bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide-Co(III) Schiff base conjugate
Authors: Harney Allison S. , Lee Jiyoun , Manus Lisa M. , Wang Peijiao , Ballweg David M. , LaBonne Carole , Meade Thomas J.
Published: August 2009

A transition metal complex targeted for the inhibition of a subset of zinc finger transcription factors has been synthesized and tested in
Xenopus laevis
. A Co(III) Schiff base complex modified with a 17-bp DNA sequence is designed to selectively inhibit Snail family transcription factors. The oligonucleotide-conjugated Co(III) complex prevents Slug, Snail, and Sip1 from binding their DNA targets whereas other transcription factors are still able to interact with their target DNA. The attachment of the oligonucleotide to the Co(III) complex increases specificity 150-fold over the unconjugated complex. Studies demonstrate that neither the oligo, or the Co(III) Schiff base complex alone, are sufficient for inactivation of Slug at concentrations that the conjugated complex mediates inhibition. Slug, Snail, and Sip1 have been implicated in the regulation of epithelial-to-mesenchymal transition in development and cancer. A complex targeted to inactivate their transcriptional activity could prove valuable as an experimental tool and a cancer therapeutic.
Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma
Authors: Lambiase Alessandro , Aloe Luigi , Centofanti Marco , Parisi Vincenzo , Mantelli Flavio , Colafrancesco Valeria , Manni Gian Luca , Bucci Massimo Gilberto , Bonini Stefano , Levi-Montalcini Rita
Published: August 2009

Elevated intraocular pressure (IOP) in glaucoma causes loss of retinal ganglion cells (RGCs) and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. We evaluated the effects of NGF eye drops in a rat model of glaucoma. We also treated 3 patients with progressive visual field defects despite IOP control. Glaucoma was induced in rats through injection of hypertonic saline into the episcleral vein. Initially, 2 doses of NGF (100 and 200 μg/mL) were tested on 24 rats, and the higher dose was found to be more effective. Glaucoma was then induced in an additional 36 rats: half untreated and half treated with 200 μg/mL NGF QID for 7 weeks. Apoptosis/survival of RGCs was evaluated by histological, biochemical, and molecular analysis. Three patients with advanced glaucoma underwent psychofunctional and electrofunctional tests at baseline, after 3 months of NGF eye drops, and after 3 months of follow-up. Seven weeks of elevated IOP caused RGC degeneration resulting in 40% cell death. Significantly less RGC loss was observed with NGF treatment (2,530 ± 121 vs. 1,850 ± 156 RGCs/mm2) associated with inhibition of cell death by apoptosis. Patients treated with NGF demonstrated long lasting improvements in visual field, optic nerve function, contrast sensitivity, and visual acuity. NGF exerted neuroprotective effects, inhibiting apoptosis of RGCs in animals with glaucoma. In 3 patients with advanced glaucoma, treatment with topical NGF improved all parameters of visual function. These results may open therapeutic perspectives for glaucoma and other neurodegenerative diseases.
Proteome-wide prediction of acetylation substrates
Authors: Basu Amrita , Rose Kristie L. , Zhang Junmei , Beavis Ronald C. , Ueberheide Beatrix , Garcia Benjamin A. , Chait Brian , Zhao Yingming , Hunt Donald F. , Segal Eran , Allis C. David , Hake Sandra B.
Published: August 2009

Acetylation is a well-studied posttranslational modification that has been associated with a broad spectrum of biological processes, notably gene regulation. Many studies have contributed to our knowledge of the enzymology underlying acetylation, including efforts to understand the molecular mechanism of substrate recognition by several acetyltransferases, but traditional experiments to determine intrinsic features of substrate site specificity have proven challenging. Here, we combine experimental methods with clustering analysis of protein sequences to predict protein acetylation based on the sequence characteristics of acetylated lysines within histones with our unique prediction tool PredMod. We define a local amino acid sequence composition that represents potential acetylation sites by implementing a clustering analysis of histone and nonhistone sequences. We show that this sequence composition has predictive power on 2 independent experimental datasets of acetylation marks. Finally, we detect acetylation for selected putative substrates using mass spectrometry, and report several nonhistone acetylated substrates in budding yeast. Our approach, combined with more traditional experimental methods, may be useful for identifying acetylated substrates proteome-wide.
Climate directly influences Eocene mammal faunal dynamics in North America
Authors: Woodburne Michael O. , Gunnell Gregg F. , Stucky Richard K.
Published: August 2009

