bluuebunny/crossref_metadata_2025 huggingface dataset:
Critical role for Syk in responses to vascular injury
Authors: Andre Patrick , Morooka Toshifumi , Sim Derek , Abe Keith , Lowell Clifford , Nanda Nisha , Delaney Suzanne , Siu Gail , Yan Yibing , Hollenbach Stan , Pandey Anjali , Gao Huiyun , Wang Yunmei , Nakajima Kohsuke , Parikh Sahil A. , Shi Can , Phillips David , Owen Whyte , Sinha Uma , Simon Daniel I.
Published: September 2011

Although current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet–dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.
Predictors of greater than 80% 2-year mortality in primary myelofibrosis: a Mayo Clinic study of 884 karyotypically annotated patients
Authors: Tefferi Ayalew , Jimma Thitina , Gangat Naseema , Vaidya Rakhee , Begna Kebede H. , Hanson Curtis A. , Van Dyke Daniel L. , Caramazza Domenica , Pardanani Animesh
Published: September 2011

DIPSS-plus (the Dynamic International Prognostic Scoring System-plus) includes 8 risk factors for survival in primary myelofibrosis. In the present study of 884 karyotypically annotated patients with primary myelofibrosis, we sought to identify 1 or 2 parameters that can reliably predict death in the first 2 years of disease. After a median of 8.2 years from time of referral to the Mayo Clinic, 564 deaths (64% of patients in the study) had been recorded. Risk factors associated with > 80% 2-year mortality included monosomal karyotype, inv(3)/i(17q) abnormalities, or any 2 of the following: circulating blasts > 9%, leukocytes ≥ 40 × 109/L, or other unfavorable karyotype. Patients with any 1 of these risk profiles (n = 52) displayed significantly shorter overall survival than those otherwise belonging to a high-risk category per DIPSS-plus (n = 298); respective median survivals were 9 and 23 months (hazard ratio 2.2, 95% confidence interval 1.6-3.1; P < .01). The present information complements DIPSS-plus in the selection of primary myelofibrosis patients for high-risk treatment approaches.
Pulmonary aspergillosis: a clinical review
Authors: Kousha M. , Tadi R. , Soubani A.O.
Published: September 2011

Aspergillusis a mould which may lead to a variety of infectious, allergic diseases depending on the host's immune status or pulmonary structure. Invasive pulmonary aspergillosis occurs primarily in patients with severe immunodeficiency. The significance of this infection has dramatically increased with growing numbers of patients with impaired immune state associated with the management of malignancy, organ transplantation, autoimmune and inflammatory conditions; critically ill patients and those with chronic obstructive pulmonary disease appear to be at an increased risk. The introduction of new noninvasive tests, combined with more effective and better-tolerated antifungal agents, has resulted in lower mortality rates associated with this infection. Chronic necrotising aspergillosis is a locally invasive disease described in patients with chronic lung disease or mild immunodeficiency. Aspergilloma is usually found in patients with previously formed cavities in the lung, whereas allergic bronchopulmonary aspergillosis, a hypersensitivity reaction toAspergillusantigens, is generally seen in patients with atopy, asthma or cystic fibrosis. This review provides an update on the evolving epidemiology and risk factors of the major manifestations ofAspergilluslung disease and the clinical manifestations that should prompt the clinician to consider these conditions. Current approaches for the diagnosis and management of these syndromes are discussed.
Beyond corticosteroids: future prospects in the management of inflammation in COPD
Authors: Roche N. , Marthan R. , Berger P. , Chambellan A. , Chanez P. , Aguilaniu B. , Brillet P-Y , Burgel P-R , Chaouat A. , Devillier P. , Escamilla R. , Louis R. , Mal H. , Muir J-F , Pérez T. , Similowski T. , Wallaert B. , Aubier M.
Published: September 2011

Inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke induces the recruitment of inflammatory cells in the airways and stimulates innate and adaptive immune mechanisms. Airway inflammation is involved in increased bronchial wall thickness, increased bronchial smooth muscle tone, mucus hypersecretion and loss of parenchymal elastic structures. Oxidative stress impairs tissue integrity, accelerates lung ageing and reduces the efficacy of corticosteroids by decreasing levels of histone deacetylase-2. Protease–antiprotease imbalance impairs tissues and is involved in inflammatory processes. Inflammation is also present in the pulmonary artery wall and at the systemic level in COPD patients, and may be involved in COPD-associated comorbidities.

Proximal airways inflammation contributes to symptoms of chronic bronchitis while distal and parenchymal inflammation relates to airflow obstruction, emphysema and hyperinflation. Basal levels of airways and systemic inflammation are increased in frequent exacerbators.

