of the animals with a sharp threshold of around 150-nmol/min mg DNA. A model incorporating both parameters predicted transplantation outcome with sensitivity and specificity of 93% and 94%, respectively. Marginal mass was not constant, depended on OCR/DNA, and increased from 2,800 to over 100,000 islet equivalents/kg body weight as OCR/DNA decreased. We conclude that measurements of OCR and OCR/DNA are useful for predicting transplantation outcome in this model system, and OCR/DNA can be used to estimate the marginal mass required for reversing diabetes. Because human clinical islet preparations in a previous study had OCR/DNA values in the range of 100–150-nmol/min mg DNA, our findings suggest that substantial improvement in transplantation outcome may accompany increasedOCR/DNAin clinical islet preparations.
doi:10.3109/08941930903410825
PMCID: PMC3786417  PMID: 20233002
marginal graft; oxygen consumption rate; transplantation outcome; predictive assay; mouse bioassay; rat islets
10.  Ductal origin hypothesis of pancreatic regeneration under attack 
Cell metabolism  2010;11(1):2-3.
doi:10.1016/j.cmet.2009.12.005
PMCID: PMC3762572  PMID: 20085728
11.  Redox-Linked Domain Movements in the Catalytic Cycle of Cytochrome P450 Reductase 
Structure(London, England:1993)  2013;21(9):1581-1589.
Summary
NADPH-cytochrome P450 reductase is a key component of the P450 mono-oxygenase drug-metabolizing system. There is evidence for a conformational equilibrium involving large-scale domain motions in this enzyme. We now show, using small-angle X-ray scattering (SAXS) and small-angle neutron scattering, that delivery of two electrons to cytochrome P450 reductase leads to a shift in this equilibrium from a compact form, similar to the crystal structure, toward an extended form, while coenzyme binding favors the compact form. We present a model for the extended form of the enzyme based on nuclear magnetic resonance and SAXS data. Using the effects of changes in solution conditions and of site-directed mutagenesis, we demonstrate that the conversion to the extended form leads to an enhanced ability to transfer electrons to cytochrome c. This structural evidence shows that domain motion is linked closely to the individual steps of the catalytic cycle of cytochrome P450 reductase, and we propose a mechanism for this.
Graphical Abstract
Highlights
•Cytochrome P450 reductase is in equilibrium between compact and extended forms•The position of the equilibrium depends on the redox state of the enzyme•The extended form favors electron transfer to cytochrome c•Domain motion is linked closely to the individual steps of the catalytic cycle
Solution scattering experiments by Huang et al. connect domain movement in cytochrome P450 reductase to individual steps in the catalytic cycle. The domain movement necessary for enzyme turnover is not achieved simply by random diffusion; rather, it is linked closely to the individual steps of the catalytic cycle.
doi:10.1016/j.str.2013.06.022
PMCID: PMC3763376  PMID: 23911089
12.  A novel phenoxy thiophene sulphonamide molecule protects against glutamate evoked oxidative injury in a neuronal cell model 
BMC Neuroscience  2013;14:93.
Background
Glutamate is one of the major neurotransmitters in the central nervous system. It is a potent neurotoxin capable of neuronal destruction through numerous signal pathways when present in high concentration. Glutamate-evoked excitotoxicity has been implicated in the etiology of many neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke. Increasing evidence has shown that reactive oxygen species (ROS) provoked by glutamate-linked oxidative stress plays a crucial role in the pathogenesis of these disorders. We previously reported the discovery of an aryl thiophene compound, 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B355252) from a proprietary library of small molecules. We showed that this compound was capable of potentiating nerve growth factor (NGF)-primed neurite outgrowth in neuronal cell models in a low NGF environment. In the present study we investigated the neuroprotective effects and signaling pathways of B355252 on glutamate-evoked excitotoxicity in HT-22, a murine hippocampal neuronal cell line.
