bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term Cognitive Decline in Older Subjects Was Not Attributable to Noncardiac Surgery or Major Illness
Authors: Avidan Michael S. , Searleman Adam C. , Storandt Martha , Barnett Kara , Vannucci Andrea , Saager Leif , Xiong Chengjie , Grant Elizabeth A. , Kaiser Dagmar , Morris John C. , Evers Alex S.
Published: October 2009

Background

Persistent postoperative cognitive decline is thought to be a public health problem, but its severity may have been overestimated because of limitations in statistical methodology. This study assessed whether long-term cognitive decline occurred after surgery or illness by using an innovative approach and including participants with early Alzheimer disease to overcome some limitations.

Methods

In this retrospective cohort study, three groups were identified from participants tested annually at the Washington University Alzheimer's Disease Research Center in St. Louis, Missouri: those with noncardiac surgery, illness, or neither. This enabled long-term tracking of cognitive function before and after surgery and illness. The effect of surgery and illness on longitudinal cognitive course was analyzed using a general linear mixed effects model. For participants without initial dementia, time to dementia onset was analyzed using sequential Cox proportional hazards regression.

Results

Of the 575 participants, 214 were nondemented and 361 had very mild or mild dementia at enrollment. Cognitive trajectories did not differ among the three groups (surgery, illness, control), although demented participants declined more markedly than nondemented participants. Of the initially nondemented participants, 23% progressed to a clinical dementia rating greater than zero, but this was not more common after surgery or illness.

Conclusions

The study did not detect long-term cognitive decline independently attributable to surgery or illness, nor were these events associated with accelerated progression to dementia. The decision to proceed with surgery in elderly people, including those with early Alzheimer disease, may be made without factoring in the specter of persistent cognitive deterioration.
Moist lower montane rainforest classification: a case study from Bwindi Impenetrable National Park, Uganda
Authors: Chaigneau Tomas , Ahrends Antje , Argent Jennifer , Riddhiraska Naboon , Marchant Rob
Published: October 2009

Moist lower montane vegetation has rarely been classified beyond broad zonational belts over large altitudinal ranges due to highly diverse species composition and structure. This study shows it is possible to further classify such forest types within Bwindi‐Impenetrable National Park (BINP), and that these assemblages can be explained by a combination of environmental conditions and past management. Botanical and environmental data were collected along some 4000 m of linear transects from the area surrounding Mubwindi Swamp, BINP. Ordination using Nonmetric Multidimensional Scaling (NMDS) and classification using Two‐way Indicator Species Analysis (TWINSPAN) successfully identified four different species assemblages. These forest types were then named on the basis of the ecological characteristics of the species within the group, and the environmental conditions influencing the distribution and past disturbance of the forest. The techniques used were in agreement for three out of the four forest types identified. Analysis using an environmental overlay showed a significant association between forest type and altitude. The results of this study indicate that a regional classification of forest types within moist lower montane forest belt using only tree species is possible, and that the forest types identified can be explained by environmental conditions and past management.
Review article: the current management of acute liver failure
Authors: CRAIG D. G. N. , LEE A. , HAYES P. C. , SIMPSON K. J.
Published: October 2009

Aliment Pharmacol Ther 31, 345–358

Background  Acute liver failure is a devastating clinical syndrome with a persistently high mortality rate despite critical care advances. Orthotopic liver transplantation (OLT) is a life‐saving treatment in selected cases, but effective use of this limited resource requires accurate prognostication because of surgical risks and the requirement for subsequent life‐long immunosuppression.

Aim  To review the aetiology of acute liver failure, discuss the evidence behind critical care management strategies and examine potential treatment alternatives to OLT.

Methods  Literature review using Ovid, PubMed and recent conference abstracts.

Results  Paracetamol remains the most common aetiology of acute liver failure in developed countries, whereas acute viral aetiologies predominate elsewhere. Cerebral oedema is a major cause of death, and its prevention and prompt recognition are vital components of critical care support, which strives to provide multiorgan support and ‘buy time’ to permit either organ regeneration or psychological and physical assessment prior to acquisition of a donor organ. Artificial liver support systems do not improve mortality in acute liver failure, whilst most other interventions have limited evidence bases to support their use.

Conclusion  Acute liver failure remains a truly challenging condition to manage, and requires early recognition and transfer of patients to specialist centres providing intensive, multidisciplinary input and, in some cases, OLT.
Increased vascular permeability precedes cellular inflammation as asthma control deteriorates
Authors: Khor Y. H. , Teoh A. K. Y. , Lam S. M. , Mo D. C. Q. , Weston S. , Reid D. W. , Walters E. H.
Published: October 2009

Background
Airway microcirculation is abnormal in asthma but the role of vascular changes in asthma deteriorations remains poorly defined. We prospectively assessed the vascular changes accompanying worsening of asthma control by using an inhaled corticosteroid (ICS) dose‐reduction model.

Objectives
To evaluate airway vascularity, vascular permeability and expression of vascular endothelial growth factor (VEGF) in early asthma deterioration induced by ICS back‐titration.

Methods
Twenty mild‐to‐moderate persistent symptomatic asthmatics on low‐to‐moderate ICS were recruited and treated with 4 weeks of high‐dose fluticasone propionate (1000 μg/day) to achieve symptom control. This was followed by dose reduction to half of the pre‐study doses for 4–8 weeks until the symptoms began to return. Endobronchial biopsy and bronchoalveolar lavage (BAL) samples were obtained after both treatment periods.