The modern effect of climate on plants and animals is well documented. Some have cautioned against assigning climate a direct role in Cenozoic land mammal faunal changes. We illustrate 3 episodes of significant mammalian reorganization in the Eocene of North America that are considered direct responses to dramatic climatic events. The first episode occurred during the Paleocene–Eocene Thermal Maximum (PETM), beginning the Eocene (55.8 Ma), and earliest Wasatchian North American Land Mammal Age (NALMA). The PETM documents a short (<170 k.y.) global temperature increase of ≈5 °C and a substantial increase in first appearances of mammals traced to climate-induced immigration. A 4-m.y. period of climatic and evolutionary stasis then ensued. The second climate episode, the late early Eocene Climatic Optimum (EECO, 53–50 Ma), is marked by a temperature increase to the highest prolonged Cenozoic ocean temperature and a similarly distinctive continental interior mean annual temperature (MAT) of 23 °C. This MAT increase [and of mean annual precipitation (MAP) to 150 cm/y) promoted a major increase in floral diversity and habitat complexity under temporally unique, moist, paratropical conditions. Subsequent climatic deterioration in a third interval, from 50 to 47 Ma, resulted in major faunal diversity loss at both continental and local scales. In this Bridgerian Crash, relative abundance shifted from very diverse, evenly represented, communities to those dominated by the condylarthHyopsodus. Rather than being “optimum,” the EECO began the greatest episode of faunal turnover of the first 15 m.y. of the Cenozoic.
From gene manager to traffic cop
Authors: Leslie Mitch
Published: August 2009

“Nuclear” protein keeps endosomes rolling.
The role of BH3-only protein Bim extends beyond inhibiting Bcl-2–like prosurvival proteins
Authors: Mérino Delphine , Giam Maybelline , Hughes Peter D. , Siggs Owen M. , Heger Klaus , O'Reilly Lorraine A. , Adams Jerry M. , Strasser Andreas , Lee Erinna F. , Fairlie Walter D. , Bouillet Philippe
Published: August 2009

Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.
Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease
Authors: Smith Andrew M. , Rahman Farooq Z. , Hayee Bu'Hussain , Graham Simon J. , Marks Daniel J.B. , Sewell Gavin W. , Palmer Christine D. , Wilde Jonathan , Foxwell Brian M.J. , Gloger Israel S. , Sweeting Trevor , Marsh Mark , Walker Ann P. , Bloom Stuart L. , Segal Anthony W.
Published: August 2009

The cause of Crohn's disease (CD) remains poorly understood. Counterintuitively, these patients possess an impaired acute inflammatory response, which could result in delayed clearance of bacteria penetrating the lining of the bowel and predispose to granuloma formation and chronicity. We tested this hypothesis in human subjects by monitoring responses to killed Escherichia coli injected subcutaneously into the forearm. Accumulation of 111In-labeled neutrophils at these sites and clearance of 32P-labeled bacteria from them were markedly impaired in CD. Locally increased blood flow and bacterial clearance were dependent on the numbers of bacteria injected. Secretion of proinflammatory cytokines by CD macrophages was grossly impaired in response to E. coli or specific Toll-like receptor agonists. Despite normal levels and stability of cytokine messenger RNA, intracellular levels of tumor necrosis factor (TNF) were abnormally low in CD macrophages. Coupled with reduced secretion, these findings indicate accelerated intracellular breakdown. Differential transcription profiles identified disease-specific genes, notably including those encoding proteins involved in vesicle trafficking. Intracellular destruction of TNF was decreased by inhibitors of lysosomal function. Together, our findings suggest that in CD macrophages, an abnormal proportion of cytokines are routed to lysosomes and degraded rather than being released through the normal secretory pathway.
Fast and accurate predictions of protein stability changes upon mutations using statistical potentials and neural networks: PoPMuSiC-2.0
Authors: Dehouck Yves , Grosfils Aline , Folch Benjamin , Gilis Dimitri , Bogaerts Philippe , Rooman Marianne
Published: August 2009

Motivation: The rational design of proteins with modified properties, through amino acid substitutions, is of crucial importance in a large variety of applications. Given the huge number of possible substitutions, every protein engineering project would benefit strongly from the guidance of in silico methods able to predict rapidly, and with reasonable accuracy, the stability changes resulting from all possible mutations in a protein.