Results
Glutamate significantly decreased HT-22 neuronal cell viability in a concentration-dependent manner as measured by the MTT assay. Co-treatment with 2, 4, and 8 μM B355252 protected against cell death caused by glutamate-induced toxicity by 9.1% (p<0.01), 26.0% (p<0.001), and 61.9% (p<0.001) respectively, compared to glutamate-treated control group. B355252 at a concentration of 8 μM fully rescued HT-22 from the neurototoxic effects of glutamate, and by itself increased cell viability by 16% (p<0.001) above untreated control. Glutamate enhanced reduction in glutathione (GSH) synthesis was reversed by 15% (p<0.01) in the presence of B355252. B355252 reduced the expression of apoptosis inducing factor (AIF) by 27%, while the proapoptotic Bcl-2 associated X protein (Bax) was strongly attenuated 3-fold. Glutamate-evoked increase in intracellular calcium (Ca2+) load and subsequent ROS production was inhibited by 71% (p<0.001) and 40% (p<0.001) respectively, to comparable level as untreated control in the presence of B355252. Glutamate significantly upregulated the phosphorylation of extracellular signal regulated kinase Erk1/2 (pERK1/2), while decreasing Erk3. In contrast, B355252 potently attenuated the glutamate-dependent activation of Erk1/2 and robustly increased the level of ERK3 in HT-22.
Conclusions
A novel phenoxy thiophene small molecule, B355252, suppresses glutamate-evoked oxidative stress in HT-22 neurons by blocking Ca2+ and ROS production, and altering the expression or phosphorylation states of Erk kinases. This molecule previously reported to enhance neurite outgrowth in the presence of sub-physiological concentrations of NGF appears to be a promising drug candidate for development as a potential therapeutic and neuroprotective agent for various neurodegenerative disorders.
doi:10.1186/1471-2202-14-93
PMCID: PMC3846642  PMID: 24004478
Glutamate; Neuroprotection; Excitotoxicity; Small molecule; Alzheimer’s disease; Oxidative stress; ERK3; Neurodegenerative disease; Phenoxy thiophene; HT-22
13.  NEUROTRANSMITTER ABNORMALITIES AND RESPONSE TO SUPPLEMENTATION IN SPG11 
Molecular genetics and metabolism  2012;107(1-2):229-233.
Objective
To report the detection of secondary neurotransmitter abnormalities in a group of SPG11 patients and describe treatment with L-dopa/carbidopa and sapropterin.
Design
Case reports
Setting
National Institutes of Health in the context of the Undiagnosed Disease Program; Children’s National Medical Center in the context of Myelin Disorders Bioregistry Program
Patients
Four SPG11 patients with a clinical picture of progressive spastic paraparesis complicated by extrapyramidal symptoms and maculopathy
Interventions
L-dopa/carbidopa and sapropterin
Results
3/4 patients presented secondary neurotransmitter abnormalities; 4/4 partially responded to L-dopa as well as sapropterin
Conclusions
In the SPG11 patient with extrapyramidal symptoms, a trial of L-dopa/carbidopa and sapropterin and/or evaluation of cerebrospinal fluid neurotransmitters should be considered.
doi:10.1016/j.ymgme.2012.05.020
PMCID: PMC3517733  PMID: 22749184
spastic paraparesis; dopa responsive dystonia; neurotransmitter disorder; SPG11
14.  The Efficacy of an Immunoisolating Membrane System for Islet Xenotransplantation in Minipigs 
PLoS ONE  2013;8(8):e70150.
Developing a device that protects xenogeneic islets to allow treatment and potentially cure of diabetes in large mammals has been a major challenge in the past decade. Using xenogeneic islets for transplantation is required in light of donor shortage and the large number of diabetic patients that qualify for islet transplantation. Until now, however, host immunoreactivity against the xenogeneic graft has been a major drawback for the use of porcine islets. Our study demonstrates the applicability of a novel immunoprotective membrane that allows successful xenotransplantation of rat islets in diabetic minipigs without immunosuppressive therapy. Rat pancreatic islets were encapsulated in highly purified alginate and integrated into a plastic macrochamber covered by a poly-membrane for subcutaneous transplantation. Diabetic Sinclair pigs were transplanted and followed for up to 90 days. We demonstrated a persistent graft function and restoration of normoglycemia without the need for immunosuppressive therapy. This concept could potentially offer an attractive strategy for a more widespread islet replacement therapy that would restore endogenous insulin secretion in diabetic patients without the need for immunosuppressive drugs and may even open up an avenue for safe utilization of xenogeneic islet donors.
doi:10.1371/journal.pone.0070150
PMCID: PMC3731363  PMID: 23936385
15.  Changes in Association between Previous Therapeutic Abortion and Preterm Birth in Scotland, 1980 to 2008: A Historical Cohort Study 
PLoS Medicine  2013;10(7):e1001481.