Results
Vascularity as measured by the number and size of blood vessels, as well as VEGF expression did not change following ICS reduction. Even on high‐dose ICS, perivascular albumin staining and BAL microalbumin levels in asthmatic subjects, as markers of permeability, were elevated when compared with normal subjects and both further increased significantly after ICS reduction. There was a significant association between changes in vascular leakiness and clinical deterioration. Increases in airway albumin correlated with previously reported increases in airway wall infiltration with T lymphocytes.

Conclusions
Our results suggest that airway vascular leakage is a major pathophysiologic feature of early asthma deterioration, occurring before recrudescence of cellular inflammation.
Midostaurin (PKC412) inhibits immunoglobulin E‐dependent activation and mediator release in human blood basophils and mast cells
Authors: Krauth M.‐T. , Mirkina I. , Herrmann H. , Baumgartner C. , Kneidinger M. , Valent P.
Published: October 2009

Background
KIT tyrosine kinase inhibitors (TKI), such as nilotinib or midostaurin (PKC412), are increasingly used in clinical trials to counteract neoplastic cell growth in patients with aggressive mast cell (MC) disorders. However, these patients suffer not only from MC infiltration and consecutive organ damage but also from MC mediator‐related symptoms.

Methods
We examined the effects of three KIT TKI, imatinib, nilotinib, and midostaurin, on IgE‐dependent mediator release in normal human blood basophils and cultured cord blood cell‐derived MC, and on spontaneous histamine secretion in the MC leukaemia cell line HMC‐1 and the basophil cell line KU812.

Results
The multi‐kinase inhibitor midostaurin that interacts with KIT and protein kinase C was found to counteract anti‐IgE‐induced mediator release in blood basophils and cultured cord blood cell‐derived MC in all samples examined. By contrast, no effects of imatinib or nilotinib on histamine secretion in basophils or MC were found. The effects of midostaurin on histamine release were dose‐dependent and occurred at pharmacologic concentrations (IC50 10‐100 nm). Midostaurin was also found to inhibit the IgE‐dependent up‐regulation of CD63 on cultured cord blood cell‐derived human MC, but did not inhibit IgE‐dependent up‐regulation of CD63 or CD203c in human blood basophils.

Conclusion
Midostaurin may be a beneficial drug in aggressive systemic mastocytosis not only because of its growth‐inhibitory effects but also because of its additional effects on activation and mediator release in MC and basophils.
The interaction of glutathione S‐transferase M1‐null variants with tobacco smoke exposure and the development of childhood asthma
Authors: Rogers A. J. , Brasch‐Andersen C. , Ionita‐Laza I. , Murphy A. , Sharma S. , Klanderman B. J. , Raby B. A.
Published: October 2009

Background
The glutathione S‐transferase M1 (GSTM1)‐null variant is a common copy number variant associated with adverse pulmonary outcomes, including asthma and airflow obstruction, with evidence of important gene‐by‐environment interactions with exposures to oxidative stress.

Objective
To explore the joint interactive effects of GSTM1 copy number and tobacco smoke exposure on the development of asthma and asthma‐related phenotypes in a family‐based cohort of childhood asthmatics.

Methods
We performed quantitative PCR‐based genotyping for GSTM1 copy number in children of self‐reported white ancestry with mild to moderate asthma in the Childhood Asthma Management Program. Questionnaire data regarding intrauterine (IUS) and post‐natal, longitudinal smoke exposure were available. We performed both family‐based and population‐based tests of association for the interaction between GSTM1 copy number and tobacco smoke exposure with asthma and asthma‐related phenotypes.

Results
Associations of GSTM1‐null variants with asthma (P=0.03), younger age of asthma symptom onset (P=0.03), and greater airflow obstruction (reduced forced expiratory volume in 1 s / forced vital capacity, P=0.01) were observed among the 50 children (10% of the cohort) with exposure to IUS. In contrast, no associations were observed between GSTM1‐null variants and asthma‐related phenotypes among children without IUS exposure. Presence of at least one copy of GSTM1 conferred protection.

Conclusion
These findings support an important gene‐by‐environment interaction between two common factors: increased risk of asthma and asthma‐related phenotypes conferred by GSTM1‐null homozygosity in children is restricted to those with a history of IUS exposure.
Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process
Authors: Negishi Masamitsu , Chiba Tetsuhiro , Saraya Atsunori , Miyagi Satoru , Iwama Atsushi
Published: October 2009

Faithful control of cell cycle checkpoint and DNA repair contributes to prevent the cells from chromosomal instability and tumorigenesis. Dnmt1‐associated protein 1 (Dmap1), a component of the NuA4 histone acetyltransferase complex, was originally identified as an interacting molecule with DNMT1 which co‐localizes with PCNA at DNA replication foci. However, its role in cellular functions remains largely unknown. Here we show that Dmap1 knockdown in mouse embryonic fibroblasts (MEFs) lead to spontaneous double‐strand breaks (DSBs), resulting in growth arrest because of p53‐dependent cell cycle checkpoint activation. Deletion of both Dmap1 and p53 in MEFs synergized towards enhanced generation of DSBs, chromosomal abnormalities and tumor development in mice. Notably, we found that, on DNA damage, Dmap1 was recruited to the damaged sites to form complexes with γ‐H2AX and replication factors, including Pcna. Depletion of Dmap1 in MEFs abrogated the stable accumulation of Pcna at the DNA damaged sites. Furthermore, the re‐introduction of Dmap1 mutants with a reduced capacity to bind Pcna failed to ameliorate the impaired DNA repair in Dmap1‐depleted cells. These findings indicate that Dmap1 is required to involve Pcna in DNA repair. Together, Dmap1 plays a crucial role in DNA repair, and is indispensable for the maintenance of chromosomal integrity.
Auxiliary role for d‐alanylated wall teichoic acid in Toll‐like receptor 2‐mediated survival of Staphylococcus aureus in macrophages
Authors: Shiratsuchi Akiko , Shimizu Kaori , Watanabe Ikuko , Hashimoto Yumi , Kurokawa Kenji , Razanajatovo Iony M. , Park Keun H. , Park Hae K. , Lee Bok L. , Sekimizu Kazuhisa , Nakanishi Yoshinobu
Published: October 2009

We previously reported that Staphylococcus aureus avoids killing within macrophages by exploiting the action of Toll‐like receptor 2 (TLR2), which leads to the c‐Jun N‐terminal kinase (JNK)‐mediated inhibition of superoxide production. To search for bacterial components responsible for this event, a series of S. aureus mutants, in which the synthesis of the cell wall was interrupted, were screened for the level of JNK activation in macrophages. In addition to a mutant lacking the lipoproteins that have been suggested to act as a TLR2 ligand, two mutant strains were found to activate the phosphorylation of JNK to a lesser extent than the parental strain, and this defect was recovered by acquisition of the corresponding wild‐type genes. Macrophages that had phagocytosed the mutant strains produced more superoxide than those engulfing the parental strain, and the mutant bacteria were more efficiently killed in macrophages than the parent. The genes mutated, dltA and tagO, encoded proteins involved in the synthesis of d‐alanylated wall teichoic acid. Unlike a cell wall fraction rich in lipoproteins, d‐alanine‐bound wall teichoic acid purified from the parent strain by itself did not activate JNK phosphorylation in macrophages. These results suggest that the d‐alanylated wall teichoic acid of S. aureus modulates the cell wall milieu for lipoproteins so that they effectively serve as a ligand for TLR2.
Eosinophils infiltrate thyroids, but have no apparent role in induction or resolution of experimental autoimmune thyroiditis in interferon‐γ−/− mice
Authors: Fang Yujiang , Chen Kemin , Jackson Daniel A. , Sharp Gordon C. , Braley‐Mullen Helen
Published: October 2009

Granulomatous experimental autoimmune thyroiditis (G‐EAT) is induced by mouse thyroglobulin (MTg)‐sensitized splenocytes activated with MTg and interleukin (IL)‐12. Our previous studies showed that, when used as donors and recipients, interferon (IFN)‐γ−/− and wild‐type (WT) DBA/1 mice both develop severe G‐EAT. Thyroid lesions in IFN‐γ−/− mice have many eosinophils and few neutrophils, while those in WT mice have extensive neutrophil infiltration and few eosinophils. Thyroid lesions in IFN‐γ−/− mice consistently resolve by day 40–50, whereas those in WT mice have ongoing inflammation and fibrosis persisting for more than 60 days. To determine if the extensive infiltration of eosinophils in thyroids of IFN‐γ−/− mice contributes to thyroid damage and/or early resolution of G‐EAT, anti‐IL‐5 was used to inhibit migration of eosinophils to thyroids. G‐EAT severity was compared at day 20 and day 40–50 in IFN‐γ−/− recipients given anti‐IL‐5 or control immunoglobulin G (IgG). Thyroids of anti‐IL‐5‐treated IFN‐γ−/− mice had few eosinophils and more neutrophils at day 20, but G‐EAT severity scores were comparable to those of control IgG‐treated mice at both day 20 and day 40–50. Expression of chemokine (C‐X‐C motif) ligand 1 (CXCL1) mRNA was higher and that of chemokine (C‐C motif) ligand 11 (CCL11) mRNA was lower in thyroids of anti‐IL‐5‐treated IFN‐γ−/− mice. IL‐5 neutralization did not influence mRNA expression of most cytokines in IFN‐γ−/− mice. Thus, inhibiting eosinophil migration to thyroids did not affect G‐EAT severity or resolution in IFN‐γ−/− mice, suggesting that eosinophil infiltration of thyroids occurs as a consequence of IFN‐γ deficiency, but these cells have no apparent pathogenic role in G‐EAT.
Maternal investment and size‐specific reproductive output in carcharhinid sharks
Authors: Hussey Nigel E. , Wintner Sabine P. , Dudley Sheldon F. J. , Cliff Geremy , Cocks David T. , Aaron MacNeil M.
Published: October 2009

1. Life‐history theory predicts that organisms will provide an optimal level of parental investment for offspring survival balanced against the effects on their own survival and future reproductive potential.

2. Optimal resource allocation models also predict an increase in reproductive output with age as expected future reproductive effort decreases. To date, maternal investment in sharks has received limited attention.

3. We found that neonatal dusky sharks (Carcharhinus obscurus) are not independent from maternal resource allocation at the point of parturition but instead are provisioned with energy reserves in the form of an enlarged liver that constitutes approximately 20% of total body mass.

4. Analysis of long‐term archived data sets showed that a large proportion of this enlarged liver is utilized during the first weeks or months of life suggesting that the reported weight loss of newborn sharks signifies a natural orientation process and is not necessarily related to prey abundance and/or indicative of high mortality rates.

5. Interrogation of near‐term pup mass in two carcharhinids, the dusky and spinner shark (Carcharhinus brevipinna), further revealed an increase in reproductive output with maternal size, with evidence for a moderate decline in the largest mothers.

6. For the dusky shark, there was a trade‐off between increasing litter size and near‐term pup mass in support of optimal offspring size theory.

7. For both the dusky and spinner shark, there was a linear increase in near‐term pup mass with month, which may indicate variable parturition strategies and/or that carcharhinids are able to adjust the length of the gestation period.

8. The identification of optimal size‐specific reproductive output has direct implications for improving the reproductive potential of exploited shark populations and for structuring future management strategies.
Interaction of functional FCER2 promoter polymorphism and phenotype‐associated haplotypes
Authors: Potaczek D. P. , Wang Q.‐H. , Sanak M. , Tokura T. , Matsuda H. , Dziedzina S. , Nakano N. , Hara M. , Ogawa H. , Szczeklik A. , Okumura K. , Nishiyama C.
Published: October 2009

Low‐affinity IgE receptor gene (FCER2) rs3760687 polymorphism was found to be associated with differential binding affinity of transcription factors Sp1 and Sp3 leading to altered transcriptional activity. Haplotypic interaction of functional FCER2 polymorphisms (rs28364072, rs2228137 and rs3760687) might potentially provide a background for genotype–phenotype associations previously observed for some rather non‐functional FCER2 variants.
Molecular variation at the HLA‐A, B, C, DRB1, DQA1, and DQB1 loci in full heritage American Indians in Arizona: private haplotypes and their evolution
Authors: Williams R. , Chen Y.‐F. , Endres R. , Middleton D. , Trucco M. , Williams J. Dunn , Knowler W.
Published: October 2009

A sample of 492 full heritage, unrelated residents of the Gila River Indian Community (GRIC) of Arizona were characterized for their high‐resolution DNA alleles at the HLA‐A, B, C, DRB1, DQA1, and DQB1 loci. Only five allelic categories are found at HLA‐A, 10 at HLA‐B, 8 at HLA‐C and HLA‐DR, and 4 at DQA1 and DQB1. There is little evidence for population structure at the 6 loci. Two ‘private’ alleles, B*5102 and B*4005, which are found nearly exclusively in American Indian populations in the desert southwest and northern Mexico, are likely new mutations after the first inhabitation of the area, the evolution of which are reflected in the contemporary distribution of their respective haplotypes. DRB1*1402 has the highest reported frequency of any specificity at the DRB1 locus, 0.7461, and serves as a sensitive probe for locating related east Asian populations. The haplotypes in this population also exhibit a highly restricted distribution and strong genetic disequilibria, which has important implications for matching solid organ and bone marrow allografts. It is shown that, when one considers HLA‐A‐B‐DRB1 homozygotes as allograft donors for all full heritage members of the GRIC, 50% of the community would find a non‐mismatched organ within the homozygotes for the six most common haplotypes. This raises questions about transplantation policy and whether, in the presence of high‐frequency private alleles and a restricted number of haplotypes, the full heritage American Indian community of the desert southwest should act as its own pool of donors for its affected members.
Intra‐renal adrenal adenoma: A compelling addition to the differential diagnosis of renal mass
Authors: Linder Brian , Hong Yoon , Jarrett Thomas
Published: October 2009

Abstract:  We report a case of an adrenal rest arising in the kidney of a 37‐year‐old male. An incidental 4.5 cm right upper pole mass with a minimal amount of fat was discovered on computed tomography scan. Laparoscopic renal exploration and biopsy revealed angiomyolipoma on frozen section. However, final pathological analysis of the partial nephrectomy specimen revealed intra‐renal adrenal adenoma. The diagnosis was confirmed by immunohistochemistries and transmission electron microscopy. We review the reported literature on intra‐renal adrenal adenoma and highlight the aspects that raise the index of suspicion for this entity on the differential diagnosis of renal masses.
Transrectal high‐intensity focused ultrasound for the treatment of localized prostate cancer: Eight‐year experience
Authors: Uchida Toyoaki , Shoji Sunao , Nakano Mayura , Hongo Satoko , Nitta Masahiro , Murota Akiko , Nagata Yoshihiro
Published: October 2009

Objective:  To report on the long‐term results of high‐intensity focused ultrasound in the treatment of localized prostate cancer.

Methods:  A total of 517 men with stage T1c–T3N0M0 prostate cancer treated with Sonablate devices (Focus Surgery, Indianapolis, IN, USA) between January 1999 and December 2007 were included in the study. Biochemical failure was defined according to the Phoenix definition (prostate‐specific antigen nadir + 2 ng/mL).

Results:  The median follow‐up period for all patients was 24.0 months (range, 2 to 88). The biochemical disease‐free rate (BDFR) in all patients at 5 years was 72%. The BDFR in patients with stage T1c, T2a, T2b, T2c and T3 groups at 5 years were 74%, 79%, 72%, 24% and 33%, respectively (P < 0.0001). BDFR in patients in the low, intermediate and high‐risk groups at 5 years were 84%, 64% and 45%, respectively (P < 0.0001). The BDFR in patients treated with or without neoadjuvant hormonal therapy at 7 years were 73% and 53% (P < 0.0001), respectively. In multivariate analysis, pretreatment prostate‐specific antigen levels (hazard ratio 1.060; P < 0.0001; 95% confidence interval 1.040–1.080), neoadjuvant hormonal therapy (hazard ratio 2.252; P < 0.0001; 95% confidence interval 1.530–3.315) and stage (P = 0.0189) were demonstrated to be statistically significant variables. Postoperative erectile dysfunction was noted in 33 out of 114 (28.9%) patients who were preoperatively potent.

Conclusions:  High‐intensity focused ultrasound therapy appears to be minimally invasive, efficacious and safe for patients with localized prostate cancer, particularly those with low‐ and intermediate‐risk cancer.
Brain metastases from testicular germ cell tumors: A retrospective analysis
Authors: Nonomura Norio , Nagahara Akira , Oka Daizo , Mukai Masatoshi , Nakai Yasutomo , Nakayama Masashi , Nishimura Kazuo , Kakimoto Kennichi , Nakamura Terukazu , Usami Michiyuki , Okuyama Akihiko , Miki Tsuneharu
Published: October 2009

Objectives:  To review our series of testicular germ cell tumors with brain metastases and to establish an optimal treatment strategy for them.

Methods:  Twenty‐seven cases of testicular germ cell tumors from three institutions were retrospectively reviewed.

Results:  Twenty‐six were non‐seminomatous tumors and only one was a seminoma. Based on the International Germ Cell Consensus Classification, two cases were classified as good prognosis, seven as intermediate prognosis and 18 as poor prognosis. Chemotherapy was carried out in all patients. Additionally, whole‐brain radiotherapy was performed in 10 cases, stereotactic radiosurgery in six, whole‐brain radiotherapy combined with stereotactic radiosurgery in three and complete surgical resection in five. Three patients received chemotherapy only. Cancer‐specific 5‐ and 10‐year survival rates were both 35.9%. The prognosis of those with brain metastases at the time of diagnosis tended to be better than those developing brain metastases during treatment. Those with a single brain metastasis showed significantly better survival than those with multiple brain metastases. No other significant prognostic factor was found at multivariate analysis.

Conclusion:  Testicular germ cell tumors with brain metastases can be managed with the combination of whole‐brain radiotherapy, stereotactic radiotherapy, and/or surgical resection in combination with chemotherapy.
An examination of amphibian sensitivity to environmental contaminants: are amphibians poor canaries?
Authors: Kerby Jacob L. , Richards‐Hrdlicka Kathryn L. , Storfer Andrew , Skelly David K.
Published: October 2009

Nearly two decades ago, the global biodiversity crisis was catapulted to the front pages of newspapers with the recognition of worldwide amphibian declines. Amphibians earned their appellation, ‘canaries in a coal mine’, because of apparent high sensitivity to human‐mediated environmental change. The most frequently cited causes for high susceptibility include permeable skin, a dual aquatic‐terrestrial life cycle and a relatively rudimentary immune system. While some researchers have questioned the basis for the canary assertion, there has been no systematic evaluation of amphibian sensitivity to environmental challenges relative to other taxa. Here, we apply a database representing thousands of toxicity tests to compare the responses of amphibians relative to that of other taxonomic groups. The use of standardized methods combined with large numbers of identical challenges enables a particularly powerful test of relative effect size. Overall, we found that amphibians only exhibit moderate relative responses to water‐borne toxins. Our findings imply that, as far as chemical contaminants are concerned, amphibians are not particularly sensitive and might more aptly be described as ‘miners in a coal mine’. To the extent that amphibian declines have been mediated by chemical contaminants, our findings suggest that population losses and extinctions may have already occurred in a variety of taxa much more sensitive than amphibians.

Ecology Letters (2010) 13: 60–67
Obesity and low‐grade inflammation: a paediatric perspective
Authors: Tam C. S. , Clément K. , Baur L. A. , Tordjman J.
Published: October 2009

Childhood obesity is a major public health problem. Low‐grade inflammation, a hallmark characterizing adult obesity, may be a pivotal mechanism linking obesity to its numerous systemic complications, with adipose tissue depots secreting and producing inflammatory mediators and visceral fat displaying an increased inflammatory profile. While knowledge is relatively scarce regarding the importance of the adipose tissue inflammation process in children, identifying its contribution in childhood obesity and the associated influences of age, sex, weight status, growth, and adipose depot phenotypes are crucial for understanding physiopathology and implementing early intervention strategies. We review the latest research linking obesity and inflammation in childhood focusing on serum inflammatory markers and the effectiveness of lifestyle interventions in improving systemic inflammation. Generally, there are significant correlations between body mass index and increased c‐reactive protein and decreased adiponectin levels in children; these levels tend to be improved in interventions resulting in ∼5% weight loss, regardless of the type or length of intervention. There is a need for further research measuring other inflammatory mediators (e.g. tumour necrosis factor (TNF)‐α, IL‐6, IL‐8) and histological studies examining immune cell infiltration in adipose tissue depots in obese children.
Construing Collective Concerns
Authors: Sauna Lawrence J. , Chang Edward C. , Parks Craig D. , Kennedy Lindsay A.
Published: October 2009

The following article has been retracted by the Editor and publishers of Psychological Science at the request of the lead author, Lawrence J. Sanna:

Sanna, L. J., Chang, E. C., Parks, C. D., & Kennedy, L. A. (2009). Construing collective concerns: Increasing cooperation by broadening construals in social dilemmas. Psychological Science, 20, 1319–1321. doi:10.1111/j.1467-9280.2009.02458.x

In a letter to the Editor (Eric Eich), Dr. Sanna wrote:

The data reported in this article are invalid and should not be considered part of the scientific literature. The responsibility for this problem rests solely with the first author, Lawrence J. Sanna. Coauthors Edward C. Chang, Craig D. Parks, and Lindsay A. Kennedy are in no way responsible for this problem.

In response, the Editor noted that Psychological Science follows the retraction guidelines developed by the Committee on Publication Ethics (COPE). Dr. Sanna was urged to follow these guidelines carefully in drafting a retraction notice, particularly with respect to stating the reasons for the retraction, to distinguish misconduct from honest error.