Inhaled corticosteroids are much less effective in COPD than in asthma, which relates to the intrinsically poor reversibility of COPD-related airflow obstruction and to molecular mechanisms of resistance relating to oxidative stress. Ongoing research aims at developing new drugs targeting more intimately COPD-specific mechanisms of inflammation, hypersecretion and tissue destruction and repair. Among new anti-inflammatory agents, phosphodiesterase-4 inhibitors have been the first to emerge.
Application of Celluspots peptide arrays for the analysis of the binding specificity of epigenetic reading domains to modified histone tails
Authors: Bock Ina , Kudithipudi Srikanth , Tamas Raluca , Kungulovski Goran , Dhayalan Arunkumar , Jeltsch Albert
Published: September 2011

Background

Epigenetic reading domains are involved in the regulation of gene expression and chromatin state by interacting with histones in a post-translational modification specific manner. A detailed knowledge of the target modifications of reading domains, including enhancing and inhibiting secondary modifications, will lead to a better understanding of the biological signaling processes mediated by reading domains.

Results

We describe the application of Celluspots peptide arrays which contain 384 histone peptides carrying 59 post translational modifications in different combinations as an inexpensive, reliable and fast method for initial screening for specific interactions of reading domains with modified histone peptides. To validate the method, we tested the binding specificities of seven known epigenetic reading domains on Celluspots peptide arrays, viz. the HP1ß and MPP8 Chromo domains, JMJD2A and 53BP1 Tudor domains, Dnmt3a PWWP domain, Rag2 PHD domain and BRD2 Bromo domain. In general, the binding results agreed with literature data with respect to the primary specificity of the reading domains, but in almost all cases we obtained additional new information concerning the influence of secondary modifications surrounding the target modification.

Conclusions

We conclude that Celluspots peptide arrays are powerful screening tools for studying the specificity of putative reading domains binding to modified histone peptides.
Clustering with position-specific constraints on variance: Applying redescending M-estimators to label-free LC-MS data analysis
Authors: Frühwirth Rudolf , Mani D R , Pyne Saumyadipta
Published: September 2011

Background

Clustering is a widely applicable pattern recognition method for discovering groups of similar observations in data. While there are a large variety of clustering algorithms, very few of these can enforce constraints on the variation of attributes for data points included in a given cluster. In particular, a clustering algorithm that can limit variation within a cluster according to that cluster's position (centroid location) can produce effective and optimal results in many important applications ranging from clustering of silicon pixels or calorimeter cells in high-energy physics to label-free liquid chromatography based mass spectrometry (LC-MS) data analysis in proteomics and metabolomics.

Results

We present MEDEA (M-Estimator with DEterministic Annealing), an M-estimator based, new unsupervised algorithm that is designed to enforce position-specific constraints on variance during the clustering process. The utility of MEDEA is demonstrated by applying it to the problem of "peak matching"--identifying the common LC-MS peaks across multiple samples--in proteomic biomarker discovery. Using real-life datasets, we show that MEDEA not only outperforms current state-of-the-art model-based clustering methods, but also results in an implementation that is significantly more efficient, and hence applicable to much larger LC-MS data sets.

Conclusions

MEDEA is an effective and efficient solution to the problem of peak matching in label-free LC-MS data. The program implementing the MEDEA algorithm, including datasets, clustering results, and supplementary information is available from the author website athttp://www.hephy.at/user/fru/medea/.
A eukaryotic-type signalling system of Pseudomonas aeruginosa contributes to oxidative stress resistance, intracellular survival and virulence
Authors: Goldová Jana , Ulrych Aleš , Hercík Kamil , Branny Pavel
Published: September 2011

Background

The genome of Pseudomonas aeruginosa contains at least three genes encoding eukaryotic-type Ser/Thr protein kinases, one of which, ppkA, has been implicated in P. aeruginosa virulence. Together with the adjacent pppA phosphatase gene, they belong to the type VI secretion system (H1-T6SS) locus, which is important for bacterial pathogenesis. To determine the biological function of this protein pair, we prepared a pppA-ppkA double mutant and characterised its phenotype and transcriptomic profiles.

Results

Phenotypic studies revealed that the mutant grew slower than the wild-type strain in minimal media and exhibited reduced secretion of pyoverdine. In addition, the mutant had altered sensitivity to oxidative and hyperosmotic stress conditions. Consequently, mutant cells had an impaired ability to survive in murine macrophages and an attenuated virulence in the plant model of infection. Whole-genome transcriptome analysis revealed that pppA-ppkA deletion affects the expression of oxidative stress-responsive genes, stationary phase σ-factor RpoS-regulated genes, and quorum-sensing regulons. The transcriptome of the pppA-ppkA mutant was also analysed under conditions of oxidative stress and showed an impaired response to the stress, manifested by a weaker induction of stress adaptation genes as well as the genes of the SOS regulon. In addition, expression of either RpoS-regulated genes or quorum-sensing-dependent genes was also affected. Complementation analysis confirmed that the transcription levels of the differentially expressed genes were specifically restored when the pppA and ppkA genes were expressed ectopically.