Gordon C. Smith and colleagues used national databases to investigate the association between previous termination of pregnancy and preterm birth in Scotland between 1980 to 2008, and whether the type of procedure was an important factor.
Please see later in the article for the Editors' Summary
Background
Numerous studies have demonstrated that therapeutic termination of pregnancy (abortion) is associated with an increased risk of subsequent preterm birth. However, the literature is inconsistent, and methods of abortion have changed dramatically over the last 30 years. We hypothesized that the association between previous abortion and the risk of preterm first birth changed in Scotland between 1 January 1980 and 31 December 2008.
Methods and Findings
We studied linked Scottish national databases of births and perinatal deaths. We analysed the risk of preterm birth in relation to the number of previous abortions in 732,719 first births (≥24 wk), adjusting for maternal characteristics. The risk (adjusted odds ratio [95% CI]) of preterm birth was modelled using logistic regression, and associations were expressed for a one-unit increase in the number of previous abortions. Previous abortion was associated with an increased risk of preterm birth (1.12 [1.09–1.16]). When analysed by year of delivery, the association was strongest in 1980–1983 (1.32 [1.21–1.43]), progressively declined between 1984 and 1999, and was no longer apparent in 2000–2003 (0.98 [0.91–1.05]) or 2004–2008 (1.02 [0.95–1.09]). A statistical test for interaction between previous abortion and year was highly statistically significant (p<0.001). Analysis of data for abortions among nulliparous women in Scotland 1992–2008 demonstrated that the proportion that were surgical without use of cervical pre-treatment decreased from 31% to 0.4%, and that the proportion of medical abortions increased from 18% to 68%.
Conclusions
Previous abortion was a risk factor for spontaneous preterm birth in Scotland in the 1980s and 1990s, but the association progressively weakened and disappeared altogether by 2000. These changes were paralleled by increasing use of medical abortion and cervical pre-treatment prior to surgical abortion. Although it is plausible that the two trends were related, we could not test this directly as the data on the method of prior abortions were not linked to individuals in the cohort. However, we speculate that modernising abortion methods may be an effective long-term strategy to reduce global rates of preterm birth.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Therapeutic termination of pregnancy is relatively common, with an estimated 40 million procedures performed worldwide every year. Until two decades ago, most terminations were performed as a surgical procedure, but now the majority of terminations are medically induced with a combination of drugs—selective progesterone receptor antagonists, such as mifepristone, and prostaglandins—that cause less damage to the woman's cervix. Although surgical terminations are still performed, nowadays prostaglandins are also used to help prevent damage to the cervix. Protecting the woman's cervix can help to reduce the risk of spontaneous preterm birth (delivery before 37 weeks gestation) in subsequent pregnancies. As many women who have abortions go on to have subsequent births, the widespread use of termination may be a significant factor in the high global rates of preterm delivery.
Why Was This Study Done?
A previous meta-analysis (a study that combines information from several studies) showed that the risk of preterm delivery was higher in women who had had a previous termination compared to women who had not. Based on this meta-analysis, UK guidelines on the care of women requesting a termination currently recommend that they be informed of the increased risk of subsequent preterm birth. However, it is biologically plausible that women undergoing medical termination or current practice for surgical termination (using prostaglandins to protect and prepare the cervix) may not have an increased risk of subsequent preterm delivery, because such approaches may cause less trauma to the cervix than traditional surgical termination. So in this study, the researchers used a large dataset from Scotland with three decades of information about previous terminations and subsequent preterm deliveries to test this possibility.
What Did the Researchers Do and Find?
The researchers linked two national databases—the Scottish Morbidity Record 02 (SMR02), which records the clinical and demographic characteristics and outcomes of all patients giving birth in Scottish maternity hospitals, and the Scottish Stillbirth and Infant Death Survey (SSBIDS), which classifies all perinatal deaths in Scotland. SMR02 data were available from 1980 onwards and also recorded each woman's self-reported total number of previous abortions, and SSBIDS data were available from 1985. Then the researchers used information from NHS National Services Scotland to examine secular trends in terminations over the past few decades, specifically, whether a recorded termination was surgical or medical, and also whether surgical abortion was preceded by cervical preparation.