Results: We exploit newly developed statistical potentials, based on a formalism that highlights the coupling between four protein sequence and structure descriptors, and take into account the amino acid volume variation upon mutation. The stability change is expressed as a linear combination of these energy functions, whose proportionality coefficients vary with the solvent accessibility of the mutated residue and are identified with the help of a neural network. A correlation coefficient of R = 0.63 and a root mean square error of σc = 1.15 kcal/mol between measured and predicted stability changes are obtained upon cross-validation. These scores reach R = 0.79, and σc = 0.86 kcal/mol after exclusion of 10% outliers. The predictive power of our method is shown to be significantly higher than that of other programs described in the literature.

Availability:  http://babylone.ulb.ac.be/popmusic

Contact:  ydehouck@ulb.ac.be

Supplementary information:  Supplementary data are available at Bioinformatics online.
A first phylogenetic analysis of Giant Pill‐Millipedes (Diplopoda: Sphaerotheriida), a new model Gondwanan taxon, with special emphasis on island gigantism
Authors: Wesener Thomas , VandenSpiegel Didier
Published: August 2009

The phylogeny of the Giant Pill‐Millipedes, order Sphaerotheriida, is investigated using a new morphological character matrix comprising 89 characters. The majority of these characters are employed for the first time in millipedes. All trees obtained agree on the monophyletic status of the Sphaerotheriida and several of its tribes, each restricted to a modern land mass. The species from Madagascar displaying island gigantism do not form a monophyletic group. The classic division of Giant Pill‐Millipedes into two families, Sphaerotheriidae and Zephronidae, was not reflected in the analysis. The genus Procyliosoma is the sister‐group to all other Sphaerotheriida, rendering the family Sphaerotheriidae paraphyletic. A new family‐level classification of Giant Pill‐Millipedes, based on the current phylogeny, is introduced. The new family Procyliosomatidae contains only the genus Procyliosoma, distributed in Australia and New Zealand. The family Zephronidae remains unchanged, while the family Sphaerotheriidae now incorporates only the African Giant Pill‐Millipede genera. All genera from southern India and Madagascar form a monophyletic group and are placed in the new family Arthrosphaeridae. The Malagasy genus Sphaeromimus is more closely related to the Indian Arthrosphaera species than to other genera from Madagascar. A biogeographical analysis identifies the group as a Gondwana taxon (with a notable absence from South America). The current phylogeny of Giant Pill‐Millipede families mirrors perfectly the suggested break‐up of Gondwana fragments 160–90 Ma. No evidence for a dispersal event could be found, highlighting the importance of Giant Pill‐Millipedes as a potential model taxon.
How confident should we be that smoking cessation treatments work?
Authors: Hughes John R.
Published: August 2009

Aim To determine (i) the concordance among recent meta‐analyses about which treatments for smoking cessation are efficacious; (ii) the similarity of odds ratios (ORs) across meta‐analyses; and (iii) among the validated treatments, the proportion of studies that found higher quit rates.

Methods Computerized literature search for meta‐analyses during the last 5 years in PubMed and PsychInfo. Data were extracted from summary tables of overall effect of validated treatments.

Results Fourteen meta‐analyses agreed 100% on the presence/absence of efficacy of 17 proven treatments. The ORs differed by <0.5 in 72/76 of the comparisons of meta‐analyses. Among 37 comparisons in 33 comparisons, >85% of the studies reported numerical superiority for the active treatment.

Conclusions The efficacy of treatments for smoking cessation are extremely reliable. This argues for inclusion of treatment as an essential feature of tobacco control and clinical practice and argues for reimbursement of smoking cessation treatments on a par with other medical and behavioral disorders.
Unplanned attempts to quit smoking: missed opportunities for health promotion?
Authors: Murray Rachael L. , Lewis Sarah A. , Coleman Timothy , Britton John , McNeill Ann
Published: August 2009

Objectives  To investigate the occurrence, determinants and reported success of unplanned and planned attempts to quit smoking, and sources of support used in these attempts.

Design  Cross‐sectional questionnaire survey of 3512 current and ex‐smokers.

Setting  Twenty‐four general practices in Nottinghamshire, UK.

Participants  Individuals who reported making a quit attempt within the last 6 months.

Measurements  Occurrence, triggers for, support used and success of planned and unplanned quit attempts.