Conclusions

Our results suggest that in addition to its crucial role in controlling the activity of P. aeruginosa H1-T6SS at the post-translational level, the PppA-PpkA pair also affects the transcription of stress-responsive genes. Based on these data, it is likely that the reduced virulence of the mutant strain results from an impaired ability to survive in the host due to the limited response to stress conditions.
The C242T polymorphism of the p22-phox gene (CYBA) is associated with higher left ventricular mass in Brazilian hypertensive patients
Authors: Schreiber Roberto , Ferreira-Sae Maria C , Ronchi Juliana A , Pio-Magalhães José A , Cipolli José A , Matos-Souza José R , Mill José G , Vercesi Aníbal E , Krieger José E , Franchini Kleber G , Pereira Alexandre C , Nadruz Junior Wilson
Published: September 2011

Background

Reactive oxygen species have been implicated in the physiopathogenesis of hypertensive end-organ damage. This study investigated the impact of the C242T polymorphism of the p22-phox gene (CYBA) on left ventricular structure in Brazilian hypertensive subjects.

Methods

We cross-sectionally evaluated 561 patients from 2 independent centers [Campinas (n = 441) and Vitória (n = 120)] by clinical history, physical examination, anthropometry, analysis of metabolic and echocardiography parameters as well as p22-phox C242T polymorphism genotyping. In addition, NADPH-oxidase activity was quantified in peripheral mononuclear cells from a subgroup of Campinas sample.

Results

Genotype frequencies in both samples were consistent with the Hardy- Weinberg equilibrium. Subjects with the T allele presented higher left ventricular mass/height2.7 than those carrying the CC genotype in Campinas (76.8 ± 1.6 vs 70.9 ± 1.4 g/m2.7; p = 0.009), and in Vitória (45.6 ± 1.9 vs 39.9 ± 1.4 g/m2.7; p = 0.023) samples. These results were confirmed by stepwise regression analyses adjusted for age, gender, blood pressure, metabolic variables and use of anti-hypertensive medications. In addition, increased NADPH-oxidase activity was detected in peripheral mononuclear cells from T allele carriers compared with CC genotype carriers (p = 0.03).

Conclusions

The T allele of the p22-phox C242T polymorphism is associated with higher left ventricular mass/height2.7 and increased NADPH-oxidase activity in Brazilian hypertensive patients. These data suggest that genetic variation within NADPH-oxidase components may modulate left ventricular remodeling in subjects with systemic hypertension.
A novel reporter of notch signalling indicates regulated and random notch activation during vertebrate neurogenesis
Authors: Vilas-Boas Filipe , Fior Rita , Swedlow Jason R , Storey Kate G , Henrique Domingos
Published: September 2011

Background

Building the complex vertebrate nervous system involves the regulated production of neurons and glia while maintaining a progenitor cell population. Neurogenesis starts asynchronously in different regions of the embryo and occurs over a long period of time, allowing progenitor cells to be exposed to multiple extrinsic signals that regulate the production of different cell types. Notch-mediated cell-cell signalling is one of the mechanisms that maintain the progenitor pool, however, little is known about how the timing of Notch activation is related to the cell cycle and the distinct modes of cell division that generate neurons. An essential tool with which to investigate the role of Notch signalling on cell by cell basis is the development a faithful reporter of Notch activity.

Results

Here we present a novel reporter for Notch activity based on the promoter of the well characterised Notch target chick Hes5-1, coupled with multiple elements that confer instability, including a destabilized nuclear Venus fluorescent protein and the 3' untranslated region (UTR) of Hes5-1. We demonstrate that this reporter faithfully recapitulates the endogenous expression of Hes5-1 and that it robustly responds to Notch activation in the chick neural tube. Analysis of the patterns of Notch activity revealed by this reporter indicates that although Notch is most frequently activated prior to mitosis it can be activated at any time within the cell cycle. Notch active progenitors undergoing mitosis generate two daughters that both continue to experience Notch signalling. However, cells lacking Notch activity before and during mitosis generate daughters with dissimilar Notch activity profiles.

Conclusions

A novel Notch reporter with multiple destabilisation elements provides a faithful read-out of endogenous Notch activity on a cell-by-cell basis, as neural progenitors progress through the cell cycle in the chick neural tube. Notch activity patterns in this cell population provide evidence for distinct Notch signalling dynamics underlying different cell division modes and for the involvement of random initiation of Notch signalling within the neuroepithelium. These findings highlight the importance of single-cell analysis in the study of the complexity of Notch activity and provide new insights into the mechanisms underlying cell fate decisions in neural progenitors.
Pegylated interferon-alfa-2a monotherapy in patients infected with HCV genotype 2 and importance of rapid virological response
Authors: Etoh Reiko , Imazeki Fumio , Kurihara Tomoko , Fukai Kenichi , Fujiwara Keiichi , Arai Makoto , Kanda Tatsuo , Mikata Rintaro , Yonemitsu Yutaka , Yokosuka Osamu
Published: September 2011

Background

Pegylated (PEG)-interferon (IFN)-alfa-2a plus ribavirin (RBV) therapy for 24 weeks is now a standard treatment protocol for patients with hepatitis C virus (HCV) genotype 2. As RBV cannot be used in certain situations, we examined whether PEG-IFN-alfa-2a monotherapy for 24 weeks or less would be sufficient to obtain a sustained virological response (SVR) in patients infected with HCV genotype 2.