Using these methods, the researchers identified that there were 757,060 live, singleton first births between 1980 and 2008 and that 56,816 women reported one previous termination, 5,790 women reported two previous terminations, and 822 women reported three previous terminations. In their analysis (adjusted for maternal characteristics) the researchers found that there was an independent association of spontaneous preterm birth, but not induced preterm birth, with previous termination. The researchers calculated that the chance (odds) of spontaneous preterm birth for one, two, and three or more previous abortions was 1.17, 1.51, and 1.64, after adjusting for maternal characteristics, including smoking. Over the time period, the researchers found that the proportion of surgical terminations without use of cervical pre-treatment decreased from 31% in 1992 to 0.4% in 2008, and over the same period the proportion of medical terminations increased from 18% to 68%. These trends are important, because in their analysis by year of delivery, the researchers found that the association between preterm delivery and previous termination was strongest in 1980–1983, progressively declined between 1984 and 1999, and was no longer present from 2000 to 2008.
What Do These Findings Mean?
These findings support the established association between previous termination and preterm delivery. But most importantly, the changes in this association over the past two decades—from strong in 1980–1983 to nonexistent in 2000–2008—a period in which the use of medical termination and pre-treatment of the cervix for surgical termination increased dramatically in Scotland, suggest that surgical termination without cervical pre-treatment is responsible for the increased risk of spontaneous preterm birth: the decrease in the proportion of this procedure over the study period may have led to the disappearance of the established association between previous termination and preterm delivery from 2000 onwards. However, these findings are limited in that the researchers could not directly test whether the two trends were related because they did not have information on the method of previous termination linked to subsequent birth outcome for individual women. However, based on the findings of this study, it is possible that using modern methods of termination of pregnancy (rather than purely surgical methods) could be a factor in reducing global rates of spontaneous preterm delivery in the future.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001481.
Wikipedia gives more information about termination of pregnancy (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information is available about the SMR02 dataset used in this study
The World Health Organization gives information on preterm birth
doi:10.1371/journal.pmed.1001481
PMCID: PMC3706322  PMID: 23874161
16.  TTK/hMPS1 Is an Attractive Therapeutic Target for Triple-Negative Breast Cancer 
PLoS ONE  2013;8(5):e63712.
Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer.
doi:10.1371/journal.pone.0063712
PMCID: PMC3658982  PMID: 23700430
17.  Clopidogrel, Turkey and a red herring? 
BMJ Case Reports  2011;2011:bcr0120113776.
The authors present the case of acute hepatitis E in a 61-year-old Edinburgh man who had returned from a holiday in Turkey 6 weeks previously. Diagnosis was ambiguous with his presentation initially attributed to a drug-induced liver injury.
doi:10.1136/bcr.01.2011.3776
PMCID: PMC3079450  PMID: 22700934
18.  Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants 
The New England journal of medicine  2012;367(14):1321-1331.
BACKGROUND
Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management.
METHODS
We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization.
RESULTS
Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11×10−38). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P = 0.02).
CONCLUSIONS
Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.)
doi:10.1056/NEJMoa1200395
PMCID: PMC3494411  PMID: 22970919
19.  Wolfram syndrome 1 and adenylyl cyclase 8 interact at the plasma membrane to regulate insulin production and secretion 
Nature cell biology  2012;14(10):1105-1112.
Endoplasmic reticulum (ER) stress causes pancreatic β-cell dysfunction and contributes to β-cell loss and the progression of type 2 diabetes1,2. Wolfram syndrome 1 (WFS1) has been shown to be an important regulator of the ER stress signalling pathway3; however, its role in β-cell function remains unclear. Here we provide evidence that WFS1 is essential for glucose- and glucagon-like peptide 1 (GLP-1)-stimulated cyclic AMP production and regulation of insulin biosynthesis and secretion. Stimulation with glucose causes WFS1 translocation from the ER to the plasma membrane, where it forms a complex with adenylyl cyclase 8 (AC8), an essential cAMP-generating enzyme in the β-cell that integrates glucose and GLP-1 signalling4. ER stress and mutant WFS1 inhibit complex formation and activation of AC8, reducing cAMP synthesis and insulin secretion. These findings reveal that an ER-stress-related protein has a distinct role outside the ER regulating both insulin biosynthesis and secretion. The reduction of WFS1 protein on the plasma membrane during ER stress is a contributing factor for β-cell dysfunction and progression of type 2 diabetes.
doi:10.1038/ncb2578
PMCID: PMC3589109  PMID: 22983116
20.  RIAM and Vinculin Binding to Talin Are Mutually Exclusive and Regulate Adhesion Assembly and Turnover* 
The Journal of Biological Chemistry  2013;288(12):8238-8249.
