bluuebunny/crossref_metadata_2025 huggingface dataset:
A bottom-up art event gave birth to a process of community empowerment in an Italian village
Authors: Sardu Claudia , Mereu Alessandra , Sotgiu Alessandra , Contu Paolo
Published: December 2011

Although community participation is a component of community empowerment, it often remains a theoretical exhortation. Reporting experiences which enable people to take control of their lives, can be useful to suggest practical elements for promoting empowerment. This article describes the experience of a Sardinian village (Ulassai), that developed into a community empowerment. The Laverack’s operational domains were used to measure the community empowerment process. The process started in 1979 ‘almost by chance’ with an art performance that was the entry point for community participation. This experience has been the foundation for the community empowerment. Citizens acquired the ‘ability of thinking and planning as a community and not mere individuals’. In the following 30 years citizens gave birth to several outcomes rooted in that event. The intermediate outcomes highlight the ‘ability of action by a group to mobilize existing resources, and act collectively against opposing forces’. The long-term outcomes demonstrate the ‘ability to integrate the cultural experiences that strengthened the community’s identification into a sustainable community asset’, and the ‘ability to cope with global environmental challenges and to collaborate on an equal basis with other stakeholders. The pathways to community empowerment, showed by the community of Ulassai, overlap with the ‘operational domains’. The Ulassai experience shows that the empowerment process can start from an event apparently unrelated to health promotion. This community experience illustrates the positive role arts can play in community development. Hence, the call for health promoters to look carefully into those situations that occur naturally in communities.
Americans’ Attitudes toward Mental Illness and Involuntary Psychiatric Medication
Authors: Mossakowski Krysia N. , Kaplan Lauren M. , Hill Terrence D.
Published: December 2011

This study uses data from the Mental Health Modules of the General Social Survey (1996 and 2006) to understand why some Americans endorse the involuntary use of psychiatric medication. Results indicated that in 1996 and 2006, 28 percent of Americans believed that people with mental illness should be forced by law to take psychiatric medication. The belief that people with mental illness are dangerous significantly contributed to Americans’ endorsement of this form of mandated treatment. Interestingly, the belief that mental illness is caused by stress increased the odds of support for mandated medication in 1996 and then reduced the odds of support in 2006. Moreover, stigmatizing preferences for social distance from those with mental illness were no longer contributing factors in 2006. It is still imperative, however, that public policy makers promote anti-stigma initiatives to reduce barriers to psychiatric treatment and counteract the public’s lingering fear of people with mental illness.
Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function
Authors: Foley Bree , Cooley Sarah , Verneris Michael R. , Pitt Michelle , Curtsinger Julie , Luo Xianghua , Lopez-Vergès Sandra , Lanier Lewis L. , Weisdorf Daniel , Miller Jeffrey S.
Published: December 2011

During mouse cytomegalovirus (CMV) infection, a population of Ly49H+ natural killer (NK) cells expands and is responsible for disease clearance through the induction of a “memory NK-cell response.” Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C+ NK cells expanded and were potent producers of IFNγ. NKG2C+ NK cells predominately expressed killer cell immunoglobulin–like receptor, and self-killer cell immunoglobulin–like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56dim NK cells. Strikingly, increased frequencies of NKG2C+ NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C+ NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.
Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial
Authors: Prandoni Paolo , Noventa Franco , Quintavalla Roberto , Bova Carlo , Cosmi Benilde , Siragusa Sergio , Bucherini Eugenio , Astorri Francesco , Cuppini Stefano , Dalla Valle Fabio , Lensing Anthonie W. A. , Prins Martin H. , Villalta Sabina
Published: December 2011

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated. This study is registered as Clinical Trial number NCT00426075.
GC-Content Normalization for RNA-Seq Data
Authors: Risso Davide , Schwartz Katja , Sherlock Gavin , Dudoit Sandrine
Published: December 2011

Background

Transcriptome sequencing (RNA-Seq) has become the assay of choice for high-throughput studies of gene expression. However, as is the case with microarrays, major technology-related artifacts and biases affect the resulting expression measures. Normalization is therefore essential to ensure accurate inference of expression levels and subsequent analyses thereof.

Results

We focus on biases related to GC-content and demonstrate the existence of strong sample-specific GC-content effects on RNA-Seq read counts, which can substantially bias differential expression analysis. We propose three simple within-lane gene-level GC-content normalization approaches and assess their performance on two different RNA-Seq datasets, involving different species and experimental designs. Our methods are compared to state-of-the-art normalization procedures in terms of bias and mean squared error for expression fold-change estimation and in terms of Type I error and p-value distributions for tests of differential expression. The exploratory data analysis and normalization methods proposed in this article are implemented in the open-source Bioconductor R package EDASeq.