To assist Dr. Sanna with this task, the Editor provided Dr. Sanna with a copy of the COPE guidelines ( http://publicationethics.org/resources/guidelines ) and a link to a retraction notice that was published in Psychological Science last year. This notice was considered a "model" by Retraction Watch, and Dr. Sanna was advised that, in keeping with this notice, he "must specify clearly the reasons for the retraction in such language that all of your coauthors agree to it."

While awaiting Dr. Sanna's reply, the Editor sought to contact Dr. Sanna's three coauthors. Although one coauthor was aware of Dr. Sanna's request to retract the 2009 Psychological Science article, the other two were not. All of the coauthors have agreed to retraction of the article, and each has received a copy of this notice.

Dr. Sanna replied by noting with regret that "research errors" have made it necessary for him to request retraction. The letter concluded with the following: "At the direction of legal counsel, I am unable to say anything further than that contained in my previous letter at this time."

Because it is unclear when, if ever, details on these research errors will be forthcoming, the Editor owes it to the journal's readership to retract the article now, even though this notice does not reflect COPE guidelines or journal policy.
LABOUR MARKET EFFECTS OF FLEXICURITY FROM A REGIONAL PERSPECTIVE
Authors: DE GROOT AYOLT J. , ELHORST J. PAUL
Published: October 2009

One of the main questions for politicians is how to introduce more flexibility in the labour market while still providing employees with ample social security. The concept of flexicurity has sprung to attention through its success in Denmark. This paper explores whether the Danish model can also be successful in other European countries. A simultaneous equations model is constructed and estimated using regional data, which is an extension of the Blanchard‐Katz model developed in 1992. It is found that a European country such as the Netherlands can permanently lower its unemployment rate and increase its participation and employment growth rates at the regional level, by 1.47, 2.08 and 1.05 percentage points respectively, if it copies the Danish model.
Analysis of the GIGYF2 gene in familial and sporadic Parkinson disease in the Spanish population
Authors: Samaranch L. , Lorenzo E. , Pastor M. A. , Riverol M. , Luquin M. R. , Rodríguez‐Oroz M. C. , Obeso J. A. , Pastor P.
Published: October 2009

Background and purpose:  Linkage analysis in familial Parkinson’s disease (PD) identified a locus in 2q36‐37 (PARK11). Sequencing of GIGYF2 identified several variants only present amongst PD individuals.

Methods:  We analyzed the presence of disease‐associated GIGYF2 variants in familial and sporadic PD from Spanish origin by sequencing of 147 PD individuals. The entire GIGYF2 coding sequence was analyzed in 122 familial PD individuals and exons 2, 4, 8–11, 14 and 25–26 were sequenced in 25 sporadic PD to identify disease‐associated variants.

Results:  We found no variants associated with PD and failed to identify any of previously PD‐associated GIGYF2 variants in our sample. We identified four novel missense changes in GIGYF2. p.Met48Ile was found in a PD individual who also was a carrier of two PARKIN mutations. p.Q1244_Q1247del variant was present only in one PD individual but not found in 70 controls. However, its location in the highly polymorphic GIGYF2 glutamine/proline‐rich region does not support a role in PD. Two variants (p.P1238insAGC and p.Q1249del) were present both in PD subjects and in controls. Additionally, the p.L1230_Q1237del variant, which was previously considered as a PD‐associated change, was found in one control.

Conclusion:  Our findings suggest that GIGYF2 mutations are not a frequent cause of PD in the Spanish population, since we found no clearly segregating variants. We propose further analyses in PD subjects from different populations to define the role of GIGYF2. A clear pathogenic mutation in other gene at 2q36‐37 in the PARK11‐linked PD families would definitively disprove GIGYF2 as the responsible gene.
Disease‐toxicant screen reveals a neuroprotective interaction between Huntington’s disease and manganese exposure
Authors: Williams B. Blairanne , Li Daphne , Wegrzynowicz Michal , Vadodaria Bhavin K. , Anderson Joel G. , Kwakye Gunnar F. , Aschner Michael , Erikson Keith M. , Bowman Aaron B.
Published: October 2009

J. Neurochem. (2010) 112, 227–237.

Recognizing the similarities between Huntington’s disease (HD) pathophysiology and the neurotoxicology of various metals, we hypothesized that they may exhibit disease‐toxicant interactions revealing cellular pathways underlying neurodegeneration. Here, we utilize metals and the STHdh mouse striatal cell line model of HD to perform a gene–environment interaction screen. We report that striatal cells expressing mutant Huntingtin exhibit elevated sensitivity to cadmium toxicity and resistance to manganese toxicity. This neuroprotective gene–environment interaction with manganese is highly specific, as it does not occur with iron, copper, zinc, cobalt, cadmium, lead, or nickel ions. Analysis of the Akt cell stress signaling pathway showed diminished activation with manganese exposure and elevated activation after cadmium exposure in the mutant cells. Direct examination of intracellular manganese levels found that mutant cells have a significant impairment in manganese accumulation. Furthermore, YAC128Q mice, a HD model, showed decreased total striatal manganese levels following manganese exposure relative to wild‐type mice. Thus, this disease‐toxicant interaction screen has revealed that expression of mutant Huntingtin results in heightened sensitivity to cadmium neurotoxicity and a selective impairment of manganese accumulation.
ACh receptors link two signaling pathways to neuroprotection against glutamate‐induced excitotoxicity in isolated RGCs
Authors: Asomugha Chinwe O. , Linn David M. , Linn Cindy L.
Published: October 2009

J. Neurochem. (2010) 112, 214–226.

Previous studies have reported that activation of nicotinic acetylcholine (ACh) receptors (nAChRs) on cultured pig retinal ganglion cells (RGCs) has a neuroprotective effect against glutamate‐induced excitotoxicity. However, the mechanism linking nAChRs to neuroprotection is unknown. Here, we tested the hypothesis that signaling cascades involving p38 mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K) → Akt are involved in linking activation of nAChRs to neuroprotection in isolated pig RGCs. In ELISA studies, regulation of phosphorylated p38 MAPK and Akt were analyzed after inducing excitotoxicity or neuroprotection in the presence and absence of specific inhibitors for p38 MAPK and PI3K. ELISA results demonstrated that ACh significantly increased phosphorylated Akt and decreased p38 MAPK. Glutamate increased phosphorylated p38 MAPK but had no significant effect on phosphorylated Akt. Other ELISA studies using p38 MAPK and PI3K inhibitors also supported the hypothesis that ACh up‐regulated Bcl‐2 levels downstream from PI3K and Akt, whereas glutamate down‐regulated Bcl‐2 levels downstream from p38 MAPK. RGC survival was subsequently assessed by culturing RGCs in conditions to induce excitotoxicity or neuroprotection in the presence or absence of specific inhibitors of p38 MAPK or PI3K. The p38 MAPK inhibitor significantly decreased the number of RGCs that died by glutamate‐induced excitotoxicity but had no effect on the number of cells that survived because of ACh‐induced neuroprotection. PI3K inhibitors significantly decreased cell survival caused by ACh‐induced neuroprotection but had no effect on cell death caused by glutamate‐induced excitotoxicity. These results demonstrate that glutamate mediates excitotoxicity through the p38 MAPK signaling pathway and that ACh provides neuroprotection by stimulating the PI3K → Akt → Bcl‐2 signaling pathway and inhibiting the p38 MAPK → Bcl‐2 pathway.
Perception of risk of adverse drug reactions: a 3‐year follow‐up of a cohort of medical students
Authors: Durrieu Geneviève , Hurault C. , Damase‐Michel C. , Montastruc J.L.
Published: October 2009

Previous studies have pointed out the question of effective training and information to health professionals on pharmacovigilance. The lack of training is known to induce inadequate use of drugs and noncompliance of patients. Pharmacology teaching is performed in the third year of medical studies at the Toulouse Faculty of Medicine. The aim of the study was to investigate the perception of risk of adverse drug reactions (ADRs) by medical students at the end of the one year pharmacology course and two years later, after clinical training period. Sixty‐seven students were interviewed in May 2005 and in October 2007. Visual analogue scales were used to define a score of perceived risk of ADRs associated with each drug class (ranking from 0 to 10) before and after pharmacology training. The drug classes evaluated were antibiotics, anticoagulants, antidepressants, aspirin, contraceptive pill, corticosteroids, drugs for arterial hypertension, drugs for diabetes (other than insulin), hypnotics, hypocholesterolaemic drugs, nonsteroidal anti‐inflammatory drugs (NSAIDs), postmenopausal hormone replacement therapy and tranquilisers. After pharmacology courses (May 2005), antidepressants were ranked as the most dangerous drugs by medical students [median score (25th–75th centiles): 7.7 (6.3–8.6)], followed by anticoagulants [7.6 (6.6–8.4)] and hypnotics [7.4 (6.1–8.1)]. Contraceptive pills was listed in the last position [median score [4.7 (2.2–6.7)]. Two years later (October 2007), anticoagulants moved into the first position [8.3 (7.3–9.2)], followed by NSAIDs [6.9 (5.0–8.4)] and aspirin [6.8 (5.8–8.4)]. Contraceptive pills remained in the last position. No change was observed for NSAIDs and aspirin, still ranked as dangerous drugs by medical students after clinical training. Values of perceived risk were significantly increased for anticoagulant (+9.2%, P < 0.01) and hypoglycemiant drugs (+27.7%, P < 0.0001). The perceived risk significantly decreased for hypocholesterolaemic (−14.3%, P < 0.0001) and antidepressant drugs (−19.5%, P < 0.0001), but not for hypnotics. The study shows that the perception of risk of ADRs by medical students was modified after clinical training. They were still aware of potentially serious ADRs associated with anticoagulants, aspirin or NSAIDs, but they remained less cautious for drugs such as antidepressants. Additional pharmacology training at the end of medical studies will be useful.
Single Nucleotide Polymorphisms of the Serotonin Transporter Gene in Migraine – An Association Study
Authors: Bayerer Bettina , Engelbergs Jörg , Savidou Irini , Boes Tanja , Küper Michael , Schorn Christoph F. , Wissmann Andreas , Knop Dietmar , Diener Hans C. , Limmroth Volker
Published: October 2009

We report a case–control study with 251 unrelated migraine patients and 192 unrelated healthy controls to evaluate an association between the polymorphisms of the 5‐HT transporter (5‐HTT) gene rs2066713 and rs1979572 and different migraine phenotypes. We found a genetic association for the A allele of rs1979572 for migraine with aura (MA) especially in women as well as a significant lower prevalence for MA for carrier of the A allele of rs2066713 in women.

These findings support previous results suggesting that the 5‐HTT gene is involved in the polygenic etiology of MA. These data further suggest that women are more likely to be clinically affected by mutations in the 5‐HTT gene than men.
Significance of quantitative measurement of heparin‐induced platelet antibodies
Authors: Javela Kaija , Kekomäki Riitta , Koskinen Sinikka
Published: October 2009

Background:  Heparin‐induced thrombocytopenia (HIT) is a prothrombotic immune‐mediated adverse drug reaction. Antigen and platelet activation assays are used for detection of antibodies. Quantitative results from platelet factor 4 (PF4)‐dependent immunoassays may lead to inter‐laboratory standardization of measurements.

Objectives:  The aim was to modify a PF4‐dependent immunoassay to measure PF4/heparin antibodies quantitatively.

Methods:  Over five consecutive years, 1070 samples from thrombocytopenic, heparin‐treated patients were analyzed by a PF4/heparin ELISA and the heparin‐induced platelet activation assay (HIPA). Results of ELISA assay were expressed as arbitrary units per liter (AU/L).

Results:  Precision of ELISA at the concentration of 50 AU/L was 3.6%. Of 1070 samples, 117 were positive for antibodies by ELISA and/or HIPA assay. The higher the antibody concentration was, the higher was the proportion of HIPA positive cases (>140 AU/L, 100%, n = 26; 100–140 AU/L, 55%, n = 20; 50–99 AU/L, 38%, n = 29; 30–49 AU/L, 17%, n = 36).

Conclusions:  The measurement of anti‐PF4/heparin antibody concentration is a new parameter that may improve the diagnosis of HIT. All samples with extremely strong antibody concentration were positive also by HIPA. For accuracy, antibody concentrations must be in the linear range of the assay and an international standard is needed.
The NF‐κB signalling pathway is involved in the LPS/IL‐2‐induced upregulation of FoxP3 expression in human CD4+CD25high regulatory T cells
Authors: Milkova Linda , Voelcker Verena , Forstreuter Inka , Sack Ulrich , Anderegg Ulf , Simon Jan‐C. , Maier‐Simon Corinna
Published: October 2009

Abstract:  Regulatory T cells (Treg) have been found to be central for host defense regulation against microbial antigens, the prevention of allergic and autoimmune diseases and the suppression of effective tumor immune responses. However, the influence of the microenvironment and the mechanisms leading to their activation in the periphery still remain unclear. In vitro infection models revealed that survival and suppressive function of Treg is improved when they are confronted with lipopolysaccharide (LPS). Because LPS initiates signalling via the receptor Toll‐like receptor 4 (TLR4) and the consequent activation of the transcription factor nuclear factor‐kappaB (NF‐κB), we investigated TLR4 expression and NF‐κB regulation in human Treg. We demonstrated that LPS in combination with IL‐2 induces human CD25+FoxP3+ T cells in vitro. FoxP3 expression of purified natural Treg increased and suppressive capacity was markedly improved compared with unstimulated Treg upon stimulation with LPS/IL‐2. Furthermore, blockade of the NF‐κB pathway by a selective inhibitor of IκB kinase (IKK)β abrogated the upregulation of FoxP3 expression. Taken together, our results suggest an important role of the NF‐κB signalling pathway for the induction and modulation of suppressive function of natural Treg, if they are confronted with TLR4‐stimulating agents such as Gram‐negative bacteria.
Nestin and SOX9 and SOX10 transcription factors are coexpressed in melanoma
Authors: Bakos Renato M. , Maier Tanja , Besch Robert , Mestel Dominik S. , Ruzicka Thomas , Sturm Richard A. , Berking Carola
Published: October 2009

Please cite this paper as: Nestin and SOX9 and SOX10 transcription factors are coexpressed in melanoma. Experimental Dermatology 2010; 19: e89–e94.

Abstract:  Nestin is an intermediate filament expressed in proliferating neural progenitor cells and has been considered as a stem cell marker. Nestin is also found in melanoma and we recently demonstrated that its expression in melanoma cell lines is regulated by the transcription factors SOX9 and SOX10, but not BRN2. In this study, the expression levels of nestin, BRN2, SOX9 and SOX10 were analysed in tissues of melanoma (n = 78) and melanocytic nevi (n = 26) by immunohistochemistry. All proteins were highly expressed in primary and metastatic melanomas and, apart from BRN2, showed much lower levels in melanocytic nevi. Significant coexpression of nestin with SOX9 and SOX10 was found in primary melanoma confirming our in vitro data. Correlation analysis with clinicopathological data revealed that nestin was significantly associated with presence of ulceration in primary tumors and SOX9 with more advanced stage of disease. Our data reveal that SOX9 and SOX10 are highly expressed in melanoma and seem to have a regulatory role in nestin expression. The association with ulceration and advanced‐stage tumors, respectively, suggests that nestin and SOX9 may be negative prognostic markers in melanoma.
Myosin and actin content of human skeletal muscle fibers following 35 days bed rest
Authors: Borina E. , Pellegrino M. A. , D'Antona G. , Bottinelli R.
Published: October 2009

Biopsy samples were taken from the vastus lateralis muscle of seven male subjects pre‐ and post‐35 days bed rest (BR). The myosin heavy chain (MHC) isoform distribution of the samples was determined by densitometry of MHC bands separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE). Individual muscle fibers were dissected from biopsy samples pre‐BR (n=143) and post‐BR (n=144). They were studied as regards cross‐sectional area (CSA), myosin content by quantitative electrophoresis and myosin actin (M/A) ratio by densitometry of myosin and actin bands of individual muscle fibers. All fibers were typed according to their MHC isoform content determined by SDS‐PAGE. A decrease in MHC‐1 relative content and an increase in MHC‐2X content of whole muscle samples were found, suggesting a slow to fast shift in muscle phenotype. Consistently, fiber type distribution was shifted toward type 2X and 2AX fibers. Muscle fiber atrophy occurred at variable extent among fiber types. Myosin concentration was significantly lower in type 1 and type 2A muscle fibers post‐BR than pre‐BR, whereas M/A ratio did not vary. The latter findings indicate a disproportionate loss of myosin compared with fiber CSA and a proportional loss of myosin and actin.