Methods

Forty-nine consecutive patients with HCV genotype 2 received PEG-IFN-alfa-2a (180 μg/week) subcutaneously without oral RBV for 8-64 weeks. HCV RNA level was determined by COBAS AMPLICOR HCV Test, v2.0.

Results

HCV RNA was equal to or less than 100 KIU/mL (defined as low viral load) in 15 of 49 patients, and the remaining 34 had HCV RNA above 100 KIU/mL (defined as high viral load). All 15 patients with low viral load achieved rapid virological response (RVR; HCV RNA negative at week 4), and also achieved SVR with an average treatment duration of 17.1 weeks. The 34 patients with high viral load were treated for 33.7 weeks on average, and 19 of them (55.9%) achieved RVR. The SVR rates of these patients were significantly higher in those with RVR than without RVR (16/19 vs. 6/15 p = 0.0074).

Conclusion

PEG-IFN-alfa-2a monotherapy for 24 weeks or less might be sufficient to treat selected patients with HCV genotype 2, especially those with low viral load and becoming negative for HCV RNA by week 4 of treatment.
NF-kappaB activation within macrophages leads to an anti-tumor phenotype in a mammary tumor lung metastasis model
Authors: Connelly Linda , Barham Whitney , Onishko Halina M , Chen Lianyi , Sherrill Taylor P , Zabuawala Tahera , Ostrowski Michael C , Blackwell Timothy S , Yull Fiona E
Published: September 2011

Introduction

Metastasis from primary tumor to the lungs is a major cause of the mortality associated with breast cancer. Both immune and inflammatory responses impact whether circulating mammary tumor cells successfully colonize the lungs leading to established metastases. Nuclear factor -kappaB (NF-κB) transcription factors regulate both immune and inflammatory responses mediated in part by the activities of macrophages. Therefore, NF-κB activity specifically within macrophages may be a critical determinant of whether circulating tumor cells successfully colonize the lungs.

Methods

To investigate NF-κB signaling within macrophages during metastasis, we developed novel inducible transgenic models which target expression of the reverse tetracycline transactivator (rtTA) to macrophages using the cfms promoter in combination with inducible transgenics that express either an activator (cIKK2) or an inhibitor (IκBα-DN). Doxycyline treatment led to activation or inhibition of NF-κB within macrophages. We used a tail vein metastasis model with mammary tumor cell lines established from MMTV-Polyoma Middle T-Antigen-derived tumors to investigate the effects of modulating NF-κB in macrophages during different temporal windows of the metastatic process.

Results

We found that activation of NF-κB in macrophages during seeding leads to a reduction in lung metastases. The mechanism involved expression of inflammatory cytokines and reactive oxygen species, leading to apoptosis of tumor cells and preventing seeding in the lung. Activation of NF-κB within macrophages after the seeding phase has no significant impact on establishment of metastases.

Conclusions

Our results have identified a brief, defined window in which activation of NF-κB has significant anti-metastatic effects and inhibition of NF-κB results in a worse outcome.
Mentoring Interdisciplinary Undergraduate Students via a Team Effort
Authors: Karsai Istvan , Knisley Jeff , Knisley Debra , Yampolsky Lev , Godbole Anant
Published: September 2011

We describe how a team approach that we developed as a mentoring strategy can be used to recruit, advance, and guide students to be more interested in the interdisciplinary field of mathematical biology, and lead to success in undergraduate research in this field. Students are introduced to research in their first semester via lab rotations. Their participation in the research of four faculty members—two from biology and two from mathematics—gives them a first-hand overview of research in quantitative biology and also some initial experience in research itself. However, one of the primary goals of the lab rotation experience is that of developing teams of students and faculty that combine mathematics and statistics with biology and the life sciences, teams that subsequently mentor undergraduate research in genuine interdisciplinary environments. Thus, the team concept serves not only as a means of establishing interdisciplinary research, but also as a means of incorporating new students into existing research efforts that will then track those students into meaningful research of their own. We report how the team concept is used to support undergraduate research in mathematical biology and what types of team-building strategies have worked for us.
RANDOM NETWORKS AND MIXING LAWS
Authors: Madden Theodore R.
Published: September 2011

Random networks are investigated as models of heterogeneous media. A general approximate structure is used where the networks are described as a system of embedded networks, and the critical behavior and averaging behavior of such networks are developed. These results are applied to a study of the electrical conductivity of porous media, with special attention to an Archie's law behavior. It appears that the wide range of crack and pore widths in rocks makes the resulting conductivity relatively insensitive to the topology of their interconnections and allows one to make reasonable predictions of rock conductivities, given the distribution of crack and pore widths. It also appears that with low porosity rocks the conductivity is controlled by the microcrack population which only accounts for a fraction of the total porosity. It would seem, therefore, that Archie's law is a feature of some general trend between porosity and crack and pore width distributions rather than a fundamental property of porous media.