Conclusions

Our within-lane normalization procedures, followed by between-lane normalization, reduce GC-content bias and lead to more accurate estimates of expression fold-changes and tests of differential expression. Such results are crucial for the biological interpretation of RNA-Seq experiments, where downstream analyses can be sensitive to the supplied lists of genes.
Structural characterization of helitrons and their stepwise capturing of gene fragments in the maize genome
Authors: Dong Yongbin , Lu Xiaomin , Song Weibin , Shi Lei , Zhang Mei , Zhao Hainan , Jiao Yinping , Lai Jinsheng
Published: December 2011

Background

As a newly identified category of DNA transposon, helitrons have been found in a large number of eukaryotes genomes. Helitrons have contributed significantly to the intra-specific genome diversity in maize. Although many characteristics of helitrons in the maize genome have been well documented, the sequence of an intact autonomous helitrons has not been identified in maize. In addition, the process of gene fragment capturing during the transposition of helitrons has not been characterized.

Results

The whole genome sequences of maize inbred line B73 were analyzed, 1,649 helitron-like transposons including 1,515 helAs and 134 helBs were identified. ZmhelA1, ZmhelB1 and ZmhelB2 all encode an open reading frame (ORF) with intact replication initiator (Rep) motif and a DNA helicase (Hel) domain, which are similar to previously reported autonomous helitrons in other organisms. The putative autonomous ZmhelB1 and ZmhelB2 contain an extra replication factor-a protein1 (RPA1) transposase (RPA-TPase) including three single strand DNA-binding domains (DBD)-A/-B/-C in the ORF. Over ninety percent of maize helitrons identified have captured gene fragments. HelAs and helBs carry 4,645 and 249 gene fragments, which yield 2,507 and 187 different genes respectively. Many helitrons contain mutilple terminal sequences, but only one 3'-terminal sequence had an intact "CTAG" motif. There were no significant differences in the 5'-termini sequence between the veritas terminal sequence and the pseudo sequence. Helitrons not only can capture fragments, but were also shown to lose internal sequences during the course of transposing.

Conclusions

Three putative autonomous elements were identified, which encoded an intact Rep motif and a DNA helicase domain, suggesting that autonomous helitrons may exist in modern maize. The results indicate that gene fragments captured during the transposition of many helitrons happen in a stepwise way, with multiple gene fragments within one helitron resulting from several sequential transpositions. In addition, we have proposed a potential mechanism regarding how helitrons with multiple termini are generated.
Comparison of ICD code-based diagnosis of obesity with measured obesity in children and the implications for health care cost estimates
Authors: Kuhle Stefan , Kirk Sara FL , Ohinmaa Arto , Veugelers Paul J
Published: December 2011

Background

Administrative health databases are a valuable research tool to assess health care utilization at the population level. However, their use in obesity research limited due to the lack of data on body weight. A potential workaround is to use the ICD code of obesity to identify obese individuals. The objective of the current study was to investigate the sensitivity and specificity of an ICD code-based diagnosis of obesity from administrative health data relative to the gold standard measured BMI.

Methods

Linkage of a population-based survey with anthropometric measures in elementary school children in 2003 with longitudinal administrative health data (physician visits and hospital discharges 1992-2006) from the Canadian province of Nova Scotia. Measured obesity was defined based on the CDC cut-offs applied to the measured BMI. An ICD code-based diagnosis obesity was defined as one or more ICD-9 (278) or ICD-10 code (E66-E68) of obesity from a physician visit or a hospital stay. Sensitivity and specificity were calculated and health care cost estimates based on measured obesity and ICD-based obesity were compared.

Results

The sensitivity of an ICD code-based obesity diagnosis was 7.4% using ICD codes between 2002 and 2004. Those correctly identified had a higher BMI and had higher health care utilization and costs.

Conclusions

An ICD diagnosis of obesity in Canadian administrative health data grossly underestimates the true prevalence of childhood obesity and overestimates the health care cost differential between obese and non-obese children.
Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial
Authors: Onland Wes , Offringa Martin , Cools Filip , De Jaegere Anne P , Rademaker Karin , Blom Henry , Cavatorta Eric , Debeer Anne , Dijk Peter H , van Heijst Arno F , Kramer Boris W , Kroon Andre A , Mohns Thilo , van Straaten Henrica L , te Pas Arjan B , Theyskens Claire , van Weissenbruch Mirjam M , van Kaam Anton H
Published: December 2011

Background

Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants.

Methods/Design

The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis.

Discussion

This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.