Background: Talin mediates RIAM-dependent integrin activation and binds vinculin, which stabilizes adhesions.
Results: Structural and biochemical data show that vinculin inhibits RIAM binding to the compact N-terminal region of the talin rod, a region essential for focal adhesion assembly.
Conclusion: Talin·RIAM complexes activate integrins at the leading edge, whereas talin·vinculin promotes adhesion maturation.
Significance: Talin changes partners in response to force-induced conformational change.
Talin activates integrins, couples them to F-actin, and recruits vinculin to focal adhesions (FAs). Here, we report the structural characterization of the talin rod: 13 helical bundles (R1–R13) organized into a compact cluster of four-helix bundles (R2–R4) within a linear chain of five-helix bundles. Nine of the bundles contain vinculin-binding sites (VBS); R2R3 are atypical, with each containing two VBS. Talin R2R3 also binds synergistically to RIAM, a Rap1 effector involved in integrin activation. Biochemical and structural data show that vinculin and RIAM binding to R2R3 is mutually exclusive. Moreover, vinculin binding requires domain unfolding, whereas RIAM binds the folded R2R3 double domain. In cells, RIAM is enriched in nascent adhesions at the leading edge whereas vinculin is enriched in FAs. We propose a model in which RIAM binding to R2R3 initially recruits talin to membranes where it activates integrins. As talin engages F-actin, force exerted on R2R3 disrupts RIAM binding and exposes the VBS, which recruit vinculin to stabilize the complex.
doi:10.1074/jbc.M112.438119
PMCID: PMC3605642  PMID: 23389036
Adhesion; Cell Biology; Integrins; Nuclear Magnetic Resonance; Structural Biology; RIAM; Focal Adhesions; Talin; Vinculin
21.  Concise Review: Pancreas Regeneration: Recent Advances and Perspectives 
The replacement of functional pancreatic β-cells is seen as an attractive potential therapy for diabetes, because diabetes results from an inadequate β-cell mass. Inducing replication of the remaining β-cells and new islet formation from progenitors within the pancreas (neogenesis) are the most direct ways to increase the β-cell mass. Stimulation of both replication and neogenesis have been reported in rodents, but their clinical significance must still be shown. Because human islet transplantation is limited by the scarcity of donors and graft failure within a few years, efforts have recently concentrated on the use of stem cells to replace the deficient β-cells. Currently, embryonic stem cells and induced pluripotent stem cells achieve high levels of β-cell differentiation, but their clinical use is still hampered by ethical issues and/or the risk of developing tumors after transplantation. Pancreatic epithelial cells (duct, acinar, or α-cells) represent an appealing alternative to stem cells because they demonstrate β-cell differentiation capacities. Yet translation of such capacity to human cells after significant in vitro expansion has yet to be achieved. Besides providing new β-cells, cell therapy also has to address the question on how to protect the transplanted cells from destruction by the immune system via either allo- or autoimmunity. Encouraging developments have been made in encapsulation and immunomodulation techniques, but many challenges still remain. Herein, we discuss recent advances in the search for β-cell replacement therapies, current strategies for circumventing the immune system, and mandatory steps for new techniques to be translated from bench to clinics.
doi:10.5966/sctm.2011-0025
PMCID: PMC3659687  PMID: 23197762
Diabetes; Pancreas; Progenitor cells; Transplantation; Cellular therapy
22.  Reverse Abdominoplasty: A Practical Option for Oncological Trunk Reconstruction 
Eplasty  2013;13:e2.
