bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of failure mode and effects analysis to treatment planning in scanned proton beam radiotherapy
Authors: Cantone Marie Claire , Ciocca Mario , Dionisi Francesco , Fossati Piero , Lorentini Stefano , Krengli Marco , Molinelli Silvia , Orecchia Roberto , Schwarz Marco , Veronese Ivan , Vitolo Viviana
Published: May 2013

Background

A multidisciplinary and multi-institutional working group applied the Failure Mode and Effects Analysis (FMEA) approach to the actively scanned proton beam radiotherapy process implemented at CNAO (Centro Nazionale di Adroterapia Oncologica), aiming at preventing accidental exposures to the patient.

Methods

FMEA was applied to the treatment planning stage and consisted of three steps: i) identification of the involved sub-processes; ii) identification and ranking of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system, iii) identification of additional safety measures to be proposed for process quality and safety improvement. RPN upper threshold for little concern of risk was set at 125.

Results

Thirty-four sub-processes were identified, twenty-two of them were judged to be potentially prone to one or more failure modes. A total of forty-four failure modes were recognized, 52% of them characterized by an RPN score equal to 80 or higher. The threshold of 125 for RPN was exceeded in five cases only. The most critical sub-process appeared related to the delineation and correction of artefacts in planning CT data. Failures associated to that sub-process were inaccurate delineation of the artefacts and incorrect proton stopping power assignment to body regions. Other significant failure modes consisted of an outdated representation of the patient anatomy, an improper selection of beam direction and of the physical beam model or dose calculation grid. The main effects of these failures were represented by wrong dose distribution (i.e. deviating from the planned one) delivered to the patient. Additional strategies for risk mitigation, easily and immediately applicable, consisted of a systematic information collection about any known implanted prosthesis directly from each patient and enforcing a short interval time between CT scan and treatment start. Moreover, (i) the investigation of dedicated CT image reconstruction algorithms, (ii) further evaluation of treatment plan robustness and (iii) implementation of independent methods for dose calculation (such as Monte Carlo simulations) may represent novel solutions to increase patient safety.

Conclusions

FMEA is a useful tool for prospective evaluation of patient safety in proton beam radiotherapy. The application of this method to the treatment planning stage lead to identify strategies for risk mitigation in addition to the safety measures already adopted in clinical practice.
Recent cancer incidence trends in an observational clinical cohort of HIV-infected patients in the US, 2000 to 2011
Authors: Yanik Elizabeth L , Tamburro Kristen , Eron Joseph J , Damania Blossom , Napravnik Sonia , Dittmer Dirk P
Published: May 2013

Background

In HIV-infected populations in developed countries, the most recent published cancer incidence trend analyses are only updated through 2008. We assessed changes in the distribution of cancer types and incidence trends among HIV-infected patients in North Carolina up until 2011.

Methods

We linked the University of North Carolina Center for AIDS Research HIV Clinical Cohort, an observational clinical cohort of 3141 HIV-infected patients, with the North Carolina Cancer registry. Cancer incidence rates were estimated across calendar years from 2000 to 2011. The distribution of cancer types was described. Incidence trends were assessed with linear regression.

Results

Across 15,022 person-years of follow-up, 202 cancers were identified (incidence rate per 100,000 person-years [IR]: 1345; 95% confidence interval [CI]: 1166, 1544). The majority of cancers were virus-related (61%), including Kaposi sarcoma (N = 32) (IR: 213; 95%CI: 146, 301), non-Hodgkin lymphoma (N = 34) (IR: 226; 95%CI: 157, 316), and anal cancer (N = 16) (IR: 107; 95%CI: 61, 173). Non-Hodgkin lymphoma was observed to decrease from 2000 to 2011 (decline of 15 cases per 100,000 person-years per calendar year, 95%CI: -27, -3). No other changes in incidence or changes in incidence trends were observed for other cancers (all P > 0.20).

Conclusions

We observed a substantial burden of a variety of cancers in this population in the last decade. Kaposi sarcoma and non-Hodgkin lymphoma were consistently two of the greatest contributors to cancer burden across calendar time. Cancer rates appeared stable across calendar years, except for non-Hodgkin lymphoma, which appeared to decrease throughout the study period.
Altered microRNA expression profile in amyotrophic lateral sclerosis: a role in the regulation of NFL mRNA levels
Authors: Campos-Melo Danae , Droppelmann Cristian A , He Zhongping , Volkening Kathryn , Strong Michael J
Published: May 2013

Background

Amyotrophic Lateral Sclerosis (ALS) is a progressive, adult onset, fatal neurodegenerative disease of motor neurons. There is emerging evidence that alterations in RNA metabolism may be critical in the pathogenesis of ALS. MicroRNAs (miRNAs) are small non-coding RNAs that are key determinants of mRNA stability. Considering that miRNAs are increasingly being recognized as having a role in a variety of neurodegenerative diseases, we decided to characterize the miRNA expression profile in spinal cord (SC) tissue in sporadic ALS (sALS) and controls. Furthermore, we performed functional analysis to identify a group of dysregulated miRNAs that could be responsible for the selective suppression of low molecular weight neurofilament (NFL) mRNA observed in ALS.

Results

Using TaqMan arrays we analyzed 664 miRNAs and found that a large number of miRNAs are differentially expressed in ventral lumbar SC in sALS compared to controls. We observed that the majority of dysregulated miRNAs are down-regulated in sALS SC tissues. Ingenuity Pathway Analysis (IPA) showed that dysregulated miRNAs are linked with nervous system function and cell death. We used two prediction algorithms to develop a panel of miRNAs that have recognition elements within the human NFL mRNA 3′UTR, and then we performed functional analysis for these miRNAs. Our results demonstrate that three miRNAs that are dysregulated in sALS (miR-146a*, miR-524-5p and miR-582-3p) are capable of interacting with NFL mRNA 3′UTR in a manner that is consistent with the suppressed steady state mRNA levels observed in spinal motor neurons in ALS.

Conclusions

The miRNA expression profile is broadly altered in the SC in sALS. Amongst these is a group of dysregulated miRNAs directly regulate the NFL mRNA 3′UTR, suggesting a role in the selective suppression of NFL mRNA in the ALS spinal motor neuron neurofilamentous aggregate formation.
The effects of prolonged running on foot posture: a repeated measures study of half marathon runners using the foot posture index and navicular height
Authors: Cowley Emma , Marsden Jonathan
Published: May 2013

Background

Different foot postures are associated with alterations in foot function, kinetics and the subsequent occurrence of injury. Little is known about changes in foot posture following prolonged weightbearing exercise. This study aimed to identify changes in foot posture after running a half marathon.

Methods

Foot posture was measured using the Foot Posture Index (FPI‐6) and navicular height in thirty volunteer participants before and after running a half marathon. FPI‐6 scores were converted to Rasch logit values and means compared for these and navicular height using an ANOVA.

Results

There was a 5 mm drop in navicular height in both feet when measured after the half marathon (P < 0.05). The FPI‐6 showed a side x time interaction with an increase in score indicating a more ‘pronated’ position in the left foot of + 2 [Rasch value + 1.7] but no change in the right foot (+ 0.4 [+ 0.76]) following the half marathon.

Conclusion

The apparent differences between the FPI‐6 and navicular height on the right foot may be because the FPI‐6 takes soft tissue contour changes into consideration whilst the navicular height focuses on skeletal changes. The changes in foot posture towards a more pronated position may have implications for foot function, and therefore risk of injury; shoe fit and comfort and also the effect of therapeutic orthoses worn during prolonged running.
Sialic acid utilization by Cronobacter sakazakii
Authors: Joseph Susan , Hariri Sumyya , Masood Naqash , Forsythe Stephen
Published: May 2013

Background

The Cronobacter genus is composed of seven species, and can cause infections in all age groups. Of particular concern is C. sakazakii, as this species is strongly associated with severe and often fatal cases of necrotizing enterocolitis and meningitis in neonates and infants. Whole genome sequencing has revealed that the nanAKT gene cluster required for the utilisation of exogenous sialic acid is unique to the C. sakazakii species (ESA_03609–13).

Sialic acid is found in breast milk, infant formula, intestinal mucin, and gangliosides in the brain, hence its metabolism by C. sakazakii is of particular interest. Therefore its metabolism could be an important virulence factor. To date, no laboratory studies demonstrating the growth of C. sakazakii on sialic acid have been published nor have there been reports of sialidase activity. The phylogenetic analysis of the nan genes is of interest to determine whether the genes have been acquired by horizontal gene transfer.

Results

Phylogenetic analysis of 19 Cronobacter strains from 7 recognised species revealed the nanAKTR genes formed a unique cluster, separate from other Enterobacteriaceae such as E. coli K1 and Citrobacter koseri, which are also associated with neonatal meningitis. The gene organisation was similar to Edwardsiella tarda in that nanE gene (N-acetylmannosamine-6-phosphate-2epimerase) was not located within the nanATK cluster. Laboratory studies confirmed that only C. sakazakii, and not the other six Cronobacter species, was able to use sialic acid as a carbon source for growth. Although the ganglioside GM1 was also used as carbon source, no candidate sialidase genes were found in the genome, instead the substrate degradation is probably due to β–galactosidase activity.

Conclusions

Given the relatively recent evolution of both C. sakazakii (15–23 million years ago) and sialic acid synthesis in vertebrates, sialic acid utilization may be an example of co-evolution by one species of the Cronobacter genus with the mammalian host. This has possibly resulted in additional virulence factors contributing to severe life-threatening infections in neonates due to the utilization of sialic acid from breast milk, infant formula, milk (oligosaccharides), mucins lining the intestinal wall, and even gangliosides in the brain after passing through the blood–brain barrier.
Subthalamic nucleus deep brain stimulation for Parkinson’s disease: 8 years of follow-up
Authors: Li Dianyou , Cao Chunyan , Zhang Jing , Zhan Shikun , Chen Shengdi , Sun Bomin
Published: May 2013

Objective

The short-term benefits of bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced Parkinson’s disease (PD) are well documented, but long-term benefits are still uncertain. The aim of this study is to evaluate the outcome of 8 years of bilateral STN stimulation to PD patients.

Methods

In this study, 31 consecutive PD patients were treated with bilateral STN stimulation. Their functional status was measured using the Activities of Daily Living section of the Unified Parkinson’s Disease Rating Scale (UPDRS-ADL) at drug on (with medication) and drug off (without medication) states preoperatively and at 1, 5, and 8 years postoperatively. In addition, Levodopa equivalent doses and stimulation parameters were also assessed.