Trial registration number

Netherlands Trial Register (NTR): NTR2768
Comparison between two pedicle screw augmentation instrumentations in adult degenerative scoliosis with osteoporosis
Authors: Xie Yang , Fu Qiang , Chen Zi-qiang , Shi Zhi-cai , Zhu Xiao-dong , Wang Chuan-feng , Li Ming
Published: December 2011

Background

The operative treatment of adult degenerative scoliosis combined with osteoporosis increase following the epidemiological development. Studies have confirmed that screws in osteoporotic spines have significant lower-screw strength with more frequent screw movements within the vertebra than normal spines. Screws augmented with Polymethylmethacrylate (PMMA) or with autogenous bone can offer more powerful corrective force and significant advantages.

Methods

A retrospective analysis was conducted on 31 consecutive patients with degenerative lumbar scoliosis combined with osteoporosis who had surgery from December 2000. All had a minimum of 2-year follow-up. All patients had posterior approach surgery. 14 of them were fixed with pedicle screw by augmentation with Polymethylmethacrylate (PMMA) and the other 17 patients with autogenous bone. Age, sex and whether smoking were similar between the two groups. Surgical time, blood loss, blood transfusion, medical cost, post surgery ICU time, hospital day, length of oral pain medicines taken, Pre-and postoperative Oswestry disability index questionnaire and surgical revision were documented and compared. Preoperative, postoperative and final follow up Cobb angle, sagittal lumbar curve, correction rate, and Follow up Cobb loss were also compared.

Results

No significant differences were found between the autogenous bone group and Polymethylmethacrylate group with regards to all the targets above except for length of oral pain medicines taken and surgery cost. 2 patients were seen leakage during operation, but there is neither damage of nerve nor symptom after operation. No revision was needed.

Conclusion

Both augmentation pedicle screw with Polymethylmethacrylate (PMMA) and autogenous bone treating degenerative lumbar scoliosis combined with osteoporosis can achieve a good surgical result. Less oral pain medicines taken are the potential benefits of Polymethylmethacrylate augmentation, but that is at the cost of more medical spending.
Devolution and public perceptions and experience of health services in Pakistan: linked cross sectional surveys in 2002 and 2004
Authors: Ansari Umaira , Cockcroft Anne , Omer Khalid , Ansari Noor MD , Khan Amir , Chaudhry Ubaid Ullah , Andersson Neil
Published: December 2011

Background

The government of Pakistan introduced devolution in 2001. Responsibility for delivery of most health services passed from provincial to district governments. Two national surveys examined public opinions, use, and experience of health services in 2001 and 2004, to assess the impact of devolution on these services from the point of view of the public.

Methods

A stratified random cluster sample drawn in 2001 and revisited in 2004 included households in all districts. Field teams administered a questionnaire covering views about available health services, use of government and private health services, and experience and satisfaction with the service. Focus groups in each community discussed reasons behind the findings, and district nazims (elected mayors) and administrators commented about implementation of devolution. Multivariate analysis, with an adjustment for clustering, examined changes over time, and associations with use and satisfaction with services in 2004.

Results

Few of 57,321 households interviewed in 2002 were satisfied with available government health services (23%), with a similar satisfaction (27%) among 53,960 households in 2004. Less households used government health services in 2004 (24%) than in 2002 (29%); the decrease was significant in the most populous province. In 2004, households were more likely to use government services if they were satisfied with the services, poorer, or less educated. The majority of users of government health services were satisfied; the increase from 63% to 67% between 2002 and 2004 was significant in two provinces. Satisfaction in 2004 was higher among users of private services (87%) or private unqualified practitioners (78%). Users of government services who received all medicines from the facility or who were given an explanation of their condition were more likely to be satisfied. Focus groups explained that people avoid government health services particularly because of bad treatment from staff, and unavailable or poor quality medicines. District nazims and administrators cited problems with implementation of devolution, especially with transfer of funds.

Conclusions

Under devolution, the public did not experience improved government health services, but devolution was not fully implemented as intended. An ongoing social audit process could provide a basis for local and national accountability of health services.
CYP2J3 Gene Delivery Reduces Insulin Resistance via Upregulation of eNOS in Fructose-treated Rats
Authors: Xu Xizhen , Tu Ling , Wang Luyun , Fang Xiaosai , Wang Dao Wen
Published: December 2011

Accumulating evidence suggests that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs) which play important roles in various pathophysiological processes. Interestingly, CYP-derived eicosanoids are vasodilatory, at least in part through their ability to activate eNOS and subsequent NO release. This study investigated the roles of eNOS in CYP2J3 gene delivery reducing blood pressure and improving insulin resistance in fructose-treated rats. CYP2J3 overexpression in vivo increased EET generation, reduced blood pressure and reversed insulin resistance as determined by insulin resistance index (HOMA-IR). Furthermore, administration of eNOS inhibitor L-NMMA significantly and partially abolished the beneficial effects of CYP2J3 gene delivery on hypertension and insulin resistance induced by fructose intake, and possible mechanism is associated with increased ET-1, ETA-receptor mRNA expression and reduced sensitivity of insulin to peripheral tissues and organs characterized by reduced activity of IRS-1/PI3K/AKT and AMPK signalling pathways. These data provide direct evidence that CYP2J3-derived EETs may alleviate insulin resistance at least in part through upregulated eNOS expression.
Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment in Tanzanian children with acute uncomplicated malaria
Authors: Carlsson Anja M , Ngasala Billy E , Dahlström Sabina , Membi Christopher , Veiga Isabel M , Rombo Lars , Abdulla Salim , Premji Zul , Gil J Pedro , Björkman Anders , Mårtensson Andreas
Published: December 2011

Background

This study aimed to explore Plasmodium falciparum population dynamics during the early phase of anti-malarial drug treatment with artemisinin-based combination therapy in children with clinical malaria in a high transmission area in Africa.

Methods

A total of 50 children aged 1-10 years with acute uncomplicated P. falciparum malaria in Bagamoyo District, Tanzania, were enrolled. Participants were hospitalized and received supervised standard treatment with artemether-lumefantrine according to body weight in six doses over 3 days. Blood samples were collected 11 times, i.e. at time of diagnosis (-2 h) and 0, 2, 4, 8, 16, 24, 36, 48, 60 and 72 h after initiation of treatment. Parasite population dynamics were assessed using nested polymerase chain reaction (PCR)-genotyping of merozoite surface protein (msp) 1 and 2.

Results

PCR-analyses from nine sequential blood samples collected after initiation of treatment identified 20 and 21 additional genotypes in 15/50 (30%) and 14/50 (28%) children with msp1 and msp2, respectively, non-detectable in the pre-treatment samples (-2 and 0 h combined). Some 15/20 (75%) and 14/21 (67%) of these genotypes were identified within 24 h, whereas 17/20 (85%) and 19/21 (90%) within 48 h for msp1 and msp2, respectively. The genotype profile was diverse, and varied considerably over time both within and between patients, molecular markers and their respective families.

Conclusion

PCR analyses from multiple blood samples collected during the early treatment phase revealed a complex picture of parasite sub-populations. This underlines the importance of interpreting PCR-outcomes with caution and suggests that the present use of PCR-adjustment from paired blood samples in anti-malarial drug trials may overestimate assessment of drug efficacy in high transmission areas in Africa.

The study is registered at http://www.clinicaltrials.gov with identifier NCT00336375.
A modified Mann iterative scheme by generalized f-projection for a countable family of relatively quasi-nonexpansive mappings and a system of generalized mixed equilibrium problems
Authors: Saewan Siwaporn , Kumam Poom
Published: December 2011

The purpose of this paper is to introduce a new hybrid projection method based on modified Mann iterative scheme by the generalized f-projection operator for a countable family of relatively quasi-nonexpansive mappings and the solutions of the system of generalized mixed equilibrium problems. Furthermore, we prove the strong convergence theorem for a countable family of relatively quasi-nonexpansive mappings in a uniformly convex and uniform smooth Banach space. Finally, we also apply our results to the problem of finding zeros of
B
-monotone mappings and maximal monotone operators. The results presented in this paper generalize and improve some well-known results in the literature.

2000 Mathematics Subject Classification: 47H05; 47H09; 47H10.
TLR3 signaling is either protective or pathogenic for the development of Theiler's virus-induced demyelinating disease depending on the time of viral infection
Authors: Jin Young-Hee , Kaneyama Tomoki , Kang Min Hyung , Kang Hyun Seok , Koh Chang-Sung , Kim Byung S
Published: December 2011

Background

We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler's murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease.

Methods

SJL/J and B6;129S-Tlr3tm1Flv/J (TLR3KO-B6) mice, and TLR3KO-SJL mice that TLR3KO-B6 mice were backcrossed to SJL/J mice for 6 generations were infected with Theiler's murine encephalomyelitis virus (2 × 105PFU) with or without treatment with 50 μg of poly IC. Cytokine production and immune responses in the CNS and periphery of infected mice were analyzed.

Results

We investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. TLR3KO-B6 mice did not develop demyelinating disease although they displayed elevated viral loads in the CNS. However, TLR3KO-SJL mice displayed increased viral loads and cellular infiltration in the CNS, accompanied by exacerbated development of demyelinating disease, compared to the normal littermate mice. Late, but not early, anti-viral CD4+and CD8+T cell responses in the CNS were compromised in TLR3KO-SJL mice. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas such activation after viral infection restrained disease development. Activation of TLR3 signaling prior to viral infection hindered the induction of protective IFN-γ-producing CD4+and CD8+T cell populations. In contrast, activation of these signals after viral infection improved the induction of IFN-γ-producing CD4+and CD8+T cells. In addition, poly IC-pretreated mice displayed elevated PDL-1 and regulatory FoxP3+CD4+T cells in the CNS, while poly IC-post-treated mice expressed reduced levels of PDL-1 and FoxP3+CD4+T cells.