Objectives: Following radical oncological resection, full-thickness upper central trunk defects present a significant challenge. Common reconstructive options include pedicled flaps, such as pectoralis major, rectus abdominis, and latissimus dorsi. In complex cases, free tissue transfer may be required. Reverse abdominoplasty, although initially described for cosmetic body contouring, can be used to reconstruct upper central trunk defects following radical tumour ablation. We present 4 such applications in the management of advanced or recurrent malignancies and review the relative indications for this approach. Methods: Four consecutive cases (2004-2010) were reviewed with respect to indication, operative procedure, and complications. Results: There were no cases of complete flap loss. One patient underwent revision for marginal flap necrosis while another developed local recurrence, requiring re-excision and reconstruction with flap advancement. Conclusions: Where pedicled flaps are unavailable or insufficient, adjacent abdominal tissue can be recruited into chest wall defects, avoiding microsurgical free tissue transfer. The authors feel that the reverse abdominoplasty is currently underused in this context and offers an excellent alternative in complex cases where other reconstructive options are unavailable, or where comorbidities preclude free-tissue transfer. The technique is versatile, simple to perform and affords an acceptable cosmetic outcome, yet is not widely reported in the literature. It has particular merit in cases with a high chance of disease recurrence, in the management of recurrent breast cancer, and in patients with multiple comorbidities. The reverse abdominoplasty should therefore be considered when evaluating patients for oncological trunk reconstruction.
PMCID: PMC3549590  PMID: 23359844
23.  Levosimendan: current data, clinical use and future development 
Heart, Lung and Vessels  2013;5(4):227-245.
Levosimendan is an inodilator indicated for the short-term treatment of acutely decompensated severe chronic heart failure, and in situations where conventional therapy is not considered adequate. The principal pharmacological effects of levosimendan are (a) increased cardiac contractility by calcium sensitisation of troponin C, (b) vasodilation, and (c) cardioprotection. These last two effects are related to the opening of sarcolemmal and mitochondrial potassium-ATP channels, respectively. Data from clinical trials indicate that levosimendan improves haemodynamics with no attendant significant increase in cardiac oxygen consumption and relieves symptoms of acute heart failure; these effects are not impaired or attenuated by the concomitant use of beta-blockers. Levosimendan also has favourable effects on neurohormone levels in heart failure patients. Levosimendan is generally well tolerated in acute heart failure patients: the most common adverse events encountered in this setting are hypotension, headache, atrial fibrillation, hypokalaemia and tachycardia. Levosimendan has also been studied in other therapeutic applications, particularly cardiac surgery - in which it has shown a range of beneficial haemodynamic and cardioprotective effects, and a favourable influence on clinical outcomes - and has been evaluated in repetitive dosing protocols in patients with advanced chronic heart failure. Levosimendan has shown preliminary positive effects in a range of conditions requiring inotropic support, including right ventricular failure, cardiogenic shock, septic shock, and Takotsubo cardiomyopathy.
PMCID: PMC3868185  PMID: 24364017
levosimendan; acute heart failure; cardiac surgery; cardioprotective inodilator; review; shock
24.  Prostate cancer in systemic lupus erythematosus 
Our research objective was to estimate prostate cancer risk in systemic lupus (SLE), relative to the age-matched general population. A progressive literature review was performed to identify SLE cohort studies with cancer registry linkage for cancer ascertainment. Data were pooled from four studies of large SLE cohorts who met these criteria. The total number of prostate cancers observed was derived by pooling the incident cases across all studies. The total expected number of prostate, derived from applying appropriate general population cancer incidence data to the observed number of patient-years of follow-up for each study, was similarly determined. The parameter of interest was the standardized incidence ratio (SIR), the ratio of observed to expected malignancies.
The four studies together provided a pool of 6,068 male SLE patients observed for a total of 38,186 patient years (mean 6.3 years). Within these subjects, 80 prostate cancers observed. In each contributing study, the number of cancers expected far exceeded that observed. The pooled SIR estimate for prostate cancer risk in males with SLE, compared to the general population, was 0.72 (95% CI 0.57, 0.89).
These data suggest a decreased risk of prostate cancer in SLE; more definite conclusions require additional data. Since alterations in androgen pathways can potentially alter prostate risk, a lower risk of prostate cancer in SLE could possibly be due to low hypoadrenergic states which some believe may occur in men with SLE; underlying genetic factors could also be at play. Further study of these issues in large cohorts is needed.
doi:10.1002/ijc.25956
PMCID: PMC3203250  PMID: 21448902
Systemic lupus erythematosus; malignancy; prostate cancer
25.  Correction: The MUC1 Extracellular Domain Subunit Is Found in Nuclear Speckles and Associates with Spliceosomes 
PLoS ONE  2012;7(10):10.1371/annotation/bb4082f7-5f88-4d64-8cab-f2e9c89b86eb.
doi:10.1371/annotation/bb4082f7-5f88-4d64-8cab-f2e9c89b86eb
PMCID: PMC3502554

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