Results  A total of 1805 (51.4%) participants returned completed questionnaires, reporting 394 quit attempts made within the previous 6 months of which 37% were unplanned. Males were significantly more likely to make an unplanned quit attempt [adjusted odds ratio (OR) 1.60, 95% confidence interval (CI) 1.04–2.46], but the occurrence of unplanned quit attempts did not differ significantly by socio‐economic group or amount smoked. The most common triggers for unplanned quit attempts were advice from a general practitioner or health professional (27.9%) and health problems (24.5%). 5.4% and 4.1% of unplanned quit attempts used National Health Service cessation services on a one to one and group basis, respectively, and more than half (51.7%) were made without any support. Nevertheless, unplanned attempts were more likely to be reported to be successful (adjusted OR 2.01, 95% CI 1.23–3.27, P < 0.01).

Conclusions  Unplanned quit attempts are common among smokers in all socio‐demographic groups, are triggered commonly by advice from a health professional and are more likely to succeed; however, the majority of these unplanned attempts are unsupported. It is important to develop methods of providing behavioural and/or pharmacological support for these attempts, and determine whether these increase cessation rates still further.
Changes in per capita alcohol sales during the partial privatization of British Columbia's retail alcohol monopoly 2003–2008: a multi‐level local area analysis
Authors: Stockwell Tim , Zhao Jinhui , Macdonald Scott , Pakula Basia , Gruenewald Paul , Holder Harold
Published: August 2009

Aim To investigate the independent effects on liquor sales of an increase in (a) the density of liquor outlets and (b) the proportion of liquor stores in private rather than government ownership in British Columbia between 2003/4 and 2007/8.

Design The British Columbia Liquor Distribution Branch provided data on litres of ethanol sold through different types of outlets in 89 local health areas of the province by beverage type. Multi‐level regression models were used to examine the relationship between per capita alcohol sales and outlet densities for different types of liquor outlet after adjusting for potential confounding social, economic and demographic factors as well as spatial and temporal autocorrelation.

Setting Liquor outlets in 89 local health areas of British Columbia, Canada.

Findings The number of private stores per 10 000 residents was associated significantly and positively with per capita sales of ethanol in beer, coolers, spirits and wine, while the reverse held for government liquor stores. Significant positive effects were also identified for the number of bars and restaurants per head of population. The percentage of liquor stores in private versus government ownership was also associated significantly with per capita alcohol sales when controlling for density of liquor stores and of on‐premise outlets (P < 0.01).

Conclusion The trend towards privatisation of liquor outlets between 2003/04 and 2007/08 in British Columbia has contributed to increased per capita sales of alcohol and hence possibly also to increased alcohol‐related harm.
Interventions with injection drug users in Ukraine
Authors: Booth Robert E. , Lehman Wayne E. K. , Dvoryak Sergey , Brewster John T. , Sinitsyna Larisa
Published: August 2009

Aims  To assess the effectiveness of a brief human immunodeficiency virus (HIV) testing and counseling intervention compared to a more time‐consuming and expensive street‐based intervention with injection drug users (IDUs).

Design  Cross‐over experimental design in which 900 IDUs were recruited, followed by a ‘wash‐out’ period with no recruitment, a reversal of intervention assignment areas and an additional recruitment of 900 IDUs with baseline and 6‐month follow‐up assessments.

Setting  Kiev, Odessa and Makeevka/Donesk Ukraine.

Participants  A total of 1798 IDUs.

Measurements  HIV testing and audio computer‐assisted self‐interview (ACASI) data on socio‐demographics, drug use and injection and sex‐related risk behaviors.

Findings  Participants in both conditions reduced their injection and sex risks significantly; however, there was little difference in outcomes between conditions. IDUs who knew they were HIV‐infected at baseline were significantly more likely to practice safe sex than those unaware or HIV‐negative; those who first learned that they were infected at baseline changed their safe sex practices significantly more than those who already knew that they were infected at baseline and those who were HIV‐negative. Younger IDUs and those injecting for a shorter period of time reported higher injection and sex risk behaviors following interventions.

Conclusions  Awareness of HIV infection by street‐recruited drug injectors is associated with reduced sex risks. Additional interventions are required for younger IDUs and those injecting for shorter periods of time.
‘I have no interest in drinking’: a cross‐national comparison of reasons why men and women abstain from alcohol use
Authors: Bernards Sharon , Graham Kathryn , Kuendig Hervé , Hettige Siri , Obot Isidore
Published: August 2009

Aims  To examine country differences in reasons for abstaining including the association of reasons with country abstaining rate and drinking pattern.

Participants  Samples of men and women from eight countries participating in the GENACIS (Gender Alcohol and Culture: an International Study) project.