Conclusions

These results suggest that TLR3-mediated signaling during viral infection protects against demyelinating disease by reducing the viral load and modulating immune responses. In contrast, premature activation of TLR3 signal transduction prior to viral infection leads to pathogenesis via over-activation of the pathogenic immune response.
Insulin-like growth factor-I peptides act centrally to decrease depression-like behavior of mice treated intraperitoneally with lipopolysaccharide
Authors: Park Sook-Eun , Lawson Marcus , Dantzer Robert , Kelley Keith W , McCusker Robert H
Published: December 2011

Centrally administered insulin-like growth factor (IGF)-I has anti-depressant activity in several rodent models, including lipopolysaccharide (LPS)-induced depression. In this study we tested the ability of IGF-I and GPE (the N-terminal tri-peptide derived from IGF-I) to alter depression-like behavior induced by intraperitoneal (i.p.) administration of LPS in a preventive and curative manner. In the first case, IGF-I (1 μg) or GPE (5 μg) was administered i.c.v. to CD-1 mice followed 30 min later by 330 μg/kg body weight i.p. LPS. In the second case, 830 μg/kg body weight LPS was given 24 h prior to either IGF-I or GPE. When administered i.p., LPS induced full-blown sickness assessed as a loss of body weight, decrease in food intake and sickness behavior. None of these indices were affected by IGF-I or GPE. LPS also induced depression-like behavior; assessed as an increased duration of immobility in the tail suspension and forced swim tests. When administered before or after LPS, IGF-I and GPE abrogated the LPS response; attenuating induction of depression-like behaviors and blocking preexistent depression-like behaviors. Similar to previous work with IGF-I, GPE decreased brain expression of cytokines in response to LPS although unlike IGF-I, GPE did not induce the expression of brain-derived neurotrophic factor (BDNF). LPS induced expression of tryptophan dioxygenases, IDO1, IDO2 and TDO2, but expression of these enzymes was not altered by GPE. Thus, both IGF-I and GPE elicit specific improvement in depression-like behavior independent of sickness, an action that could be due to their anti-inflammatory properties.
Rotavirus NSP4 is secreted from infected cells as an oligomeric lipoprotein and binds to glycosaminoglycans on the surface of non-infected cells
Authors: Didsbury Alicia , Wang Carol , Verdon Daniel , Sewell Mary A , McIntosh Julie D , Taylor John A
Published: December 2011

Background

Nonstructural glycoprotein 4 (NSP4) encoded by rotavirus is the only viral protein currently believed to function as an enterotoxin. NSP4 is synthesized as an intracellular transmembrane glycoprotein and as such is essential for virus assembly. Infection of polarized Caco-2 cells with rotavirus also results in the secretion of glycosylated NSP4 apparently in a soluble form despite retention of its transmembrane domain. We have examined the structure, solubility and cell-binding properties of this secreted form of NSP4 to further understand the biochemical basis for its enterotoxic function. We show here that NSP4 is secreted as discrete detergent-sensitive oligomers in a complex with phospholipids and demonstrate that this secreted form of NSP4 can bind to glycosaminoglycans present on the surface of a range of different cell types.

Methods

NSP4 was purified from the medium of infected cells after ultracentrifugation and ultrafiltration by successive lectin-affinity and ion exchange chromatography. Oligomerisation of NSP4 was examined by density gradient centrifugation and chemical crosslinking and the lipid content was assessed by analytical thin layer chromatography and flame ionization detection. Binding of NSP4 to various cell lines was measured using a flow cytometric-based assay.

Results

Secreted NSP4 formed oligomers that contained phospholipid but dissociated to a dimeric species in the presence of non-ionic detergent. The purified glycoprotein binds to the surface of various non-infected cells of distinct lineage. Binding of NSP4 to HT-29, a cell line of intestinal origin, is saturable and independent of divalent cations. Complementary biochemical approaches reveal that NSP4 binds to sulfated glycosaminoglycans on the plasma membrane.

Conclusion

Our study is the first to analyze an authentic (i.e. non-recombinant) form of NSP4 that is secreted from virus-infected cells. Despite retention of the transmembrane domain, secreted NSP4 remains soluble in an aqueous environment as an oligomeric lipoprotein that can bind to various cell types via an interaction with glycosaminoglycans. This broad cellular tropism exhibited by NSP4 may have implications for the pathophysiology of rotavirus disease.
Radiotherapy and "new" drugs-new side effects?
Authors: Niyazi Maximilian , Maihoefer Cornelius , Krause Mechthild , Rödel Claus , Budach Wilfried , Belka Claus
Published: December 2011

Background and purpose

Targeted drugs have augmented the cancer treatment armamentarium. Based on the molecular specificity, it was initially believed that these drugs had significantly less side effects. However, currently it is accepted that all of these agents have their specific side effects. Based on the given multimodal approach, special emphasis has to be placed on putative interactions of conventional cytostatic drugs, targeted agents and other modalities. The interaction of targeted drugs with radiation harbours special risks, since the awareness for interactions and even synergistic toxicities is lacking. At present, only limited is data available regarding combinations of targeted drugs and radiotherapy. This review gives an overview on the current knowledge on such combined treatments.

Materials and methods

Using the following MESH headings and combinations of these terms pubmed database was searched: Radiotherapy AND cetuximab/trastuzumab/panitumumab/nimotuzumab, bevacizumab, sunitinib/sorafenib/lapatinib/gefitinib/erlotinib/sirolimus, thalidomide/lenalidomide as well as erythropoietin. For citation crosscheck the ISI web of science database was used employing the same search terms.

Results

Several classes of targeted substances may be distinguished: Small molecules including kinase inhibitors and specific inhibitors, antibodies, and anti-angiogenic agents. Combination of these agents with radiotherapy may lead to specific toxicities or negatively influence the efficacy of RT. Though there is only little information on the interaction of molecular targeted radiation and radiotherapy in clinical settings, several critical incidents are reported.

Conclusions

The addition of molecular targeted drugs to conventional radiotherapy outside of approved regimens or clinical trials warrants a careful consideration especially when used in conjunction in hypo-fractionated regimens. Clinical trials are urgently needed in order to address the open question in regard to efficacy, early and late toxicity.
Treatment with gefitinib after erlotinib-induced liver injury: a case report
Authors: Nakatomi Katsumi , Nakamura Yoichi , Tetsuya Iida , Kohno Shigeru
Published: December 2011

Introduction

Gefitinib and erlotinib have minor differences in their chemical structures, and thus it remains unclear whether the hepatotoxicity induced by one compound is affected by the other. The case of a patient who developed erlotinib-induced liver injury and was then treated with gefitinib without hepatic toxicity or disease progression is presented.

Case presentation

A 31-year-old Japanese woman, who never smoked and who was diagnosed as having lung adenocarcinoma with carcinomatous meningitis, was treated with erlotinib. She developed erlotinib-induced liver injury after four weeks of treatment. The treatment was stopped right away, but the symptoms of meningitis re-appeared immediately. Gefitinib treatment was started and continued without recurrence of drug-induced liver injury.

Conclusion

Gefitinib appears to be a potential treatment option after erlotinib-induced liver injury.
Professional liability insurance in Obstetrics and Gynaecology: estimate of the level of knowledge about malpractice insurance policies and definition of an informative tool for the management of the professional activity
Authors: Scurria Serena , Asmundo Alessio , Crinò Claudio , Gualniera Patrizia
Published: December 2011

Background

In recent years, due to the increasingly hostile environment in the medical malpractice field and related lawsuits in Italy, physicians began informing themselves regarding their comprehensive medical malpractice coverage.

Methods

In order to estimate the level of knowledge of medical professionals on liability insurance coverage for healthcare malpractice, a sample of 60 hospital health professionals of the obstetrics and gynaecology area of Messina (Sicily, Italy) were recluted. A survey was administered to evaluate their knowledge as to the meaning of professional liability insurance coverage but above all on the most frequent policy forms ("loss occurrence", "claims made" and "I-II risk"). Professionals were classified according to age and professional title and descriptive statistics were calculated for all the professional groups and answers.

Results

Most of the surveyed professionals were unaware or had very bad knowledge of the professional liability insurance coverage negotiated by the general manager, so most of the personnel believed it useful to subscribe individual "private" policies. Several subjects declared they were aware of the possibility of obtaining an extended coverage for gross negligence and substantially all the surveyed had never seen the loss occurrence and claims made form of the policy. Moreover, the sample was practically unaware of the related issues about insurance coverage for damages related to breaches on informed consent. The results revealed the relative lack of knowledge--among the operators in the field of obstetrics and gynaecology--of the effective coverage provided by the policies signed by the hospital managers for damages in medical malpractice. The authors thus proposed a useful information tool to help professionals working in obstetrics and gynaecology regarding aspects of insurance coverage provided on the basis of Italian civil law.

Conclusion

Italy must introduce a compulsory insurance system which could absorb, through a mechanism of "distribution of risk", the malpractice litigation and its costs. This will provide compensation in accidental cases where it wouldn't be possible to demonstrate carelessness, imprudence and/or lack of skill.
Dependence of NMDA/GSK-3β Mediated Metaplasticity on TRPM2 Channels at Hippocampal CA3-CA1 Synapses
Authors: Xie Yu-Feng , Belrose Jillian C , Lei Gang , Tymianski Michael , Mori Yasuo , MacDonald John F , Jackson Michael F
Published: December 2011

Transient receptor potential melastatin 2 (TRPM2) is a calcium permeable non-selective cation channel that functions as a sensor of cellular redox status. Highly expressed within the CNS, we have previously demonstrated the functional expression of these channels in CA1 pyramidal neurons of the hippocampus. Although implicated in oxidative stress-induced neuronal cell death, and potentially in neurodegenerative disease, the physiological role of TRPM2 in the central nervous system is unknown. Interestingly, we have shown that the activation of these channels may be sensitized by co-incident NMDA receptor activation, suggesting a potential contribution of TRPM2 to synaptic transmission. Using hippocampal cultures and slices from TRPM2 null mice we demonstrate that the loss of these channels selectively impairs NMDAR-dependent long-term depression (LTD) while sparing long-term
potentiation. Impaired LTD resulted from an inhibition of GSK-3β, through increased phosphorylation, and a reduction in the expression of PSD95 and AMPARs. Notably, LTD could
be rescued in TRPM2 null mice by recruitment of GSK-3β signaling following dopamine D2 receptor stimulation. We propose that TRPM2 channels play a key role in hippocampal synaptic plasticity.
A genome-wide linkage study of mammographic density, a risk factor for breast cancer
Authors: Greenwood Celia MT , Paterson Andrew D , Linton Linda , Andrulis Irene L , Apicella Carmel , Dimitromanolakis Apostolos , Kriukov Valentina , Martin Lisa J , Salleh Ayesha , Samiltchuk Elena , Parekh Rashmi V , Southey Melissa C , John Esther M , Hopper John L , Boyd Norman F , Rommens Johanna M
Published: December 2011

Introduction

Mammographic breast density is a highly heritable (h2 > 0.6) and strong risk factor for breast cancer. We conducted a genome-wide linkage study to identify loci influencing mammographic breast density (MD).

Methods

Epidemiological data were assembled on 1,415 families from the Australia, Northern California and Ontario sites of the Breast Cancer Family Registry, and additional families recruited in Australia and Ontario. Families consisted of sister pairs with age-matched mammograms and data on factors known to influence MD. Single nucleotide polymorphism (SNP) genotyping was performed on 3,952 individuals using the Illumina Infinium 6K linkage panel.

Results

Using a variance components method, genome-wide linkage analysis was performed using quantitative traits obtained by adjusting MD measurements for known covariates. Our primary trait was formed by fitting a linear model to the square root of the percentage of the breast area that was dense (PMD), adjusting for age at mammogram, number of live births, menopausal status, weight, height, weight squared, and menopausal hormone therapy. The maximum logarithm of odds (LOD) score from the genome-wide scan was on chromosome 7p14.1-p13 (LOD = 2.69; 63.5 cM) for covariate-adjusted PMD, with a 1-LOD interval spanning 8.6 cM. A similar signal was seen for the covariate adjusted area of the breast that was dense (DA) phenotype. Simulations showed that the complete sample had adequate power to detect LOD scores of 3 or 3.5 for a locus accounting for 20% of phenotypic variance. A modest peak initially seen on chromosome 7q32.3-q34 increased in strength when only the 513 families with at least two sisters below 50 years of age were included in the analysis (LOD 3.2; 140.7 cM, 1-LOD interval spanning 9.6 cM). In a subgroup analysis, we also found a LOD score of 3.3 for DA phenotype on chromosome 12.11.22-q13.11 (60.8 cM, 1-LOD interval spanning 9.3 cM), overlapping a region identified in a previous study.

Conclusions

The suggestive peaks and the larger linkage signal seen in the subset of pedigrees with younger participants highlight regions of interest for further study to identify genes that determine MD, with the goal of understanding mammographic density and its involvement in susceptibility to breast cancer.
Role of IFN-γ in the establishment of anterior chamber-associated immune deviation (ACAID)-induced CD8+ T regulatory cells
Authors: Paunicka Kathryn , Chen Peter W , Niederkorn Jerry Y
Published: December 2011

Introduction of alloantigens into the AC induces a form of immune tolerance known as ACAID, which induces antigen-specific CD8+ Tregs, contributing to ocular immune privilege by down-regulating immune responses. Recent evidence suggests IFN-γ is needed for the suppressive function of CD8+ ACAID Tregs. This study tested the hypothesis that IFN-γ is needed for alloantigen-specific ACAID CD8+ Tregs to execute their suppressive function but is not required for the establishment of ACAID CD8+ Tregs. To address this hypothesis, ACAID was induced by injecting BALB/c spleen cells into the AC of WT C57BL/6 mice, IFN-γ−/− C57BL/6 mice, or anti-IFN-γ-treated WT C57BL/6 mice. LAT assays using C57BL/6 APCs as stimulators, CD4+ T cells from C57BL/6 mice previously immunized toward BALB/c alloantigens as effector cells, and IFN-γ-competent, IFN-γ−/−, or IFN-γR−/− CD8+ Tregs were used to evaluate the suppressive function of CD8+ ACAID Tregs in response to IFN-γ. IFN-γ−/− mice or mice treated with anti-IFN-γ antibody prior to AC injection of alloantigen failed to develop ACAID. The suppressive function of IFN-γ−/− ACAID CD8+ Tregs was restored through the administration of exogenous IFN-γ. This suppressive responsiveness toward IFN-γ was CD8+ Treg-intrinsic, as CD8+ Tregs from IFN-γR−/− mice, which were primed in the AC with alloantigens, were not able to suppress alloantigen-specific DTH responses. These results indicate that IFN-γ is not needed for the induction of CD8+ ACAID Tregs but is required for ACAID Tregs to exert the suppression of allospecific DTH responses.
ERK Signaling, But Not c-Raf, Is Required for Gonadotropin-Releasing Hormone (GnRH)-Induced Regulation of Nur77 in Pituitary Gonadotropes
Authors: Bliss Stuart P. , Navratil Amy M. , Xie Jianjun , Miller Andrew , Baccarini Manuela , Roberson Mark S.
Published: December 2011

Stimulation of pituitary gonadotropes by hypothalamic GnRH leads to the rapid expression of several immediate early genes that play key roles in orchestrating the response of the gonadotrope to hypothalamic stimuli. Elucidation of the signaling mechanisms that couple the GnRH receptor to this immediate early gene repertoire is critical for understanding the molecular basis of GnRH action. Here we identify signaling mechanisms that underlie regulation of the orphan nuclear receptor Nur77 as a GnRH-responsive immediate early gene in αT3-1 cells and mouse gonadotropes in culture. Using a variety of approaches, we show that GnRH-induced transcriptional upregulation of Nur77 in αT3-1 cells is dependent on calcium, protein kinase C (PKC), and ERK signaling. Transcriptional activity of Nur77 within the gonadotrope is regulated posttranslationally by GnRH signaling via PKC but not ERK activity. Surprisingly, neither activation of the ERK pathway nor the transcriptional response of Nur77 to GnRH requires the activity of c-Raf kinase. In corroboration of these results, Nur77 responsiveness to GnRH was maintained in gonadotropes from mice with pituitary-targeted ablation of c-Raf kinase. In contrast, gonadotropes from mice with pituitary deficiency of ERK signaling failed to up-regulate Nur77 after GnRH stimulation. These results further clarify the role of ERK and PKC signaling in regulation of the GnRH-induced immediate early gene program as well as GnRH-induced transcription-stimulating activity of Nur77 in the gonadotrope and shed new light on the complex functional organization of this signaling pathway in the pituitary gonadotrope.
A Novel Antiinflammatory Role for the Short-Chain Fatty Acids in Human Labor
Authors: Voltolini Chiara , Battersby Sharon , Etherington Sophie L. , Petraglia Felice , Norman Jane E. , Jabbour Henry N.
Published: December 2011

Human parturition is an inflammatory process that can be activated prematurely by pathological stimuli. This study investigated the expression of G protein-coupled receptors GPR43 and GPR41 receptors in human uteroplacental tissues and the role of short-chain fatty acids (SCFA) in modulating inflammatory pathways in fetal membranes. Expression of GPR43 and GPR41 was investigated in uteroplacental tissues collected from women delivering at term or preterm after ethical approval and patient informed consent. The effect of SCFA on expression of inflammatory genes was assessed in amnion explants after culture with a mimetic of infection (lipopolysaccharide, LPS). Sodium propionate effect on LPS-induced neutrophil chemotaxis was evaluated by transwell assay. GPR43 and GPR41 mRNA expression was higher in myometrium and fetal membranes collected from women after the onset of labor. GPR43 protein expression localized to immune cells and vascular endothelium in the myometrium and epithelium of fetal membranes. Treatment with LPS significantly increased mRNA expression of GPR43 and inflammatory genes. Cotreatment with LPS and sodium propionate decreased LPS-induced expression of inflammatory genes including IL-6, IL-8, cyclooxygenase-2, IL-1α, intercellular adhesion molecule-1, and platelet endothelial cell adhesion molecule-1 but not IL-1β or lymphocyte function-associated antigen-1. Sodium propionate reduced LPS-induced neutrophil chemotaxis and protein secretion of the neutrophil chemoattractant IL-8. Finally, fetal membrane expression of GPR43 was significantly higher in women delivering preterm with evidence of infection. GPR43-SCFA interactions may represent novel pathways that regulate inflammatory processes involved in human labor. Suppression of inflammatory pathways by SCFA may be therapeutically beneficial for pregnant women at risk of pathogen-induced preterm delivery.