The law of the geometric mean is an accurate predictor of the physical properties of a mixture of different materials. This mixing law can result from an equal balance of series and parallel arrangements which can be produced by an appropriate distribution of shapes.

A brief look is given to problems of anisotropic distributions for the conductivity problem and it is shown how the averaging process greatly dilutes the microscopic anisotropy in producing the macroscopic properties.
A FIELD TEST OF THE MAGNETOMETRIC RESISTIVITY (MMR) METHOD
Authors: Edwards R. N. , Howell E. C.
Published: September 2011

The electrical prospecting method, known as the Magnetometric Resistivity (MMR) method, is based on the measurement of the low level (about 100 milligamma), low‐frequency (1–5 Hz) magnetic fields associated with noninductive current flow in the ground. The horizontal component of the magnetic field is measured along profiles which are at right angles to a baseline joining two widely separated current electrodes.

The field test was conducted on a plateau in the western cordillera, where the topography is characterized by steep hills, bold ridges, gullies and narrow canyons. A steep faulted contact between basement rocks of differing resistivity is exposed on one flank of the plateau, beneath over 500 m of Tertiary volcanics and sediments.

The object of the test was to determine if the basement contact could be mapped by the MMR method, working entirely on top of the plateau. The plan position of the contact could be inferred approximately from measurements at the outcrop.

The object was achieved with a minimum of data processing. Using a theoretical model which resembles a thick, outcropping vertical dike of infinite vertical extent, the contrast in resistivity across the contact is estimated. A further model, that of an exponential “alpha” center, is also fitted to the data in an effort to pin‐point an anomalous region which may have unusually high conductivity.
Disorders of gender identity
Authors: Barrett James
Published: September 2011

Gender identity disorders are not common. The most frequent is dual-role transvestism, but it rarely needs medical attention. The least frequent is transsexualism. Transsexualism is not usually indicative of serious psychopathology. Diagnoses should be made by a gender identity clinic and never by the patient, and a clear change of gender role should precede any hormone treatment. Patients must have lived and thrived entirely in their new gender role for at least 2 years before any genital surgery is undertaken. However, bilateral mastectomy might be considered for females after a year of life in a male role. With these selection criteria, the outcomes of surgery are generally good. In the UK, individuals may legally change their recorded sex, usually after gender reassignment treatment.
Mania in late life
Authors: Richards Felicity , Curtice Martin
Published: September 2011

Mania in late life is a serious disorder that demands specialist assessment and management. However, it is greatly under-researched, with only a paucity of studies specifically analysing older populations. The mainstay of the old age psychiatry workload will inevitably be concerned with assessing and managing dementia and depression, but the steady rise in the aging population with longer survival means that there will be an increase in absolute numbers of older people presenting with mania. There are no specific treatment algorithms available for mania in late life. This article reviews mania and hypomania in late life and concentrates on diagnosis, assessment and treatment, as well as on the management considerations associated with this important age group.
Abortion and mental health: quantitative synthesis and analysis
of research published 1995–2009
Authors: Coleman Priscilla K.
Published: September 2011

Background

Given the methodological limitations of recently published qualitative
reviews of abortion and mental health, a quantitative synthesis was
deemed necessary to represent more accurately the published literature
and to provide clarity to clinicians.

Aims

To measure the association between abortion and indicators of adverse
mental health, with subgroup effects calculated based on comparison
groups (no abortion, unintended pregnancy delivered, pregnancy delivered)
and particular outcomes. A secondary objective was to calculate
population-attributable risk (PAR) statistics for each outcome.

Method

After the application of methodologically based selection criteria and
extraction rules to minimise bias, the sample comprised 22 studies, 36
measures of effect and 877 181 participants (163 831 experienced an
abortion). Random effects pooled odds ratios were computed using adjusted
odds ratios from the original studies and PAR statistics were derived
from the pooled odds ratios.

Results

Women who had undergone an abortion experienced an 81% increased risk of
mental health problems, and nearly 10% of the incidence of mental health
problems was shown to be attributable to abortion. The strongest subgroup
estimates of increased risk occurred when abortion was compared with term
pregnancy and when the outcomes pertained to substance use and suicidal
behaviour.

Conclusions

This review offers the largest quantitative estimate of mental health
risks associated with abortion available in the world literature. Calling
into question the conclusions from traditional reviews, the results
revealed a moderate to highly increased risk of mental health problems
after abortion. Consistent with the tenets of evidence-based medicine,
this information should inform the delivery of abortion services.
Differential outcome of schizophrenia: where we are and where we would like to be
Authors: Gureje Oye , Cohen Alex
Published: September 2011

Studies examining comparative outcomes of schizophrenia in high-income countries with those in low- and middle-income countries remain of interest to researchers and may be of value in understanding some environmental factors that influence the course and outcome of the disorder. The view that the disorder has a better outcome in low- and middle-income countries compared with high-income countries, even though widespread and supported by a set of World Health Organization (WHO) studies, requires further testing and exploration. Unfortunately, although not insurmountable, the obstacles for such studies both in terms of implementation and interpretation are considerable.
Schizophrenia with the 22q11.2 deletion and additional genetic
defects: case history
Authors: Toyosima M. , Maekawa M. , Toyota T. , Iwayama Y. , Arai M. , Ichikawa T. , Miyashita M. , Arinami T. , Itokawa M. , Yoshikawa T.
Published: September 2011

The 22q11.2 deletion is the most prominent known genetic risk factor for
schizophrenia, but its penetrance is at most approximately 50% suggesting
that additional risk factors are required for disease progression. We
examined a woman with schizophrenia with this deletion for such risk
factors. She had high plasma pentosidine levels (‘carbonyl stress’) and a
frameshift mutation in the responsible gene, GLO1. She also
had a constant exotropia, so we examined the PHOX2B gene
associated with both schizophrenia and strabismus, and detected a 5-alanine
deletion. We propose that the combination of these genetic defects may have
exceeded the threshold for the manifestation of schizophrenia.
Increasing the employment rate for people with longer-term mental health problems
Authors: Rinaldi Miles , Montibeller Tatiana , Perkins Rachel
Published: September 2011

Aims and method

To examine the effects of implementing the individual placement and support (IPS) approach within four community mental health teams (CMHTs). Demographic, clinical and vocational data were collected through a repeated cross-sectional survey. Additionally, a service user experience survey was conducted.

Results

The IPS approach appears to have a significant effect on the employment rates of service users; a higher proportion felt able to return to employment and a smaller proportion believed they were unable to work because of their mental health problems. Employment rates for service users appear to be independent of general employment rates.

Clinical implications

Implementing IPS appears to increase the employment rates in CMHTs resulting in increased service user expectations of being able to return to work.
Effect of Lifestyle Intervention on Features of Polycystic Ovarian Syndrome, Metabolic Syndrome, and Intima-Media Thickness in Obese Adolescent Girls
Authors: Lass Nina , Kleber Michaela , Winkel Katrin , Wunsch Rainer , Reinehr Thomas
Published: September 2011

Context:

Polycystic ovarian syndrome (PCOS) is associated with cardiovascular risk factors (CRF). Lifestyle intervention is regarded as therapy of choice even if studies in adolescent girls with PCOS are scarce.

Objective:

Our objective was to analyze the impact of lifestyle intervention on menses irregularities, hyperandrogenemia, CRF, and intima-media thickness (IMT) in adolescent girls with PCOS.

Patients:

Patients included 59 obese girls with PCOS aged 12–18 yr.

Intervention:

Intervention was a 1-yr lifestyle intervention based on nutrition education, exercise training, and behavior therapy.

Main Outcome Measures:

Menses cycles, IMT, waist circumference, blood pressure, fasting lipids, insulin, glucose, testosterone, dehydroepiandrosterone sulfate, androstenedione, and SHBG were evaluated.

Results:

In contrast to the 33 girls without weight loss, the 26 girls reducing their body mass index during the lifestyle intervention (by a mean of −3.9 kg/m2) improved most CRF and decreased their IMT (by a mean of −0.01 cm). Testosterone concentrations decreased (by a mean of −0.3 nmol/liter) and SHBG concentrations increased (by a mean of +8 ng/ml) significantly in girls with weight loss in contrast to girls with increasing weight. The prevalence of amenorrhea (−42%) and oligoamenorrhea (−19%) decreased in the girls with weight loss. The changes in insulin in the 1-yr follow-up were significantly correlated to changes in testosterone (r = 0.38; P = 0.002) and SHBG (r = −0.35; P = 0.048). A linear regression model with changes in IMT as dependent variable demonstrated a significant association with changes in blood pressure and weight status but not with changes in testosterone.

Conclusions:

Weight loss due to lifestyle intervention is effective to treat menses irregularities, normalize androgens, and improve CRF and IMT in obese adolescent girls with PCOS.
Imagining the Miscellaneous Nation: James Watson's Choice Collection of Comic and Serious Scots Poems
Authors: Davis Leith
Published: September 2011

As the first published anthology of Scottish poetry, the Choice Collection of Comic and Serious Scots Poems has long been regarded as a milestone in Scottish literary history. But acknowledgments of the Choice Collection's importance have historically been coupled with criticisms about its content. In particular, the Collection has been taken to task for its seeming disregard for genre or tone. This essay seeks to reevaluate the assessment of the Choice Collection as a “flawed” text by considering the Collection in relation to several contemporary miscellanies. Furthermore, it investigates the national impulse behind Watson's employment of this particular genre. Recognizing the competing interests at stake in the Scottish political landscape of 1706, Watson uses the imaginative space of the miscellany to bring readers of different tastes and interests together to promote the cause of Scotland at a time when the nation's very existence was under threat. Such a rereading of Watson's collection also contributes toward a reevaluation of the impression that Scottish literature after the Act of Union is pathologically split, a reflection of what G. Gregory Smith referred to as the “Caledonian antisyzygy.”
The Contested Meaning of 9/11
Authors: O'Brien Jim
Published: September 2011

How to interpret and understand the terror attacks of September 11, 2001, has been a recurrent theme of politics in the United States during the past decade. At the outset, the administration of George W. Bush framed the attacks in a way that has had lasting influence. In this view, the country was targeted because of its freedoms and high ideals, and the attacks constituted a declaration of war, to which the United States could respond in kind against targets of its choice. This interpretation led to wars in Afghanistan and Iraq, but over time it has run into opposition at home and abroad. Even as it retains residual power, this view of 9/11 has helped create a situation in which “the world's only superpower” has proven unable to shape events in the way its leaders would like.
Remembering 9/11's Pentagon Victims and Reframing History in Arlington National Cemetery
Authors: McElya Micki
Published: September 2011

In Arlington National Cemetery on September 12, 2002, the defense secretary, Donald H. Rumsfeld, presided over the burial with full military honors of a single casket containing unidentified remains intended to represent all 184 victims of the 9/11 Pentagon attack, a number that included civilian and military personnel on the ground and passengers on American Airlines Flight 77. Their collective grave, marked by a four-and-a-half-foot granite monument, sits within eyesight of the building where they died. The Pentagon Group Burial Marker, folded at the time of its dedication into Bush administration justifications for the planned invasion of Iraq, is today linked both in official and unofficial discourses to a set of monuments and graves scattered throughout the cemetery related to incidents of terrorism in the post-Vietnam era. The linkage gains fresh urgency as casualties mount from what has been defined as a war against terrorism. This article argues that these monuments are freighted with new historical meanings, justifications, and claims to legitimacy, drawn into a longer story of American victimization, Islamic aggression, reluctant empire, and triumphant U.S. nationalism and military virtue.
“Get Your War On”
Authors: Melnick Jeffrey
Published: September 2011

This pedagogical essay invites readers to consider how the work of cultural “first responders” to the 9/11 attacks—most notably David Rees, with his online comic Get Your War On—reached students at a small business college in the Northeast. Melnick is interested, above all, in tracking what he calls “stages” of student response to materials that initially seem too radical or culturally challenging. This essay explores how rapidly in the “post-9/11” the most extreme cultural creations came to seem relatively tame and unthreatening.
Teaching 9/11
Authors: Shihade Magid
Published: September 2011

In this essay, I discuss my experience of teaching a course on 9/11 at several universities in the United States and at one in Pakistan. The essay emphasizes the importance of teaching this course to critically engage students with policies that have followed the event and with how they have had an impact on people in the United States and abroad. The experience of teaching the class, especially in the United States, showed mixed results. While initially administrators welcomed the idea of teaching this topic, partially due to some students' complaints I was never asked to teach the course again. Another interesting finding is that although Pakistani students had greater awareness of the impact of U.S. policies after 9/11, the language of security and terror has managed to become global. In the essay that follows, I discuss this experience at its different stages.
THE CLOUD OF KNOWING
Authors: Allen Barry
Published: September 2011

In this monograph-length article, which inaugurates a multipart symposium titled “Fuzzy Studies,” the significance and virtues of blur are investigated through the whole history of Chinese intellectual tradition. In the Western tradition, the blur of becoming seems to disqualify an object for knowledge; nothing can be an object of knowledge until the blur is resolved and clarity attained. Chinese tradition offers suggestive examples of the thought that blur, so far from being incompatible with knowledge, might be its condition of possibility and the explanation of its value. This article traces the development of this thought (the compatibility of knowledge and original becoming) in the work of the classical Confucian and Daoist thinkers, the art-of-war literature, Chan Buddhism, and medieval Neoconfucianism, with an eye to its usefulness for Western philosophy of knowledge.
Prdm1a and miR-499 act sequentially to restrict Sox6 activity to the fast-twitch muscle lineage in the zebrafish embryo
Authors: Wang XinGang , Ono Yosuke , Tan Swee Chuan , Chai Ruth JinFen , Parkin Caroline , Ingham Philip W.
Published: September 2011

Sox6 has been proposed to play a conserved role in vertebrate skeletal muscle fibre type specification. In zebrafish, sox6 transcription is repressed in slow-twitch progenitors by the Prdm1a transcription factor. Here we identify sox6 cis-regulatory sequences that drive fast-twitch-specific expression in a Prdm1a-dependent manner. We show that sox6 transcription subsequently becomes derepressed in slow-twitch fibres, whereas Sox6 protein remains restricted to fast-twitch fibres. We find that translational repression of sox6 is mediated by miR-499, the slow-twitch-specific expression of which is in turn controlled by Prdm1a, forming a regulatory loop that initiates and maintains the slow-twitch muscle lineage.
Bivalirudin Dosing Adjustments for Reduced Renal Function with or Without Hemodialysis in the Management of Heparin-Induced Thrombocytopenia
Authors: Tsu Laura V , Dager William E
Published: September 2011

Background:

While not approved by the Food and Drug Administration for treatment of heparin-induced thrombocytopenia (HIT), except in patients undergoing percutaneous interventions, the direct thrombin inhibitor bivalirudin is a treatment option that is gaining use. An initial dose of bivalirudin 0.15–0.2 mg/kg/h, adjusted to an activated partial thromboplastin time (aPTT) of 1.5–2.5 times the baseline value, has been suggested. Initial dosing in patients with renal dysfunction, including those on hemodialysis, is unclear.

Objective:

To evaluate initial bivalirudin dosing requirements in patients with and without renal dysfunction, including patients on different forms of dialysis.

Methods:

A retrospective analysis of 135 patients treated with bivalirudin for HIT between June 2004 and October 2009 was conducted at a tertiary care medical center. The patients were divided into groups, based on renal function. Patients receiving dialysis were divided into 3 subgroups based on the mode of hemodialysis: intermittent hemodialysis (IHD, n = 24), sustained low-efficiency daily diafiltration (SLEDD, n = 12), or continuous renal replacement therapy (CRRT, n = 5). Patients not receiving dialysis were separated into 3 subgroups based on calculated creatinine clearance (CrCl): CrCl >60 mL/min (n = 52), CrCl 30–60 mL/min (n = 26), and CrCl <30 mL/min (n = 16).

Results:

Compared with patients with normal renal function (CrCl >60 mL/min), patients with differing degrees of renal dysfunction (CrCl 30–60 and <30 mL/min) required lower doses of bivalirudin to achieve aPTT goal (0.13 vs 0.08 vs 0.05 mg/kg/h, respectively; p < 0.001). Patients on dialysis (IHD, SLEDD, CRRT) also required dose reductions (0.07, 0.09, and 0.07 mg/kg/h) compared with patients with normal renal function, but higher dosing requirements than patients not receiving dialysis with CrCl <30 mL/min.

Conclusions:

Patients with renal dysfunction require a reduced dose of bivalirudin to reach a therapeutic aPTT goal. Slightly higher doses may be observed in patients receiving hemodialysis.
Compartmentalization of the GABABReceptor Signaling Complex Is Required for Presynaptic Inhibition at Hippocampal Synapses
Authors: Laviv Tal , Vertkin Irena , Berdichevsky Yevgeny , Fogel Hilla , Riven Inbal , Bettler Bernhard , Slesinger Paul A. , Slutsky Inna
Published: September 2011

Presynaptic inhibition via G-protein-coupled receptors (GPCRs) and voltage-gated Ca2+channels constitutes a widespread regulatory mechanism of synaptic strength. Yet, the mechanism of intermolecular coupling underlying GPCR-mediated signaling at central synapses remains unresolved. Using FRET spectroscopy, we provide evidence for formation of spatially restricted (<100 Å) complexes between GABABreceptors composed of GB1a/GB2subunits, Gαoβ1γ2G-protein heterotrimer, and CaV2.2 channels in hippocampal boutons. GABA release was not required for the assembly but for structural reorganization of the precoupled complex. Unexpectedly, GB1adeletion disrupted intermolecular associations within the complex. The GB1aproximal C-terminal domain was essential for association of the receptor, CaV2.2 and Gβγ, but was dispensable for agonist-induced receptor activation and cAMP inhibition. Functionally, boutons lacking this complex-formation domain displayed impaired presynaptic inhibition of Ca2+transients and synaptic vesicle release. Thus, compartmentalization of the GABAB1areceptor, Gβγ, and CaV2.2 channel in a signaling complex is required for presynaptic inhibition at hippocampal synapses.
Accelerated Age-Related Cognitive Decline and Neurodegeneration, Caused by Deficient DNA Repair
Authors: Borgesius Nils Z. , de Waard Monique C. , van der Pluijm Ingrid , Omrani Azar , Zondag Gerben C. M. , van der Horst Gijsbertus T. J. , Melton David W. , Hoeijmakers Jan H. J. , Jaarsma Dick , Elgersma Ype
Published: September 2011

Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage ofErcc1Δ/−mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.
Neural Basis of Adaptive Response Time Adjustment during Saccade Countermanding
Authors: Pouget Pierre , Logan Gordon D. , Palmeri Thomas J. , Boucher Leanne , Paré Martin , Schall Jeffrey D.
Published: September 2011

Humans and macaque monkeys adjust their response time adaptively in stop-signal (countermanding) tasks, responding slower after stop-signal trials than after control trials with no stop signal. We investigated the neural mechanism underlying this adaptive response time adjustment in macaque monkeys performing a saccade countermanding task. Earlier research showed that movements are initiated when the random accumulation of presaccadic movement-related activity reaches a fixed threshold. We found that a systematic delay in response time after stop-signal trials was accomplished not through a change of threshold, baseline, or accumulation rate, but instead through a change in the time when activity first began to accumulate. The neurons underlying movement initiation have been identified with stochastic accumulator models of response time performance. Therefore, this new result provides surprising new insights into the neural instantiation of stochastic accumulator models and the mechanisms through which executive control can be exerted.