Methods  Surveys were conducted with 3338 life‐time abstainers and 3105 former drinkers. Respondents selected all applicable reasons for not drinking from a provided list. Analyses included two‐level hierarchical linear modelling (HLM) regression.

Findings  Reasons for abstaining differed significantly for life‐time abstainers compared to former drinkers, by gender and age, and by country‐level abstaining rate and frequency of drinking. Life‐time abstainers were more likely than former drinkers to endorse ‘no interest’, ‘religion’ and ‘upbringing’ and more reasons overall. Gender differences, especially among former drinkers, suggested that norms restricting drinking may influence reasons that women abstain (‘no interest’, ‘not liking taste’) while drinking experiences may be more important considerations for men (‘afraid of alcohol problems’, ‘bad effect on activities’). Younger age was associated with normative reasons (‘no interest’, ‘taste’, ‘waste of money’) and possibly bad experiences (‘afraid of problems’). Reasons such as ‘religion’, ‘waste of money’ and ‘afraid of alcohol problems’ were associated with higher country‐level rates of abstaining. Higher endorsement of ‘drinking is bad for health’ and ‘taste’ were associated with a country pattern of less frequent drinking while ‘not liking effects’ was associated with higher drinking frequency.

Conclusions  Reasons for abstaining depend on type of abstainer, gender, age and country drinking norms and patterns.
Subtypes of major depression in substance dependence
Authors: Niciu Mark J. , Chan Grace , Gelernter Joel , Arias Albert J. , Douglas Kara , Weiss Roger , Anton Raymond F. , Farrer Lindsay , Cubells Joseph F. , Kranzler Henry R.
Published: August 2009

Aims  This study evaluated features that differentiate subtypes of major depressive episode (MDE) in the context of substance dependence (SD).

Design  Secondary data analysis using pooled data from family‐based and case–control genetic studies of SD.

Setting  Community recruitment through academic medical centers.

Participants  A total of 1929 unrelated subjects with alcohol and/or drug dependence.

Measurements  Demographics, diagnostic criteria for psychiatric and substance use disorders and related clinical features were obtained using the Semi‐Structured Assessment for Drug Dependence and Alcoholism. We compared four groups: no life‐time MDE (no MDE), independent MDE only (I‐MDE), substance‐induced MDE only (SI‐MDE) and both types of MDE.

Findings  Psychiatric measures were better predictors of MDE subtype than substance‐related or socio‐demographic ones. Subjects with both types of MDE reported more life‐time depressive symptoms and comorbid anxiety disorders and were more likely to have attempted suicide than subjects with I‐MDE or SI‐MDE. Subjects with both types of MDE, like those with I‐MDE, were also more likely than subjects with SI‐MDE to be alcohol‐dependent only than either drug‐dependent only or both alcohol‐ and drug‐dependent.

Conclusions  SD individuals with both types of MDE have greater psychiatric severity than those with I‐MDE only or SI‐MDE only. These and other features that distinguish among the MDE subtypes have important diagnostic and potential therapeutic implications.
Dexamethasone administration inhibits skeletal muscle expression of the androgen receptor and IGF‐1 – implications for steroid‐induced myopathy
Authors: Inder Warrick J. , Jang Christina , Obeyesekere Varuni R. , Alford Frank P.
Published: August 2009

Context  Glucocorticoids are a well‐recognized cause of muscle weakness. The early effects of glucocorticoids on skeletal muscle (SkM) androgen and IGF‐1 pathways have not been previously investigated in human subjects.

Objective  To determine if administration of the potent glucocorticoid dexamethasone down‐regulates SkM androgen receptor and the IGF‐1 signalling pathway.

Methods and subjects  Twenty‐four subjects (12 men and 12 women), including 12 with type 2 diabetes and 12 nondiabetics were enrolled. Venous blood sampling and biopsy of vastus lateralis were performed before and after administration of oral dexamethasone 4 mg/day for 4 days.

Main outcome measures  Changes in plasma testosterone and IGF‐1, SkM androgen receptor mRNA, SkM IGF‐1mRNA and SkM IGF‐1 receptor mRNA by quantitative RT‐PCR after dexamethasone.

Results  Relative expression of SkM androgen receptor was similar in male (1·63 ± 0·37) vs. female (1·57 ± 0·30) subjects, despite the significant difference in plasma testosterone levels. Plasma IGF‐1 and SkM expression of IGF‐1 and IGF‐1 receptor were also similar between males and females. Following dexamethasone, there was a significant down‐regulation of SkM androgen receptor (1·60 ± 0·23 vs. 1·11 ± 0·16, P < 0·05) and IGF‐1 (1·72 ± 0·29 vs. 1·06 ± 0·14, P < 0·05) mRNA, but no change in expression of the IGF‐1 receptor. Plasma testosterone fell significantly in both sexes (male: 15·0 ± 1·3 vs. 11·3 ± 1·2 nmol/l, P < 0·01, female: 1·8 ± 0·5 vs. 0·5 ± 0·1 nmol/l, P < 0·05).

Conclusions  Exogenous steroid excess results in relative androgen deficiency at two levels, reduced circulating testosterone and SkM androgen receptor mRNA, along with reduced SkM IGF‐1 mRNA. These defects may contribute to the development of steroid‐induced myopathy.
Polymorphisms of the UCP2 gene are associated with proliferative diabetic retinopathy in patients with diabetes mellitus
Authors: Crispim Daisy , Fagundes Nelson J. R. , Dos Santos Kátia G. , Rheinheimer Jakeline , Bouças Ana P. , De Souza Bianca M. , Macedo Gabriel S. , Leiria Leonardo B. , Gross Jorge L. , Canani Luís H.
Published: August 2009

Background and objective  Uncoupling protein 2 (UCP2) plays a role in controlling reactive oxygen species (ROS) production by mitochondria. As ROS overproduction is related to diabetic retinopathy (DR), UCP2 gene polymorphisms might be involved in the development of this complication. We investigated whether the −866G/A (rs659366), Ala55Val (rs660339) and 45 bp insertion/deletion (Ins/Del) polymorphisms in the UCP2 gene might be associated with proliferative DR (PDR).

Design and methods  In this case–control study, we analysed 501 type 2 diabetic patients (242 patients with PDR and 259 subjects without any degree of DR) and 196 type 1 diabetic patients (85 cases with PDR and 111 without DR). Haplotypes constructed from the combination of the three UCP2 polymorphisms were inferred using a Bayesian statistical method.

Results  In the type 2 diabetic group, multivariate analyses confirmed that the haplotype [A Val Ins] was an independent risk factor for PDR when present in one [adjusted odds ratio (aOR) = 2·12; P = 0·006], at least one (aOR = 2·75; P = 0·00001), or two copies (aOR = 5·30; P = 0·00001), suggesting an additive model of inheritance. Nevertheless, in type 1 diabetic patients, the association of this haplotype with PDR was confirmed only when it was present in at least one (aOR = 2·68; P = 0·014) or two copies (aOR = 6·02; P = 0·005).

Conclusions  The haplotype [A Val Ins] seems to be an important risk factor associated with PDR in both type 2 and 1 diabetic groups.
Increased oxidized low density lipoprotein associated with high ceruloplasmin activity in patients with active acromegaly
Authors: Boero L. , Cuniberti L. , Magnani N. , Manavela M. , Yapur V. , Bustos M. , Gómez Rosso L. , Meroño T. , Marziali L. , Viale L. , Evelson P. , Negri G. , Brites F.
Published: August 2009

Objective  Active acromegaly is associated with increased mortality from cardiovascular causes. Several studies have shown increased atherogenic risk factors and biomarkers of inflammation and atherosclerosis in association with growth hormone excess. The aim of this study was to evaluate oxidized low density lipoprotein (oxLDL) levels and some modulators of LDL oxidative modification in patients with acromegaly.

Design  Open transversal study.

Patients  Fifteen patients with active acromegaly and 15 controls were studied.

Measurements  We evaluated the levels of oxLDL, thiobarbituric acid reactive substances (TBARS), ceruloplasmin, bilirubin, uric acid and total reactive antioxidant potential, and the activities of ceruloplasmin, myeloperoxidase, superoxide distmutase, paraoxonase 1, and platelet activating factor acethylhydrolase. Statistical analysis was performed including body mass index as a covariate or as a fixed variable.

Results  Patients with acromegaly showed significantly higher levels of oxLDL (120 ± 19 vs. 86 ± 20 U/l, P < 0·001) and endothelin (P < 0·05), increased ceruloplasmin activity (P < 0·01) and a trend towards higher values in TBARS concentration (P = 0·07) in comparison to healthy controls. OxLDL was positively associated with GH, IGF‐I and its binding protein 3 (r = 0·63, P < 0·001; r = 0·53, P < 0·01; and r = 0·56, P < 0·01; respectively). OxLDL showed direct associations with endothelin‐1 (r = 0·53, P < 0·01) and ceruloplasmin activity (r = 0·43, P < 0·05). The other parameters evaluated were similar in both groups.

Conclusions  The increase in plasma oxLDL levels, a direct marker of the plaque formation, could constitute a link between atherosclerosis and active acromegaly. LDL oxidation would not be the consequence of diminished antioxidant defences, but of an enhancement in prooxidant factors like ceruloplasmin.
Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment
Authors: DEN UIJL I. , MAUSER‐BUNSCHOTEN E. P. , ROOSENDAAL G. , SCHUTGENS R. , FISCHER K.
Published: August 2009

Summary.  Currently, efficacy of a new factor concentrate is mostly judged by its ability to achieve haemostasis after a bleeding episode. However, in patients on prophylaxis, the effectiveness in preventing bleeds, and thus joint damage, is most important. An albumin‐free recombinant factor VIII (FVIII) concentrate was introduced in the Netherlands in 2004. In this study, the efficacy of a new recombinant plasma/albumin‐free FVIII concentrate (rAHF‐PFM, Advate®) was assessed by comparing bleeding frequency and factor consumption before and after switching to the new product, on both prophylactic and on‐demand treatment. Eighty‐two previously treated haemophilia A patients with  at least 1‐year clinical follow‐up were included in this study. Data on 410 patient‐years were analysed, including 165 patient‐years on other clotting factor products, and 245 patient‐years on the new concentrate. In total, 19 628 368 IU of other factor concentrates were administered, to treat 839 bleeds, including 578 joint bleeds and cover 104 years of prophylactic treatment. For rAHF‐PFM 33 082 250 IU FVIII, were used to treat 1144 bleeds, including 734 joint bleeds and cover 175 years of prophylactic treatment. No inhibitors, seroconversions or other serious adverse events were observed. Annual FVIII consumption per kg and annual number of joint bleeds before and after switching to the new albumin‐free recombinant factor concentrate were similar in all patients. In conclusion, rAHF‐PFM is equally effective as other clotting factor concentrates for prophylactic treatment in severe haemophilia.
Macrophage interleukin‐6 and tumour necrosis factor‐α are induced by coronavirus fixation to Toll‐like receptor 2/heparan sulphate receptors but not carcinoembryonic cell adhesion antigen 1a
Authors: Jacques Alexandre , Bleau Christian , Turbide Claire , Beauchemin Nicole , Lamontagne Lucie
Published: August 2009

A rapid antiviral immune response may be related to viral interaction with the host cell leading to activation of macrophages via pattern recognition receptors (PPRs) or specific viral receptors. Carcinoembryonic cell adhesion antigen 1a (CEACAM1a) is the specific receptor for the mouse hepatitis virus (MHV), a coronavirus known to induce acute viral hepatitis in mice. The objective of this study was to understand the mechanisms responsible for the secretion of high‐pathogenic MHV3‐induced inflammatory cytokines. We report that the induction of the pro‐inflammatory cytokines interleukin (IL)‐6 and tumour necrosis factor (TNF)‐α in peritoneal macrophages does not depend on CEACAM1a, as demonstrated in cells isolated from Ceacam1a−/− mice. The induction of IL‐6 and TNF‐α production was related rather to the fixation of the spike (S) protein of MHV3 on Toll‐like receptor 2 (TLR2) in regions enriched in heparan sulphate and did not rely on viral replication, as demonstrated with denatured S protein and UV‐inactivated virus. High levels of IL‐6 and TNF‐α were produced in livers from infected C57BL/6 mice but not in livers from Tlr2−/− mice. The histopathological observations were correlated with the levels of those inflammatory cytokines. Depending on mouse strain, the viral fixation to heparan sulfate/TLR2 stimulated differently the p38 mitogen‐activated protein kinase (MAPK) and nuclear factor (NF)‐κB in the induction of IL‐6 and TNF‐α. These results suggest that TLR2 and heparan sulphate receptors can act as new viral PPRs involved in inflammatory responses.
Hypoxia skews dendritic cells to a T helper type 2‐stimulating phenotype and promotes tumour cell migration by dendritic cell‐derived osteopontin
Authors: Yang Meixiang , Ma Chunhong , Liu Shuxun , Sun Jintang , Shao Qianqian , Gao Wenjuan , Zhang Yan , Li Zewu , Xie Qi , Dong Zhaogang , Qu Xun
Published: August 2009

It is well recognized that tissue microenvironments are involved in regulating the development and function of dendritic cells (DC). Oxygen supply, which varies in different tissues, has been accepted as an important microenvironmental factor in regulating the biological functions of several immune cells and as being involved in tumour progression and metastasis. However, little is known about the effect of hypoxia on the biological functions of DC and the effect of these hypoxia‐conditioned DC on tumour metastasis. In this study, we analysed the transcriptional profiles of human monocyte‐derived immature DC (imDC) and mature DC (mDC) cultured under normoxia and hypoxia by microarray, and found a body of potential targets regulating the functions of DC during hypoxia. In addition, the phagocytic ability of hypoxic imDC markedly decreased compared with that of normoxic imDC. Importantly, hypoxic DC poorly induced the proliferation of allogeneic T cells, but polarized allogeneic CD4+ naive T cells into a T helper type 2 (Th2) response. Moreover, hypoxic DC secreted large amounts of osteopontin, which were responsible for the enhanced migration of tumour cells. Therefore, our study provides new insights into the biological functions of DC under hypoxic conditions and one of mechanisms underlying tumour immune escape during hypoxia.
Role of pathogenic T cells and autoantibodies in relapse and progression of myelin oligodendrocyte glycoprotein‐induced autoimmune encephalomyelitis in LEW.1AV1 rats
Authors: Matsumoto Yoh , Park Il‐Kwon , Hiraki Keiko , Ohtani Shin , Kohyama Kuniko
Published: August 2009

Accumulating evidence suggests that T cells and autoantibodies reactive with myelin oligodendrocyte glycoprotein (MOG) play a critical role in the pathogenesis of multiple sclerosis (MS). In the present study, we have tried to elucidate the pathomechanisms of development and progression of the disease by analysing T cells and autoantibodies in MOG‐induced rat experimental autoimmune encephalomyelitis (EAE), which exhibits various clinical subtypes mimicking MS. Analysis using overlapping peptides revealed that encephalitogenic epitopes resided in peptide 7 (P7, residue 91–108) and P8 (residue 103–125) of MOG. Immunization with MOGP7 and MOGP8 induced relapsing–remitting or secondary progressive EAE. T cells taken from MOG‐immunized and MOGP7‐immunized rats responded to MOG and MOGP7 and sera from MOG‐immunized rats reacted to MOG and MOGP1. Significant epitope spreading was not observed at either T‐cell or antibody levels. Interestingly, sera from MOGP7‐immunized rats with clinical signs did not react to MOG and MOG peptides throughout the observation period, suggesting that disease development and relapse in MOGP7‐induced EAE occur without autoantibodies. However, MOGP7 immunization with adoptive transfer of anti‐MOG antibodies aggravated the clinical course of EAE only slightly. Analysis of antibodies against conformational epitope (cme) suggests that anti‐MOGcme may play a role in the pathogenicity of anti‐MOG antibodies. Collectively, these findings demonstrated that relapse of a certain type of MOG‐induced EAE occurs without autoantibodies but that autoantibodies may play a role in disease progression. Relapses and the progression of MS‐mimicking EAE are differently immunoregulated so immunotherapy should be designed appropriately on the basis of precise information.
Increased cyclooxygenase activity impairs apoptosis of inflammatory neutrophils in mice lacking gelatinase B/matrix metalloproteinase‐9
Authors: Kolaczkowska Elzbieta , Plytycz Barbara , Arnold Bernd , Piccard Helene , Opdenakker Ghislain
Published: August 2009

Matrix metalloproteinase‐9 (MMP‐9)/gelatinase B plays an important role in neutrophil infiltration during inflammation and cyclooxygenases (COX‐1 and COX‐2) and their products are important regulators of inflammation. Recently, we reported that a genetic lack of MMP‐9 impairs neutrophil infiltration during early zymosan‐induced peritonitis but at later stages (> 24 hr) neutrophils persist in the peritoneal cavity. Here we show that this is the result of impaired apoptosis of MMP‐9−/−‐derived leucocytes. As enhanced COX‐1 expression was reported in MMP‐9−/−mice, we evaluated the hypothesis that altered COX expression induced the above phenomenon as COX‐dependent prostaglandins can act either anti‐apoptotically (PGE2) or pro‐apoptotically (PGD2). The current data demonstrate that messenger RNA and protein expression of both COX isoforms and their activities are increased in MMP‐9−/−mice during late peritonitis. Application of selective COX inhibitors revealed enhanced COX‐1‐dependent PGE2production and impaired COX‐2‐dependent PGD2synthesis in MMP‐9−/−mice. