bluuebunny/crossref_metadata_2025 huggingface dataset:
Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis
Authors: D’hooghe MB , Haentjens P , Nagels G , Garmyn M , De Keyser J
Published: September 2011

Background: Sunlight and vitamin D have been inversely associated with the risk of multiple sclerosis (MS).

Objective: We investigated sunlight exposure and sun sensitivity in relation to disability progression in MS.

Methods: We conducted a survey among persons with MS, registered by the Flemish MS society, Belgium, and stratified data according to relapsing-onset and progressive-onset MS. We used Kaplan–Meier survival and Cox proportional hazard regression analyses with time to Expanded Disability Status Scale (EDSS) 6 as outcome measure. Hazard ratios for the time from onset and from birth were calculated for the potentially predictive variables, adjusting for age at onset, gender and immunomodulatory treatment.

Results: 704 (51.3%) of the 1372 respondents had reached EDSS 6. In relapsing-onset MS, respondents reporting equal or higher levels of sun exposure than persons of the same age in the last 10 years had a decreased risk of reaching EDSS 6. In progressive-onset MS, increased sun sensitivity was associated with an increased hazard of reaching EDSS 6.

Conclusion: The association of higher sun exposure with a better outcome in relapsing-onset MS may be explained by either a protective effect or reverse causality. Mechanisms underlying sun sensitivity might influence progression in progressive-onset MS.
Prevention and treatment of venous thromboembolism in patients with cancer
Authors: Hogg Kerstin , Carrier Marc
Published: September 2011

Venous thromboembolism (VTE) is the second leading cause of death and a major cause of morbidity in patients with cancer. Pharmacologic thromboprophylaxis is recommended in all hospitalized cancer patients without contraindications to anticoagulants. The role of thromboprophylaxis in outpatients undergoing chemotherapy is less certain because of the diversity of the tumor types and their associated risks of VTE and bleeding. Thromboprophylaxis should only be considered in patients at high risk for VTE. Cancer patients with a newly diagnosed VTE should be preferably treated with low-molecular-weight heparin for a minimum of 3–6 months. Treatment duration should be individualized based on the clinical status and stage of the cancer, the risk of recurrent VTE, the risk of bleeding, and personal preference of the patient. Further research is required to assess the role of the new oral anticoagulants (direct Xa and thrombin inhibitors) for this high-risk population.
A physical map of Brassica oleracea shows complexity of chromosomal changes following recursive paleopolyploidizations
Authors: Wang Xiyin , Torres Manuel J , Pierce Gary , Lemke Cornelia , Nelson Lisa K , Yuksel Bayram , Bowers John E , Marler Barry , Xiao Yongli , Lin Lifeng , Epps Ethan , Sarazen Heidi , Rogers Carl , Karunakaran Santhosh , Ingles Jennifer , Giattina Emily , Mun Jeong-Hwan , Seol Young-Joo , Park Beom-Seok , Amasino Richard M , Quiros Carlos F , Osborn Thomas C , Pires J Chris , Town Christopher , Paterson Andrew H
Published: September 2011

Background

Evolution of the Brassica species has been recursively affected by polyploidy events, and comparison to their relative, Arabidopsis thaliana, provides means to explore their genomic complexity.

Results

A genome-wide physical map of a rapid-cycling strain of B. oleracea was constructed by integrating high-information-content fingerprinting (HICF) of Bacterial Artificial Chromosome (BAC) clones with hybridization to sequence-tagged probes. Using 2907 contigs of two or more BACs, we performed several lines of comparative genomic analysis. Interspecific DNA synteny is much better preserved in euchromatin than heterochromatin, showing the qualitative difference in evolution of these respective genomic domains. About 67% of contigs can be aligned to the Arabidopsis genome, with 96.5% corresponding to euchromatic regions, and 3.5% (shown to contain repetitive sequences) to pericentromeric regions. Overgo probe hybridization data showed that contigs aligned to Arabidopsis euchromatin contain ~80% of low-copy-number genes, while genes with high copy number are much more frequently associated with pericentromeric regions. We identified 39 interchromosomal breakpoints during the diversification of B. oleracea and Arabidopsis thaliana, a relatively high level of genomic change since their divergence. Comparison of the B. oleracea physical map with Arabidopsis and other available eudicot genomes showed appreciable 'shadowing' produced by more ancient polyploidies, resulting in a web of relatedness among contigs which increased genomic complexity.

Conclusions

A high-resolution genetically-anchored physical map sheds light on Brassica genome organization and advances positional cloning of specific genes, and may help to validate genome sequence assembly and alignment to chromosomes.

All the physical mapping data is freely shared at a WebFPC site (http://lulu.pgml.uga.edu/fpc/WebAGCoL/brassica/WebFPC/; Temporarily password-protected: account: pgml; password: 123qwe123.
Identification and comparative analysis of drought-associated microRNAs in two cowpea genotypes
Authors: Barrera-Figueroa Blanca E , Gao Lei , Diop Ndeye N , Wu Zhigang , Ehlers Jeffrey D , Roberts Philip A , Close Timothy J , Zhu Jian-Kang , Liu Renyi
Published: September 2011

Background

Cowpea (Vigna unguiculata) is an important crop in arid and semi-arid regions and is a good model for studying drought tolerance. MicroRNAs (miRNAs) are known to play critical roles in plant stress responses, but drought-associated miRNAs have not been identified in cowpea. In addition, it is not understood how miRNAs might contribute to different capacities of drought tolerance in different cowpea genotypes.

Results

We generated deep sequencing small RNA reads from two cowpea genotypes (CB46, drought-sensitive, and IT93K503-1, drought-tolerant) that grew under well-watered and drought stress conditions. We mapped small RNA reads to cowpea genomic sequences and identified 157 miRNA genes that belong to 89 families. Among 44 drought-associated miRNAs, 30 were upregulated in drought condition and 14 were downregulated. Although miRNA expression was in general consistent in two genotypes, we found that nine miRNAs were predominantly or exclusively expressed in one of the two genotypes and that 11 miRNAs were drought-regulated in only one genotype, but not the other.

Conclusions

These results suggest that miRNAs may play important roles in drought tolerance in cowpea and may be a key factor in determining the level of drought tolerance in different cowpea genotypes.
Molecular detection of fluoroquinolone-resistance in multi-drug resistant tuberculosis in Cambodia suggests low association with XDR phenotypes
Authors: Surcouf Corinne , Heng Seiha , Pierre-Audigier Catherine , Cadet-Daniel Véronique , Namouchi Amine , Murray Alan , Gicquel Brigitte , Guillard Bertrand
Published: September 2011

Background

Drug susceptibility testing (DST) remains an important concern for implementing treatment of MDR tuberculosis patients. Implementation of molecular tests for drug resistance identification would facilitate DST particularly in developing countries where culturing is difficult to perform. We have characterized multidrug resistant strains in Cambodia using MDTDRsl tests, drug target sequencing and phenotypic tests.

Methods

A total of 65 non-MDR and 101 MDR TB isolates collected between May 2007 and June 2009 were tested for resistance to fluoroquinolones and aminoglycosides/cyclic peptides using the GenoType® MTBDRsl assay and gene sequencing. Rifampicin resistance (RMP-R) was tested using gene sequencing and genotyping was assessed by spoligotyping.

Results

A total of 95 of the 101 MDR strains were confirmed to be RMP-R by rpoB gene sequencing. Fourteen of the 101 MDR isolates (14%) carried a gyrA mutation associated with fluoroquinolone-resistance (FQ-R) (detected by the MTBDRsl assay and sequencing) compared with only 1 (1.5%) of the 65 non-MDR strains. Only 1 (1%) of the MDR isolates was found to be XDR TB. The MDR group contained a higher proportion of Beijing or Beijing like strains (58%) than the non MDR group (28%). This percentage is higher in MDR FQ-R strains (71%).

Conclusions

The new GenoType® MTBDRsl assay combined with molecular tests to detect RMP-R and isoniazid resistance (INH-R) represents a valuable tool for the detection of XDR TB. In Cambodia there is a low rate of XDR amongst MDR TB including MDR FQ-R TB. This suggests a low association between FQ-R and XDR TB. Strain spoligotyping confirms Beijing strains to be more prone to accumulate antibiotic resistance.
Chronic instability of the anterior tibiofibular syndesmosis of the ankle. Arthroscopic findings and results of anatomical reconstruction
Authors: Wagener Marc L , Beumer Annechien , Swierstra Bart A
Published: September 2011

Background

The arthroscopic findings in patients with chronic anterior syndesmotic instability that need reconstructive surgery have never been described extensively.

Methods

In 12 patients the clinical suspicion of chronic instability of the syndesmosis was confirmed during arthroscopy of the ankle. All findings during the arthroscopy were scored. Anatomical reconstruction of the anterior tibiofibular syndesmosis was performed in all patients. The AOFAS score was assessed to evaluate the result of the reconstruction. At an average of 43 months after the reconstruction all patients were seen for follow-up.

Results

The syndesmosis being easily accessible for the 3 mm transverse end of probe which could be rotated around its longitudinal axis in all cases during arthroscopy of the ankle joint, confirmed the diagnosis. Cartilage damage was seen in 8 ankles, of which in 7 patients the damage was situated at the medial side of the ankle joint. The intraarticular part of anterior tibiofibular ligament was visibly damaged in 5 patients. Synovitis was seen in all but one ankle joint. After surgical reconstruction the AOFAS score improved from an average of 72 pre-operatively to 92 post-operatively.

Conclusions

To confirm the clinical suspicion, the final diagnosis of chronic instability of the anterior syndesmosis can be made during arthroscopy of the ankle. Cartilage damage to the medial side of the tibiotalar joint is often seen and might be the result of syndesmotic instability. Good results are achieved by anatomic reconstruction of the anterior syndesmosis, and all patients in this study would undergo the surgery again if necessary.
In vitro activities of novel 4-HPR derivatives on a panel of rhabdoid and other tumor cell lines
Authors: Smith Melissa E , Das Bhaskar C , Kalpana Ganjam V
Published: September 2011

Background

Rhabdoid tumors (RTs) are aggressive pediatric malignancies with poor prognosis. N-(4-hydroxy phenyl) retinamide (4-HPR or fenretinide) is a potential chemotherapeutic for RTs with activity correlated to its ability to down-modulate Cyclin D1. Previously, we synthesized novel halogen-substituted and peptidomimetic-derivatives of 4-HPR that retained activity in MON RT cells. Here we analyzed the effect of 4-HPR in inhibiting the growth of several RT, glioma, and breast cancer cell lines and tested their effect on cell cycle, apoptosis and Cyclin D1 expression.

Methods

Effect of compounds on RT cell cycle profiles, and cell death were assessed by MTS cell survival assays and FACS analysis. The effects of treatment on Cyclin D1 expression were determined by immunoblotting. The efficacy of these compounds on glioma and breast cancer cell lines was also determined using MTS assays.

Results

Low micromolar concentrations of 4-HPR derivatives inhibited cell survival of all RT cells tested. The 4-HPR derivatives altered RT cell cycle profiles and induced high levels of cell death that was correlated with their potency. ATRA exhibited high IC50 values in all cell lines tested and did not cause cell death. In MON RT cells, the iodo-substituted compounds were more active than 4-HPR in inducing cell cycle arrest and apoptosis. Additionally, the activity of the compounds correlated with their ability to down-modulate Cyclin D1: while active compounds reduced Cyclin D1 levels, inactive ATRA did not. In glioma and breast cancer cell lines, 4-HPR and 4-HPR derivatives showed variable efficacy.

Conclusions

Here we demonstrate, for the first time, that the inhibitory activities of novel halogen-substituted and peptidomimetic derivatives of 4-HPR are correlated to their ability to induce cell death and down-modulate Cyclin D1. These 4-HPR derivatives showed varied potencies in breast cancer and glioma cell lines. These data indicate that further studies are warranted on these derivatives of 4-HPR due to their low IC50s in RT cells. These derivatives are of general interest, as conjugation of halogen radioisotopes such as 18F, 124I, or 131I to 4-HPR will allow us to combine chemotherapy and radiotherapy with a single drug, and to perform PET/SPECT imaging studies in the future.
Ligand-dependent differences in estrogen receptor beta-interacting proteins identified in lung adenocarcinoma cells corresponds to estrogenic responses
Authors: Ivanova MM , Abner SM , Pierce WM , Klinge CM
Published: September 2011

Background

A recent epidemiological study demonstrated a reduced risk of lung cancer mortality in breast cancer patients using antiestrogens. These and other data implicate a role for estrogens in lung cancer, particularly nonsmall cell lung cancer (NSCLC). Approximately 61% of human NSCLC tumors express nuclear estrogen receptor β (ERβ); however, the role of ERβ and estrogens in NSCLC is likely to be multifactorial. Here we tested the hypothesis that proteins interacting with ERβ in human lung adenocarcinoma cells that respond proliferatively to estradiol (E2) are distinct from those in non-E2-responsive cells.

Methods

FLAG affinity purification of FLAG-ERβ-interacting proteins was used to isolate ERβ-interacting proteins in whole cell extracts from E2 proliferative H1793 and non-E2-proliferative A549 lung adenocarcinoma cell lines. Following trypsin digestion, proteins were identified using liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS). Proteomic data were analyzed using Ingenuity Pathway Analysis. Select results were confirmed by coimmunoprecipitation.

Results

LC-MS/MS identified 27 non-redundant ERβ-interacting proteins. ERβ-interacting proteins included hsp70, hsp60, vimentin, histones and calmodulin. Ingenuity Pathway Analysis of the ERβ-interacting proteins revealed differences in molecular and functional networks between H1793 and A549 lung adenocarcinoma cells. Coimmunoprecipitation experiments in these and other lung adenocarcinoma cells confirmed that ERβ and EGFR interact in a gender-dependent manner and in response to E2 or EGF. BRCA1 interacted with ERβ in A549 cell lines and in human lung adenocarcinoma tumors, but not normal lung tissue.

Conclusion

Our results identify specific differences in ERβ-interacting proteins in lung adenocarcinoma cells corresponding to ligand-dependent differences in estrogenic responses.
Parotid gland-recovery after radiotherapy in the head and neck region - 36 months follow-up of a prospective clinical study
Authors: Hey Jeremias , Setz Juergen , Gerlach Reinhard , Janich Martin , Hildebrandt Guido , Vordermark Dirk , Gernhardt Christian R , Kuhnt Thomas
Published: September 2011

Background

The aim of the present study was to evaluate the recovery potential of the parotid glands after using either 3D-conformal-radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) by sparing one single parotid gland.

Methods

Between 06/2002 and 10/2008, 117 patients with head and neck cancer were included in this prospective, non-randomised clinical study. All patients were treated with curative intent. Salivary gland function was assessed by measuring stimulated salivary flow at the beginning, during and at the end of radiotherapy as well as 1, 6, 12, 24, and 36 months after treatment. Measurements were converted to flow rates and normalized relative to rates before treatment. Mean doses (Dmean) were calculated from dose-volume histograms based on computed tomographies of the parotid glands.

Results

Patients were grouped according to the Dmean of the spared parotid gland having the lowest radiation exposure: Group I - Dmean < 26 Gy (n = 36), group II - Dmean 26-40 Gy (n = 45), and group III - Dmean > 40 Gy (n = 36). 15/117 (13%) patients received IMRT. By using IMRT as compared to 3D-CRT the Dmean of the spared parotid gland could be significantly reduced (Dmean IMRT vs. 3D-CRT: 21.7 vs. 34.4 Gy, p < 0.001). The relative salivary flow rates (RFSR) as a function of the mean parotid dose after 24 and 36 months was in group I 66% and 74%, in group II 56% and 49%, and in group III 31% and 24%, respectively. Multiple linear regression analyses revealed that the parotid gland dose and the tumor site were the independent determinants 12 and 36 months after the end of RT. Patients of group I and II parotid gland function did recover at 12, 24, and 36 months after the end of RT.

Conclusions

If a Dmean < 26 Gy for at least one parotid gland can be achieved then this is sufficient to reach complete recovery of pre-RT salivary flow rates. The radiation volume which depends on tumor site did significantly impact on the Dmean of the parotids, and thus on the saliva flow and recovery of parotid gland.
Estimating the budget impact of orphan medicines in Europe: 2010 - 2020
Authors: Schey Carina , Milanova Tsveta , Hutchings Adam
Published: September 2011

Background

Orphan drugs are a growing issue of importance to European healthcare policy makers. The success of orphan drug legislation in Europe has resulted in an increasing number of licensed medicines for rare diseases, and many more yet unlicensed products have received orphan drug designation. Increasingly the concerns amongst policy makers relate to issues of patient access and affordability, yet few studies have sought to estimate the future budget impact of orphan drugs. The aim of this study was to predict the total cost of orphan medicines in Europe between 2010 and 2020 as a percentage of total European pharmaceutical expenditure.

Methods

A disease-based epidemiological model was created based upon trends in the designation and approval of new orphan medicines, prevalence estimates for orphan diseases, and historical price and sales data for orphan drugs in Europe (defined as Eurozone + UK). The analysis incorporated two stages:

1) Predicting the number of diseases for which new orphan drugs will be approved over the next decade, based on an analysis of trends from the EU registry of orphan medicines;

2) stimating the average ex-factory drug cost across an orphan disease life cycle, from the year in which the first orphan medicine is launched to the point where the first medicine loses marketing exclusivity.

The two sets of information were combined to quantify the annual cost of orphan drugs from 2010 through 2020.

Results

The results from the model predicted a steady increase in the cumulative number of diseases for which an orphan drug is approved, averaging just over 5 new diseases per year over the next 10 years. The annual per patient cost of existing orphan drugs was seen to vary between €1,251 and €407,631, with the median cost being €32,242 per year. The share of the total pharmaceutical market represented by orphan drugs is predicted to increase from 3.3% in 2010 to a peak of 4.6% in 2016 after which it is expected to level off through 2020, as growth falls into line with that in the wider pharmaceutical market. In sensitivity analysis peak-year orphan drug budget impact ranged between 3% - 6.6%.

Conclusions

Although European orphan drug legislation has led to an increase in the number of approved orphan drugs, the growth in cost, as a proportion of total pharmaceutical expenditure, is likely to plateau over the next decade as orphan growth rates converge on those in the broader pharmaceutical market. Given the assumptions and simplifications inherent in such a projection, there is uncertainty around the base case forecast and further research is needed to monitor how trends develop. However, fears that growth in orphan drug expenditure will lead to unsustainable cost escalation do not appear to be justified. Furthermore, based on the results of this budget impact forecast, the European orphan drug legislation is not leading to a disproportionate impact on pharmaceutical expenditure.
Non-small cell lung carcinoma in an adolescent manifested by acute paraplegia due to spinal metastases: a case report
Authors: Ackert Ulrike , Haffner Dieter , Classen Carl Friedrich
Published: September 2011

Introduction

Bronchial carcinomas in childhood and adolescence are extremely rare; only individual cases have been reported previously.

Case presentation

We report on a 16-year-old Caucasian German boy with non-small cell lung carcinoma (squamous cell non-small cell lung carcinoma) stage IV, T4N2M1, without epidermal growth factor receptor overexpression and/or mutation or k-ras mutation. He presented with paraplegia due to spinal metastases of the bronchial carcinoma. No familial predisposition or toxin exposure was identified. Treatment following adult protocols consisted of surgical intervention for spinal metastases, first-line cisplatinum and gemcitabine, irradiation and second-line docetaxel. After a transient response our patient experienced disease progression and died about 10 months later.

Conclusion

Response and survival in our 16-year-old patient were similar to adult patients with stage IV non-small cell lung carcinoma.
Bridging the social and the biomedical: engaging the social and political sciences in HIV research
Authors: Kippax Susan C , Holt Martin , Friedman Samuel R
Published: September 2011

This supplement to the Journal of the International AIDS Society focuses on the engagement of the social and political sciences within HIV research and, in particular, maintaining a productive relationship between social and biomedical perspectives on HIV. It responds to a number of concerns raised primarily by social scientists, but also recognized as important by biomedical and public health researchers. These concerns include how best to understand the impact of medical technologies (such as HIV treatments, HIV testing, viral load testing, male circumcision, microbicides, and pre‐and post‐exposure prophylaxis) on sexual cultures, drug practices, relationships and social networks in different cultural, economic and political contexts. The supplement is also concerned with how we might examine the relationship between HIV prevention and treatment, understand the social and political mobilization required to tackle HIV, and sustain the range of disciplinary approaches needed to inform and guide responses to the global pandemic. The six articles included in the supplement demonstrate the value of fostering high quality social and political research to inform, guide and challenge our collaborative responses to HIV/AIDS.
Effective detection of rare variants in pooled DNA samples using Cross-pool tailcurve analysis
Authors: Niranjan Tejasvi S , Adamczyk Abby , Bravo Héctor Corrada , Taub Margaret A , Wheelan Sarah J , Irizarry Rafael , Wang Tao
Published: September 2011

Sequencing targeted DNA regions in large samples is necessary to discover the full spectrum of rare variants. We report an effective Illumina sequencing strategy utilizing pooled samples with novel quality (Srfim) and filtering (SERVIC
4
E) algorithms. We sequenced 24 exons in two cohorts of 480 samples each, identifying 47 coding variants, including 30 present once per cohort. Validation by Sanger sequencing revealed an excellent combination of sensitivity and specificity for variant detection in pooled samples of both cohorts as compared to publicly available algorithms.
Classification of unknown primary tumors with a data-driven method based on a large microarray reference database
Authors: Ojala Kalle A , Kilpinen Sami K , Kallioniemi Olli P
Published: September 2011

We present a new method to analyze cancer of unknown primary origin (CUP) samples. Our method achieves good results with classification accuracy (88% leave-one-out cross validation for primary tumors from 56 categories, 78% for CUP samples), and can also be used to study CUP samples on a gene-by-gene basis. It is not tied to any a priori defined gene set as many previous methods, and is adaptable to emerging new information.
The multiple roles of the CD8 coreceptor in T cell biology: opportunities for the selective modulation of self-reactive cytotoxic T cells
Authors: Laugel Bruno , Cole David K , Clement Mathew , Wooldridge Linda , Price David A , Sewell Andrew K
Published: September 2011

Short peptide fragments generated by intracellular protein cleavage are presented on the surface of most nucleated cells bound to highly polymorphic MHCI molecules. These pMHCI complexes constitute an interface that allows the immune system to identify and eradicate anomalous cells, such as those that harbor infectious agents, through the activation of CTLs. Molecular recognition of pMHCI complexes is mediated primarily by clonally distributed TCRs expressed on the surface of CTLs. The coreceptor CD8 contributes to this antigen-recognition process by binding to a largely invariant region of the MHCI molecule and by promoting intracellular signaling, the effects of which serve to enhance TCR stimuli triggered by cognate ligands. Recent investigations have shed light on the role of CD8 in the activation of MHCI-restricted, antigen-experienced T cells and in the processes of T cell selection and lineage commitment in the thymus. Here, we review these data and discuss their implications for the development of potential therapeutic strategies that selectively target pathogenic CTL responses erroneously directed against self-derived antigens.
Toll-Like Receptor-3 Ligation-Induced Indoleamine 2, 3-Dioxygenase Expression in Human Trophoblasts
Authors: Wang Bo , Koga Kaori , Osuga Yutaka , Cardenas Ingrid , Izumi Gentaro , Takamura Masashi , Hirata Tetsuya , Yoshino Osamu , Hirota Yasushi , Harada Miyuki , Mor Gil , Taketani Yuji
Published: September 2011

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades an essential amino acid, tryptophan, and plays a role in inhibiting the proliferation of T cells and intracellular pathogens. Inhibiting IDO in mice leads to fetal rejection, suggesting its significance in establishing pregnancy. Toll-like receptor 3 (TLR-3) is a key component of the innate immune system that recognizes viral double-stranded RNA and triggers immune reactions by producing type I interferon. Using a human trophoblast cell culture system, we studied the effect of TLR-3 ligation on IDO expression and function by treating trophoblasts with polyinosinic-polycytidylic acid [poly(I:C)] (a synthetic double stranded RNA, which mimics viral RNA). Real-time PCR and Western blot analysis revealed that IDO mRNA and protein expression was significantly induced by poly(I:C). The activity of IDO was also increased by poly(I:C) given that the l-kynurenine concentrations were elevated in conditioned media. Conditioned media from poly(I:C)-treated trophoblasts were found to inhibit the proliferation of human T cells significantly. Poly(I:C) was also shown to induce interferon (IFN)-β mRNA expression in trophoblasts. Recombinant human IFN-β increased IDO mRNA expression in trophoblasts more rapidly than poly(I:C). Pretreating with neutralizing antibody against IFN-β significantly suppressed IDO induction by poly(I:C). Collectively we have demonstrated that ligation of TLR-3 by poly(I:C) induces IDO expression in human first-trimester trophoblasts via an IFN-β-dependent pathway. These findings suggest that upon viral infection, trophoblasts induce IDO and in turn contribute to antimicrobial activity and maintenance of fetomaternal tolerance.
Fetal Hypothalamus-Pituitary-Adrenal Responses to Estradiol Sulfate
Authors: Wood Charles E.
Published: September 2011

Estradiol (E2) is an important modifier of the activity of the fetal hypothalamus-pituitary-adrenal axis. We have reported that estradiol-3-sulfate (E2SO4) circulates in fetal blood in far higher concentrations than E2 and that the fetal brain expresses steroid sulfatase, required for local deconjugation of E2SO4. We performed the present study to test the hypothesis that chronic infusion of E2SO4 chronically increases ACTH and cortisol secretion and that it shortens gestation. Chronically catheterized fetal sheep were treated with E2SO4 intracerebroventricular (n = 5), E2SO4 iv (n = 4), or no steroid infusion (control group, n = 5). Fetuses were subjected to arterial blood sampling every other day until spontaneous birth for plasma hormone analysis. Treatment with E2SO4 attenuated preparturient increases in ACTH secretion near term without affecting the ontogenetic rise in plasma cortisol. Infusion of E2SO4 intracerebroventricularly significantly increased plasma E2, plasma E2SO4, and plasma progesterone and shortened gestation compared with all other groups. These results are consistent with the conclusion that E2SO4: 1) interacts with the hypothalamus-pituitary-adrenal axis primarily by stimulating cortisol secretion and inhibiting ACTH and pro-ACTH secretion by negative feedback; and 2) stimulates the secretion of E2 and E2SO4. We conclude that the endocrine response to E2SO4 in the fetus is not identical with the response to E2.
Testosterone treatment fails to accelerate disease in a transgenic mouse model of spinal and bulbar muscular atrophy
Authors: Chevalier-Larsen Erica S. , Merry Diane E.
Published: September 2011

Evidence from multiple animal models demonstrates that testosterone plays a crucial role in the progression of symptoms in spinal and bulbar muscular atrophy (SBMA), a condition that results in neurodegeneration and muscle atrophy in affected men. Mice bearing a transgene encoding a human androgen receptor (AR) that contains a stretch of 112 glutamines (expanded polyglutamine tract; AR112Q mice) reproduce several aspects of the human disease. We treated transgenic male AR112Q mice with testosterone for 6 months. Surprisingly, testosterone treatment of AR112Q males did not exacerbate the disease. Although transgenic AR112Q males exhibited functional deficits when compared with non-transgenics, long-term testosterone treatment had no effect on motor function. Testosterone treatment also failed to affect cellular markers of disease, including inclusion formation (the accumulation of large nuclear aggregates of mutant AR protein) and levels of unphosphorylated neurofilament heavy chain. These data suggest that the mechanism of disease in SBMA saturates at close to endogenous hormone levels and that individuals with SBMA who take, or have taken, testosterone for its putative therapeutic properties are unlikely to suffer adverse effects.
The development of endotoxin tolerance, and the role of hypothalamo-pituitary-adrenal function and glucocorticoids in Pekin ducks
Authors: Marais Manette , Maloney Shane K. , Gray David A.
Published: September 2011

Endotoxin tolerance represents a state of abated immunological responsiveness to pyrogens, which, in mammals, leads to the decline or abolition of the fever response. The development of endotoxin tolerance in birds is not well understood; consequently, the impact of repeated pathogenic exposure on the avian febrile response, and thus on the ability of birds to fight recurrent infection, is not known. We determined the effect of repeated injections of lipopolysaccharide (LPS) on the febrile response of Pekin ducks. We gave ducks five injections of LPS, spaced 1, 4 or 10 days apart, and recorded their core body temperature with abdominally implanted temperature data loggers. Once we established that Pekin ducks developed endotoxin tolerance, we investigated the effect of repeated injections of LPS on the central and peripheral segments of the hypothalamo-pituitary-adrenal (HPA) axis in an attempt to elucidate the role of glucocorticoids in the modulation of the febrile response during the tolerant period. When our ducks became tolerant to LPS, they had significantly higher basal levels of plasma corticosterone (CORT, the principal glucocorticoid in birds), and their HPA response to treatment with LPS was blunted. We propose that the augmented levels of basal plasma CORT resulted from sensitized HPA function, and this, in turn, contributed to the development of endotoxin tolerance. Regulation of the circulating level of CORT might be a possible target for the re-establishment of appropriate immune responses in birds.
Mechanisms producing coordinated function across the breadth of a large biarticular thigh muscle
Authors: Carr Jennifer A. , Ellerby David J. , Rubenson Jonas , Marsh Richard L.
Published: September 2011

We examined the hypothesis that structural features of the iliotibialis lateralis pars postacetabularis (ILPO) in guinea fowl allow this large muscle to maintain equivalent function along its anterior–posterior axis. The ILPO, the largest muscle in the hindlimb of the guinea fowl, is a hip and knee extensor. The fascicles of the ILPO originate across a broad region of the ilium and ischium posterior to the hip. Its long posterior fascicles span the length of the thigh and insert directly on the patellar tendon complex. However, its anterior fascicles are shorter and insert on a narrow aponeurosis that forms a tendinous band along the anterior edge of the muscle and is connected distally to the patellar tendon. The biarticular ILPO is actively lengthened and then actively shortened during stance. The moment arm of the fascicles at the hip increases along the anterior to posterior axis, whereas the moment arm at the knee is constant for all fascicles. Using electromyography and sonomicrometry, we examined the activity and strain of posterior and anterior fascicles of the ILPO. The activation was not significantly different in the anterior and posterior fascicles. Although we found significant differences in active lengthening and shortening strain between the anterior and posterior fascicles, the differences were small. The majority of shortening strain is caused by hip extension and the inverse relationship between hip moment arm and fascicle length along the anterior–posterior axis was found to have a major role in ensuring similar shortening strain. However, because the knee moment arm is the same for all fascicles, knee flexion in early stance was predicted to produce much larger lengthening strains in the short anterior fascicles than our measured values at this location. We propose that active lengthening of the anterior fascicles was lower than predicted because the aponeurotic tendon of insertion of the anterior fascicles was stretched and only a portion of the lengthening had to be accommodated by the active muscle fascicles.
Function of a large biarticular hip and knee extensor during walking and running in guinea fowl (Numida meleagris)
Authors: Carr Jennifer A. , Ellerby David J. , Marsh Richard L.
Published: September 2011

Physiological and anatomical evidence suggests that in birds the iliotibialis lateralis pars postacetabularis (ILPO) is functionally important for running. Incorporating regional information, we estimated the mean sarcomere strain trajectory and electromyographic (EMG) amplitude of the ILPO during level and incline walking and running. Using these data and data in the literature of muscle energy use, we examined three hypotheses: (1) active lengthening will occur on the ascending limb of the length–tension curve to avoid potential damage caused by stretch on the descending limb; (2) the active strain cycle will shift to favor active shortening when the birds run uphill and shortening will occur on the plateau and shallow ascending limb of the length–tension curve; and (3) measures of EMG intensity will correlate with energy use when the mechanical function of the muscle is similar. Supporting the first hypothesis, we found that the mean sarcomere lengths at the end of active lengthening during level locomotion were smaller than the predicted length at the start of the plateau of the length–tension curve. Supporting the second hypothesis, the magnitude of active lengthening decreased with increasing slope, whereas active shortening increased. In evaluating the relationship between EMG amplitude and energy use (hypothesis 3), we found that although increases in EMG intensity with speed, slope and loading were positively correlated with muscle energy use, the quantitative relationships between these variables differed greatly under different conditions. The relative changes in EMG intensity and energy use by the muscle probably varied because of changes in the mechanical function of the muscle that altered the ratio of muscle energy use to active muscle volume. Considering the overall function of the cycle of active lengthening and shortening of the fascicles of the ILPO, we conclude that the function of active lengthening is unlikely to be energy conservation and may instead be related to promoting stability at the knee. The work required to lengthen the ILPO during stance is provided by co-contracting knee flexors. We suggest that this potentially energetically expensive co-contraction serves to stabilize the knee in early stance by increasing the mechanical impedance of the joint.
Are NHS foundation trusts able and willing to exercise autonomy? ‘You can take a horse to water…’
Authors: Exworthy Mark , Frosini Francesca , Jones Lorelei
Published: September 2011

Foundation trusts (FTs) have been a central part of the government's National Health Service (NHS) reforms in England since 2004. They illustrate the government's claim to decentralization, by granting greater autonomy to high performing organizations. The number of FTs has grown steadily, reaching 131 in September 2010, over 50% of eligible trusts. Despite this growth, and notwithstanding the fact that organizations which initially became FTs were previously high performing, doubts remain about the implementation of the FT policy. This article examines the implementation of FTs in the NHS and focuses on the nature and exercise of autonomy by FTs. It argues that the ability of FTs to exercise autonomy is in place, but the (relatively limited) extent of implementation may be explained by trusts’ lack of willingness to exercise such autonomy. Such unwillingness may be because of continued centralization, unclear policy and financial regimes, fear of negative impacts on relations with other local organizations, and awareness of greater risk to the FT, among others. Addressing the tension between FTs’ ability and willingness to exercise autonomy will largely explain the extent to which the government's provider side reforms will be implemented.
Probiotics for Disease Prevention: A Focus on Ventilator-Associated Pneumonia
Authors: Bailey Jennifer L , Yeung Siu Yan
Published: September 2011

Objective:

To summarize published data regarding the safety and efficacy of probiotics in the prevention of ventilator-associated pneumonia (VAP).

Data Sources:

PubMed databases (January 2000-August 2011) were searched and a bibliographic review of published articles was performed to identify original reports of probiotic administration for the prevention of VAP using the search terms probiotics, synbiotics, and ventilator-associated pneumonia.

Study Selection and Data Extraction:

Two pilot studies, 2 randomized controlled trials (RCTs), and 1 meta-analysis have addressed probiotic use for VAP prevention and were included in the review.

Data Synthesis:

VAP frequently occurs in mechanically ventilated patients. Given the lack of new antimicrobial agents, probiotics have been studied for their ability to modify human microflora colonization. Two studies examining pathogen colonization rates favored probiotics, with reduced incidence and increased duration until the emergence of new species. One prospective RCT found significant reduction in the incidence of VAP and colonization rates, but no significant difference in patient disposition outcomes. Another RCT examining 28-day mortality found no overall benefit with probiotic use and no reduction in colonization rates.

Conclusions:

Clinical trials have failed to demonstrate a consistent beneficial effect of probiotics in mechanically ventilated patients; thus, they are not recommended for routine clinical use. However, heterogeneity among study designs may hinder this assessment and the designs should be unified in future research.
Decision Process Evolution in Customer Channel Choice
Authors: Valentini Sara , Montaguti Elisa , Neslin Scott A.
Published: September 2011

The growing number of sales channels through which customers can make purchases has made it imperative for managers to understand how customers decide which channels to use. However, this presents a significant challenge because there is reason to believe the channel decision process evolves over the lifetime of the customer. The authors document the existence and nature of this phenomenon by analyzing the evolution of a customer's channel choice decision process from a trial stage to a posttrial stage. First, they analyze data for a book retailer and replicate their analysis using data from a durables and apparel retailer. Their results suggest that (1) customers’ decision processes do evolve, (2) a minority but sizeable segment changes decision processes within the observation period, and (3) customers who change do so from a decision process in which they are highly responsive to marketing to one in which they are less responsive. The authors illustrate and discuss the implications for both managers and researchers.
When Do Consumers Eat More? The Role of Appearance Self-Esteem and Food Packaging Cues
Authors: Argo Jennifer J. , White Katherine
Published: September 2011

Prior research has found that under certain conditions, small packages can paradoxically increase consumption. The authors build on this work by suggesting that people low in appearance self-esteem (ASE) are particularly sensitive to external control properties (i.e., packaging-related factors that signal the ability of packaging to regulate food intake) and, as a result, increase consumption levels when packages are small (vs. large or absent). Factors that highlight the external control properties of small packages, such as the visibility of product quantity, location of the caloric content, and communicated caloric content, further increase consumption, particularly among people with low ASE. The underlying process appears to be, at least in part, cognitively driven. The effects are mitigated when participants are under cognitive load, and the findings are mediated by cognitions regarding the ability of small packages to regulate food intake. The results have important practical implications suggesting that to quell the effects of small packages on overconsumption, emphasis on the external control properties of small packages should be minimized.
An Exploratory Study of the Behavior and Perceptions of College Students with Respect to Regular, Light, and Ultralight Cigarettes
Authors: Smith Karen H. , Stutts Mary Ann , Zank Gail M.
Published: September 2011

The authors perform an exploratory survey that examines the smoking behavior, perceptions, and quitting intentions of 579 college students, an important segment because of their large numbers, their education, and the fact that many of them begin smoking during college. Unlike findings from prior studies of adults, most college students in the sample did not perceive that light cigarettes are safer than regular cigarettes or that ultralight cigarettes are safer than light cigarettes, but rather they perceived lights to provide sensory benefits (e.g., milder, lighter taste) over regular cigarettes. This was especially true for former and current smokers. The majority of smokers were nondaily smokers, many of whom have no thoughts of quitting. This is a concern because these nondaily smokers may not consider their smoking behavior risky. In addition, nondaily college student smokers who are primarily social smokers constitute a large group of young adults for which there is little research into the health risks from smoking.
Consuming Direct-to-Consumer Genetic Tests: The Role of Genetic Literacy and Knowledge Calibration
Authors: Pearson Yvette E. , Liu-Thompkins Yuping
Published: September 2011

As direct-to-consumer marketing of medical genetic tests grows in popularity, there is an increasing need to better understand the ethical and public policy implications of such products. The complexity of genetic tests raises serious concerns about whether consumers possess the knowledge to make sound decisions about their use. This research examines the effects of educational intervention and feedback on consumers’ genetic literacy and calibration—the gap between consumers’ actual knowledge and how much they think they know. The authors find that consumers’ genetic knowledge was generally low and that people tended to underestimate their knowledge level. Furthermore, consumers’ perceived rather than actual knowledge levels drove attitude and purchase intention. Regarding the effect of educational intervention, exposure to an online educational module improved both genetic knowledge and calibration. Offering instant feedback resulted in greater knowledge gain than delayed feedback. The worst learning outcome occurred when feedback was both delayed and brief. On the basis of these findings, the authors offer recommendations for formulating ethically sound public policies in this area.
Altered Visual Experience Induces Instructive Changes of Orientation Preference in Mouse Visual Cortex
Authors: Kreile Anne K. , Bonhoeffer Tobias , Hübener Mark
Published: September 2011

Stripe rearing, the restriction of visual experience to contours of only one orientation, leads to an overrepresentation of the experienced orientation among neurons in the visual cortex. It is unclear, however, how these changes are brought about. Are they caused by silencing of neurons tuned to non-experienced orientations, or do some neurons change their preferred orientation? To address this question, we stripe-reared juvenile mice using cylinder lens goggles. Following stripe rearing, the orientation preference of cortical neurons was determined with two-photon calcium imaging. This allowed us to sample all neurons in a given field of view, including the non-responsive ones, thus overcoming a fundamental limitation of extracellular electrophysiological recordings. Stripe rearing for 3 weeks resulted in a clear overrepresentation of the experienced orientation in cortical layer 2/3. Closer inspection revealed that the stripe rearing effect changed with depth in cortex: The fraction of responsive neurons decreased in upper layer 2/3, but changed very little deeper in this layer. At the same time, the overrepresentation of the experienced orientation was strongest in lower layer 2/3. Thus, diverse mechanisms contribute to the overall stripe rearing effect, but for neurons in lower layer 2/3 the effect is mediated by an instructive mechanism, which alters the orientation tuning of individual neurons.