Results

After 8 years of STN stimulation, the UPDRS-ADL scores were improved by 4% at drug off status (P > 0.05) and 22% at drug on status (P < 0.05) compared with baseline; the levodopa daily doses were reduced by 28% (P < 0.05) compared with baseline; the stimulation voltage and pulse width were not changed, but the stimulation frequency was decreased remarkably compared with the 5 years of follow-up. Adverse events were observed in 6 patients, including misplacement of the electrode and skin erosion requiring further surgery. All events were resolved without permanent sequelae. 2 patients died of aspiration pneumonia 6 and 7 years after surgery.

Conclusions

The marked improvement in UPDRS-ADL scores were still observed after 8 years of bilateral STN stimulation with medication.
Innate immune response after adenoviral gene delivery into skin is mediated by AIM2, NALP3, DAI and mda5
Authors: Schulte Matthias , Sorkin Michael , Al-Benna Sammy , Stupka Jadwiga , Hirsch Tobias , Daigeler Adrien , Kesting Marco Rainer , Steinau Hans-Ulrich , Jacobsen Frank , Steinstraesser Lars
Published: May 2013

Methods for human skin gene therapy requires efficient and stable introduction of genes into skin cells. Transient cutaneous gene therapy is an attractive approach in the treatment of skin diseases. The ‘Achilles heel’ of adenoviral gene therapy is its immunogenicity and many aspects of adenovirus induced cutaneous immune reaction still remain unanswered, particularly the role of keratinocytes. Therefore, human keratinocytes were transfected with adenoviral DNA and cytokine expression was analyzed. Moreover, adenoviral transduction of full-skin was performed ex vivo and in vivo. We observed cytokine induction after cytoplasmatic internalization of adenoviral DNA into epidermal cells. Inhibition of AIM2, NALP3, DAI or mda5 downregulated the cytokine response. Transduction of immunocompetent mice led to a detectable transgene expression for 12 days. Re-application of the vector led to a decrease in intensity and duration of transgene expression limited to 4 days and an increased cytokine expression. In contrast, immunodeficient mice showed a reduced expression of cytokines after DNA internalization. AIM2, NALP3, DAI and mda5 are essential in the induction of an innate immune response towards adenoviral DNA. This immune reaction leads to a decrease in transduction efficiency of the vector after re-application and modulation of these receptor systems stabilizes transgene expression.
Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer's disease
Authors: Webster Scott J , Bachstetter Adam D , Van Eldik Linda J
Published: May 2013

Introduction

Despite the extensive mechanistic and pathological characterization of the amyloid precursor protein (APP)/presenilin-1 (PS-1) knock-in mouse model of Alzheimer's disease (AD), very little is known about the AD-relevant behavioral deficits in this model. Characterization of the baseline behavioral performance in a variety of functional tasks and identification of the temporal onset of behavioral impairments are important to provide a foundation for future preclinical testing of AD therapeutics. Here we perform a comprehensive behavioral characterization of this model, discuss how the observed behavior correlates with the mechanistic and pathological observations of others, and compare this model with other commonly used AD mouse models.

Methods

Four different groups of mice ranging across the lifespan of this model (test groups: 7, 11, 15, and 24 months old) were run in a behavioral test battery consisting of tasks to assess motor function (grip strength, rotor rod, beam walk, open field ambulatory movement), anxiety-related behavior (open field time spent in peripheral zone vs. center zone, elevated plus maze), and cognitive function (novel object recognition, radial arm water maze).

Results

There were no differences in motor function or anxiety-related behavior between APP/PS-1 knock-in mice and wild-type counterpart mice for any age group. Cognitive deficits in both recognition memory (novel object recognition) and spatial reference memory (radial arm water maze) became apparent for the knock-in animals as the disease progressed.

Conclusion

This is the first reported comprehensive behavioral analysis of the APP/PS1 knock-in mouse model of AD. The lack of motor/coordination deficits or abnormal anxiety levels, coupled with the age/disease-related cognitive decline and high physiological relevance of this model, make it well suited for utilization in preclinical testing of AD-relevant therapeutics.
Serum microRNA expression as an early marker for breast cancer risk in prospectively collected samples from the Sister Study cohort
Authors: Godfrey Ashley C , Xu Zongli , Weinberg Clarice R , Getts Robert C , Wade Paul A , DeRoo Lisa A , Sandler Dale P , Taylor Jack A
Published: May 2013

Introduction

MicroRNAs (miRNAs) are small, non-coding, single-stranded RNAs between 18-22 nucleotides long that regulate gene expression. Expression of miRNAs is altered in tumor compared to normal tissue; there is some evidence that these changes may be reflected in the serum of cancer cases compared to healthy individuals. This has yet to be examined in a prospective study where samples are collected before diagnosis.

Methods

We used Affymetrix arrays to examine serum miRNA expression profiles in 410 participants in the Sister Study, a prospective cohort study of 50,884 women. All women in the cohort had never been diagnosed with breast cancer at the time of enrollment. We compared global miRNA expression patterns in 205 women who subsequently developed breast cancer and 205 women who remained breast cancer-free. In addition within the case group we examined the association of miRNA expression in serum with different tumor characteristics, including hormone status (ER, PR, and HER-2) and lymph node status.

Results

Overall, 414 of 1,105 of the human miRNAs on the chip were expressed above background levels in 50 or more women. When the average expression among controls was compared to cases using conditional logistic regression, 21 miRNAs were found to be differentially expressed (P≤.05). Using qRT-PCR on a small, independent sample of 5 cases and 5 controls we verified overexpression of the 3 highest expressing miRNAs among cases, miR-18a, miR-181a, and miR-222; the differences were not statistically significant in this small set. The 21 differentially expressed miRNAs are known to target at least 82 genes; using the gene list for pathway analysis we found enrichment of genes involved in cancer-related processes. In a separate case-case analyses restricted to the 21 miRNAs, we found 7 miRNAs with differential expression for women whose breast tumors differed by HER-2 expression, and 10 miRNAs with differential expression by nodal status.

Conclusions

miRNA levels in serum show a number of small differences between women who later develop cancer versus those who remain cancer-free.
Plasma levels of mitochondrial and nuclear DNA in patients with massive pulmonary embolism in the emergency department: a prospective cohort study
Authors: Arnalich Francisco , Maldifassi Maria Constanza , Ciria Enrique , Codoceo Rosa , Renart Jaime , Fernández-Capitán Carmen , Herruzo Rafael , Garcia-Rio Francisco , López-Collazo Eduardo , Montiel Carmen
Published: May 2013

Introduction

Cell-free plasma mitochondrial DNA (mt-DNA) and nuclear DNA (n-DNA) are biomarkers with prognostic utility in conditions associated with a high rate of cell death. This exploratory study aimed to determine the plasma levels of both nucleic acids in patients with massive and submassive pulmonary embolism (PE) and to compare them with other biomarkers, such as heart-type fatty acid-binding protein (H-FABP) and troponin I (Tn-I)

Methods

This was a prospective observational study of 37 consecutive patients with massive PE, 37 patients with submassive PE, and 37 healthy subjects. Quantifications of plasma mt-DNA and n-DNA with real-time quantitative polymerase chain reaction (PCR), and plasma H-FABP and Tn-I by commercial assays, were done on blood samples drawn within 4 hours after presentation at the emergency department.

Results

Plasma mt-DNA and n-DNA concentrations were much higher in patients with massive PE (median, 2,970 GE/ml; interquartile range (IQR), 1,050 to 5,485; and 3,325 GE/ml, IQR: 1,080 to 5,790, respectively) than in patients with submassive PE (870 GE/ml and 1,245 GE/ml, respectively; P < 0.01) or controls (185 GE/ml and 520 GE/ml, respectively). Eighteen patients with massive PE died of a PE-related cause by day 15 of observation. Plasma mt-DNA and n-DNA values were 2.3-fold and 1.9-fold higher in the subgroup of nonsurviving patients than in survivors. H-FABP and Tn-I values were also higher in patients with massive PE who died (7.3 ng/ml and 0.023 ng/ml, respectively) than in those who survived (6.4 ng/ml, and 0.016 ng/ml, respectively). By receiver operating curve (ROC) analysis, the best cutoff values for predicting 15-day mortality were 3,380 GE/ml for mt-DNA, 6.8 ng/ml for H-FABP, 3,625 GE/ml for n-DNA, and 0.020 ng/ml for Tn-I, based on the calculated areas under the curve (AUCs) of 0.89 (95% confidence interval (CI), 0.78 to 0.99), 0.76 (95% CI, 0.69 to 093), 0.73 (95% CI, 0.58 to 0.91), and 0.59 (95% CI, 0.41 to 0.79), respectively. By stepwise logistic regression, a plasma mt-DNA concentration greater than 3,380 GE/ml (adjusted odds ratio (OR), 8.22; 95% CI, 1.72 to 39.18; P < 0.001) and a plasma value of H-FBAP >6.8 ng/ml (OR, 5.36; 95% CI, 1.06 to 27.08; P < 0.01) were the only independent predictors of mortality.

Conclusions

mt-DNA and H-FBAP might be promising markers for predicting 15-day mortality in massive PE, with mt-DNA having better prognostic accuracy.
Sleep, anxiety and fatigue in family members of patients admitted to the intensive care unit: a questionnaire study
Authors: Day Alex , Haj-Bakri Samer , Lubchansky Stephanie , Mehta Sangeeta
Published: May 2013

Introduction

Family members of critically ill patients often experience increased incidence of physical and mental health issues. One of the first ways family members suffer is by losing sleep. The purpose of this study is to understand sleep quality, levels of fatigue and anxiety, and factors contributing to poor sleep in adult family members of critically ill patients.

Methods

A questionnaire was designed to evaluate sleep, fatigue and anxiety during the intensive care unit (ICU) admission. We incorporated three validated instruments: General Sleep Disturbance Scale (GSDS), Beck Anxiety Index (BAI) and Lee Fatigue Scale (NRS-F). Adult family members of patients in ICU for more than 24 hours were approached for questionnaire completion. Patient demographics were recorded.

Results

The study population consisted of 94 respondents, (49.1 ± 12.9 years, 52.7% male); 43.6% were children and 21.3% were spouses of ICU patients. Sleep quality was rated as poor/very poor by 43.5% of respondents, and good/very good by 15.2%. The most common factors contributing to poor sleep were anxiety (43.6%), tension (28.7%) and fear (24.5%). Respondents' most common suggestions to improve sleep were more information regarding the patient's health (24.5%) and relaxation techniques (21.3%). Mean GSDS score was 38.2 ± 19.3, with 58.1% of respondents experiencing moderate to severe sleep disturbance. Mean BAI was 12.3 ± 10.2, with 20.7% of respondents experiencing moderate to severe anxiety. Mean NRS-F was 3.8 ± 2.5, with 57.6% of respondents experiencing moderate to high fatigue. Family members who spent one or more nights in the hospital had significantly higher GSDS, BAI and NRS-F scores. The patient's Acute Physiology and Chronic Health Evaluation (APACHE) II score at survey completion correlated significantly with family members' GSDS, BAI and NRS-F.

Conclusion

The majority of family members of ICU patients experience moderate to severe sleep disturbance and fatigue, and mild anxiety.
Limits of normality of quantitative thoracic CT analysis
Authors: Cressoni Massimo , Gallazzi Elisabetta , Chiurazzi Chiara , Marino Antonella , Brioni Matteo , Menga Federica , Cigada Irene , Amini Martina , Lemos Alessandro , Lazzerini Marco , Carlesso Eleonora , Cadringher Paolo , Chiumello Davide , Gattinoni Luciano
Published: May 2013

Introduction

Although computed tomography (CT) is widely used to investigate different pathologies, quantitative data from normal populations are scarce. Reference values may be useful to estimate the anatomical or physiological changes induced by various diseases.

Methods

We analyzed 100 helical CT scans taken for clinical purposes and referred as nonpathological by the radiologist. Profiles were manually outlined on each CT scan slice and each voxel was classified according to its gas/tissue ratio. For regional analysis, the lungs were divided into 10 sterno-vertebral levels.

Results

We studied 53 males and 47 females (age 64 ± 13 years); males had a greater total lung volume, lung gas volume and lung tissue. Noninflated tissue averaged 7 ± 4% of the total lung weight, poorly inflated tissue averaged 18 ± 3%, normally inflated tissue averaged 65 ± 8% and overinflated tissue averaged 11 ± 7%. We found a significant correlation between lung weight and subject's height (P <0.0001, r2 = 0.49); the total lung capacity in a supine position was 4,066 ± 1,190 ml, ~1,800 ml less than the predicted total lung capacity in a sitting position. Superimposed pressure averaged 2.6 ± 0.5 cmH2O.

Conclusion

Subjects without lung disease present significant amounts of poorly inflated and overinflated tissue. Normal lung weight can be predicted from patient's height with reasonable confidence.
3′,4′-Dimethoxyflavone and valproic acid promotes the proliferation of human hematopoietic stem cells
Authors: Kaur Kiranpreet , Mirlashari Mohammad Reza , Kvalheim Gunnar , Kjeldsen-Kragh Jens
Published: May 2013

Introduction

Human hematopoietic stem cells (HSCs) have been clinically used for transplantation and gene and cellular therapy for more than 4 decades. However, this use is limited because of the challenges in the ex vivo culturing of HSCs. The major hurdle is to amplify these cells without losing their self-renewing property.

Methods

In our study, we tested 3′,4′-dimethoxyflavone (3′4′-DMF) and valproic acid (VPA) on the ex vivo expansion of HSCs under both normoxic (20% O2) and hypoxic (1% O2) conditions. 3′4′-DMF is a widely used anticancer drug that acts as a competitive antagonist of the aryl hydrocarbon receptor. VPA is a potent inhibitor of histone deacetylase and is used in the treatment of neurologic disorders.

Results

Culturing HSCs (from mobilized peripheral blood) under normoxia, with 3′4′-DMF and VPA, highly preserved the CD34 positivity (3′4′-DMF, 22.1%, VPA, 20.3%) after 1 week and strongly enhanced the CD34+ cells (3′4′-DMF, 27.8 fold; VPA, 34.1 fold) compared with the control cultures (11.6% and 14.4 fold). Addition of 3′4′-DMF and VPA also resulted in more primary colonies and replating efficiency compared with control cultures. Although no significant effect was observed on the enhancement of CD34+ cells under hypoxia, the number of primary colonies was significantly higher than the control cultures.

Conclusions

Based on these findings, this study presents, for the first time, in vitro evidence for a new and relevant effect of 3′4′-DMF on human HSCs. In addition, the results suggest a potential clinical use of 3′4′-DMF and VPA in HSC therapy.
Shared polygenic contribution between childhood attention-deficit hyperactivity disorder and adult schizophrenia
Authors: Hamshere Marian L. , Stergiakouli Evangelia , Langley Kate , Martin Joanna , Holmans Peter , Kent Lindsey , Owen Michael J. , Gill Michael , Thapar Anita , O'Donovan Mick , Craddock Nick
Published: May 2013

Background

There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.

Aims

To determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.

Method

We used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.

Results

Schizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 104, R2 = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 ×10−6, R2 × 0.59%).

Conclusions

This increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries.
Reducing duration of untreated psychosis: care pathways to early intervention in psychosis services
Authors: Birchwood Max , Connor Charlotte , Lester Helen , Patterson Paul , Freemantle Nick , Marshall Max , Fowler David , Lewis Shôn , Jones Peter , Amos Tim , Everard Linda , Singh Swaran P.
Published: May 2013

Background

Interventions to reduce treatment delay in first-episode psychosis have met with mixed results. Systematic reviews highlight the need for greater understanding of delays within the care pathway if successful strategies are to be developed.

Aims

To document the care-pathway components of duration of untreated psychosis (DUP) and their link with delays in accessing specialised early intervention services (EIS). To model the likely impact on efforts to reduce DUP of targeted changes in the care pathway.

Method

Data for 343 individuals from the Birmingham, UK, lead site of the National EDEN cohort study were analysed.

Results

A third of the cohort had a DUP exceeding 6 months. The greatest contribution to DUP for the whole cohort came from delays within mental health services, followed by help-seeking delays. It was found that delay in reaching EIS was strongly correlated with longer DUP.

Conclusions

Community education and awareness campaigns to reduce DUP may be constrained by later delays within mental health services, especially access to EIS. Our methodology, based on analysis of care pathways, will have international application when devising strategies to reduce DUP.

Declarations of interest

None.
Cardiovascular and metabolic risk profile in young people at familial risk of depression
Authors: Mannie Zola N. , Williams Clare , Diesch Jonathan , Steptoe Andrew , Leeson Paul , Cowen Philip J.
Published: May 2013

Background

Depression is associated with increased risk of several general medical conditions, including diabetes and cardiovascular disease. The nature of the association is complex and may involve bidirectional causation or a common pathophysiology.

Aims

To determine whether young people without depression but at increased familial risk have altered metabolic and blood pressure markers relative to matched controls.

Method

We studied young people (n = 85), who had a parent with depression but no personal history of depressive illness (FH+) and healthy controls (n = 69). Cardiovascular risk profile was assessed by a fasting blood sample to measure insulin, glucose, lipids and high-sensitivity C-reactive protein (CRP) and blood pressure was measured centrally and peripherally. Arterial stiffness and waking cortisol concentration were also measured.

Results

Compared with controls, the FH+ group demonstrated increased peripheral and central systolic blood pressure, increased arterial stiffness and diminished insulin sensitivity but they did not differ from controls in measures of lipids, CRP or waking cortisol.

Conclusions

Our data suggest that young people at increased familial risk of depression show evidence of altered cardiovascular risk profile in young adulthood even in the absence of depressive symptoms. It is possible therefore that vulnerability to conditions such as hypertension and diabetes may precede the onset of major depression and may share common risk factors.
The Contexts of Marguerite Duras's Homophobia
Authors: Lucey Michael
Published: May 2013

This article proposes a contextualization of Marguerite Duras's 1983 book, The Malady of Death, along with some of her other writings and statements from around that time. These writings register her long-term intimate relationship with a much younger gay man whom she called Yann Andréa, and also record a good deal of violently homophobic discourse. My contention is that there is something to be learned by taking the sexuality that Duras shared with Andréa to be a misfit one — one that we can to a certain degree recognize in practice but that we have no easy discourse or category to capture and/or to denote. Misfit sexualities, I argue, exist mostly in context, in interaction, in the relations between texts and the interactive processes that produce them. To attempt to contextualize a work such as The Malady of Death in this way is not to rely on or to take up any literary theory or practice of intertextuality. Rather it involves attempting to reconstruct something of the social world (mainly a part of “literary” Paris from the 1950s through the 1980s) in which such a work intervened, and attempting to understand the particular cultural concepts for understanding various ideologies and practices of sexuality it invoked, and in which it was implicated.
“From the Margins You Push So That the Center Implodes”
Authors: Talmor Ruti
Published: May 2013

This article offers a cross-sectional analysis of queer media production, exhibition, and reception in South Africa, homing in on lesbian media production through interviews with Makgano Mamabolo, cowriter and coproducer of Society, a hit series on mainstream South African television (2007, 2009 – 2010), and Zethu Matebeni, cowriter, codirector, and coproducer of Breaking Out of the Box (2011), a documentary that has screened on the film festival, academic, and activist circuits. Shifting focus away from the predominantly European-American context of most media scholarship, the article explores forces that shape queer media production in the country, including South Africa's particular media landscape, tensions between and within local, continental, and international queer politics, and generational differences between those who grew up in the struggle against apartheid and those coming of age today.
The Aurora B-mediated phosphorylation of SHCBP1 regulates cytokinetic furrow ingression
Authors: Asano Eri , Hasegawa Hitoki , Hyodo Toshinori , Ito Satoko , Maeda Masao , Takahashi Masahide , Hamaguchi Michinari , Senga Takeshi
Published: May 2013

Centralspindlin, which is composed of MgcRacGAP and MKLP1, is essential for central spindle formation and cytokinetic furrow ingression. MgcRacGAP utilizes its GAP domain to inactivate Rac1 and induce furrow ingression in mammalian cells. In this report, we present a novel regulatory mechanism for furrowing that is mediated by the phosphorylation of SHC SH2-domain binding protein 1 (SHCBP1), a binding partner of centralspindlin, by Aurora B (AurB). AurB phosphorylates Ser634 of SHCBP1 during mitosis. A phosphorylation site mutant, S634A-SHCBP1, was prematurely recruited to the central spindle during anaphase and inhibited furrowing. An in vitro GAP assay demonstrated that SHCBP1 can suppress the MgcRacGAP-mediated inactivation of Rac1. In addition, the inhibition of Rac1 activity rescued the furrowing defect induced by S634A-SHCBP1 expression. Thus, AurB phosphorylates SHCBP1 to prevent the premature localization of SHCBP1 to the central spindle and ensures that MgcRacGAP inactivates Rac1 to promote the ingression of the cytokinetic furrow.
ε-tubulin is essential in Tetrahymena thermophila for the assembly and stability of basal bodies
Authors: Ross Ian , Clarissa Christina , Giddings Thomas H. , Winey Mark
Published: May 2013

Basal bodies and centrioles are conserved microtubule-based organelles whose improper assembly leads to a number of diseases, including ciliopathies and cancer. Tubulin family members are conserved components of these structures that are integral to their proper formation and function. We have identified the ε-tubulin gene in Tetrahymena thermophila and localized the protein through fluorescence of a tagged allele to basal bodies. Immuno-electron microscopy has shown that ε-tubulin localizes primarily to the core microtubule scaffold. A complete genomic knockout of ε-tubulin has revealed that it is an essential gene required for the assembly and maintenance of the triplet microtubule blades of basal bodies. We have conducted site-directed mutagenesis of the ε-tubulin gene and shown that residues within the nucleotide-binding domain, longitudinal interacting domains, and C-terminal tail are required for proper function. A single amino acid change of Thr150, a conserved residue in the nucleotide-binding domain, to Val is a conditional mutation that results in defects in the spatial and temporal assembly of basal bodies as well as their stability. We have genetically separated functions for the domains of ε-tubulin and identified a novel role for the nucleotide-binding domain in the regulation of basal body assembly and stability.
A dual role for the βPS integrin myospheroid in mediating Drosophila embryonic macrophage migration
Authors: Comber Kate , Huelsmann Sven , Evans Iwan , Sánchez-Sánchez Besaid J. , Chalmers Andrew , Reuter Rolf , Wood Will , Martín-Bermudo Maria D.
Published: May 2013

Throughout embryonic development, macrophages not only constitute the first line of defense against infection but also help to sculpt organs and tissues of the embryo by removing dead cells and secreting extracellular matrix components. Key to their function is the ability of embryonic macrophages to migrate and disperse throughout the embryo. Yet despite these important developmental functions, little is known about the molecular mechanisms underlying embryonic macrophage migration in vivo. Integrins are key regulators of many of the adult macrophage responses, but their role in embryonic macrophages remains poorly characterized. Here, we have used Drosophila macrophages (haemocytes) as a model system to address the role of integrins during embryonic macrophage dispersal in vivo. We show that the main βPS integrin, myospheroid, affects haemocyte migration in two ways; by shaping the 3-dimensional environment in which haemocytes migrate and by regulating the migration of haemocytes themselves. Live imaging reveals a requirement for myospheroid within haemocytes for coordinating the microtubule and actin dynamics, and in enabling haemocyte developmental dispersal, contact repulsion and inflammatory migration towards wounds.
Gain of function of the immune system caused by a ryanodine receptor 1 mutation
Authors: Vukcevic Mirko , Zorzato Francesco , Keck Simone , Tsakiris Dimitrios A. , Keiser Jennifer , Maizels Rick M. , Treves Susan
Published: May 2013

Mutations in RYR1, the gene encoding ryanodine receptor 1, are linked to a variety of neuromuscular disorders including Malignant Hyperthermia (MH) a pharmacogenetic hypermetabolic disease caused by dysregulation of calcium in skeletal muscle. RYR1 encodes a calcium channel that is predominantly expressed in skeletal muscle sarcoplasmic reticulum where it is involved in releasing the calcium necessary for muscle contraction. Other tissues however, including cells of the immune system, have been shown to express ryanodine receptor 1; in dendritic cells its activation leads to increased surface expression of major histocompatibility complex II molecules and provides synergistic signals leading to cell maturation. In the present study we investigated the impact of an MH mutation on the immune system by studying the RYR1Y522S knock in mouse. Our results show that there are subtle but significant differences both in resting non-challenged mice as well as in mice treated with antigenic stimuli, in particular the knock- in mice (i) have dendritic cells that are more efficient at stimulating T cell proliferation; (ii) have higher levels of natural IgG1 and IgE antibodies and (iii) are faster and more efficient at mounting a specific immune response in the early phases of immunization. We suggest that some gain of function MH-linked RYR1 mutations may offer selective immune advantages to their carriers. Furthermore, our results raise the intriguing possibility that pharmacological activation of RyR1 may be exploited for the development of new classes of vaccines and adjuvants.
G1 control in mammalian cells
Authors: Reed Steven I. , Bailly Eric , Dulic Vjekoslav , Hengst Ludger , Resnitzky Dalia , Slingerland Joyce
Published: May 2013

Cyclin-dependent kinases (Cdks) control the major cell cycle transitions in eukaryotic cells. On the basis of a variety of experiments where cyclin function either is impaired or enhanced, D-type cyclins as well as cyclins E and A have been linked to G1 and G1/S phase roles in mammalian cells. We therefore sought to determine if agents that block the G1/S phase transition do so at the level of regulating the Cdk activities associated with these cyclins. A variety of conditions that lead to G1 arrest were found to correlate with accumulation of G1-specific Cdk inhibitors, including treatment of fibroblasts with ionizing radiation, treatment of epithelial cells with TGF-P, treatment of HeLa cells with the drug lovastatin, and removal of essential growth factors from a variety of different cell types. Mechanistically, inhibition of Cdks was found to involve the stoichiometric binding of Cdk inhibitor proteins. p21Wafl/CiP1 was associated with DNA damage induced arrest while p27Kip1/p28Ick1 accumulated under a variety of antiproliferative conditions.
Structure and function of SH2 domains
Authors: Marengere Luc E. M. , Pawson Tony
Published: May 2013

In order for cells to respond to their environment, a series of regulated molecular events has to take place. External signalling molecules bind to cellular receptors and thereby trigger the activation of multiple intracellular pathways, which modify cellular phenotypes. The cell-surface receptors for a wide range of polypeptide hormones possess protein tyrosine kinase activity, which is induced by binding of the appropriate extracellular ligand. Tyrosine phosphorylation can act as a molecular switch, by initiat- ing the recruitment of cytoplasmic effector molecules containing Src homology (SH) 2 domains, to activated receptors. These SH2-containing proteins, in turn, regulate intracellular signalling pathways. Here, we discuss the role of tyrosine phosphorylation in triggering signalling pathways, as well as the functions of SH2 domains, which mediate these events through phosphotyrosine-dependent protein-protein interactions.
Drosophila in cancer research: the first fifty tumor suppressor genes
Authors: Watson Kellie L. , Justice Robin W. , Bryant Peter J.
Published: May 2013

In Drosophila, over 50 genes have been identified in which loss-of-function mutations lead to excess cell proliferation in the embryo, in the central nervous system, imaginal discs or hematopoietic organs of the larva, or in the adult gonads. Twenty-two of these genes have been cloned and characterized at the molecular level, and nine of them show clear homology to mammalian genes. Most of these mammalian genes had not been previously implicated in cell proliferation control. Overgrowth in some of the mutants involves conversion to a cell type that, in normal development, shows more cell proliferation than the original cell type. Thus the neurogenic mutants, including Notch, show conversion of epidermal cells to neuroblasts, leading to the ‘neurogenic’ phenotype of excess nervous tissue. The ovarian tumor mutants show conversion of the female germ line to a cell type resembling the male germ line, which undergoes more proliferation than the female germ line. Mutations of the fat locus cause hyperplastic overgrowth of imaginal discs, in which the epithelial structure is largely intact. The predicted fat protein product is a giant relative of cadherins, supporting indications from human cancer that cadherins play an important role in tumor suppression. Mutations in the lethal(2)giant larvae and lethal(1)discs large genes cause neoplastic overgrowth of imaginal discs as well as the larval brain. The dlg gene encodes a membrane-associated guanylate kinase homolog that is localized at septate junctions between epithelial cells. This protein is a member of a family of homologs that also includes two proteins found at mammalian tight junctions (ZO-1 and ZO-2) and a protein found at mammalian synaptic junctions (PSD-95/SAP90). Genes in which mutations cause blood cell overproduction include aberrant immune response-8, which encodes the RpS6 ribosomal protein and hopscotch, which encodes a putative non-receptor protein tyrosine kinase. The gene products identified by ovarian tumor mutants do not show clear amino acid sequence homology to known proteins. Drosophila provides an opportunity to rapidly identify and characterize tumor suppressor genes, many of which have mammalian homologs that might also be involved in cell proliferation control and tumor suppression.
bcl-2 in cancer, development and apoptosis
Authors: Hockenbery David M.
Published: May 2013

The bcl-2 gene provides a window on the basic cellular machinery of apoptosis or programmed cell death, a process involved in virtually all biologic events in multicel-lular organisms, but particularly relevant to neoplasia and development, bcl-2 gene function supports cell survival and appears to lie at a nodal point in pathways leading to acti-vation or execution of apoptosis. Carcinogenesis may involve several steps at which cell death programs are normally activated and are bypassed in cancer cells, including apoptotic pathways activated by several oncogenes. Functional redundancy and the complexity of the regulation of cell survival are demonstrated by the less than expected phenotype of bcl-2 knockout mice and the cloning of several bcl-2 related genes, some of which promote cell death. The molecular function for bcl-2 is unknown, but several lines of evidence support a role in protection from oxidative stress. These studies suggest that many environmental perturbations and genetic pathways converge to disrupt a metabolic balance between oxidant generation and anti-oxidant defenses.
Regulation of the cell cycle timing of Start in fission yeast by the rum1+ gene
Authors: Moreno Sergio , Labib Karim , Correa Jaime , Nurse Paul
Published: May 2013

We have identified the rum1+ gene as a new regulator of the G1-phase of the fission yeast cell cycle. rum1+ deter-mines the cell cycle timing of Start, by maintaining cells in a pre-Start state until they have attained a minimal critical mass. Cells lacking rum1+ are unable to arrest in pre-Start G1 in response to nitrogen starvation and are subsequently sterile. In addition, rum1+ prevents entry into mitosis from pre-Start G1, as shown by the fact that cdclO mutants in the absence of rum1+ undergo lethal mitosis without entering S-phase.
Synthesis of Nanometer-sized Hollow Calcium Tungstate Particles by Using Micelles of Poly(styrene-b-acrylic acid-b-ethylene oxide) as a Soft Template
Authors: Zhai Shuo , Manako Yukitaka , Yusa Shin-ichi , Nakashima Kenichi
Published: May 2013

Hollow calcium tungstate (CaWO4) nanospheres with well-controlled shape and size have been successfully synthesized for the first time by templating micelles of poly(styrene-b-acrylic acid-b-ethylene oxide) (PS-b-PAA-b-PEO). This polymer forms a micelle with a PS core, a PAA shell, and a PEO corona in aqueous solutions. Calcium chloride (CaCl2) and sodium tungstate (Na2WO4) were used as precursors of CaWO4. In the synthesis, the PS core acts as a template for cavities of the hollow particles, the PAA shell is beneficial for arresting calcium ions for further mineralizing, and the PEO corona stabilizes the CaWO4-polymer nanocomposite to prevent secondary aggregate formation. The hollow CaWO4 nanoparticles have a spherical shape with an outer diameter narrowly distributed at 22.7 ± 1.0 nm and a shell thickness at 6.7 ± 0.4 nm.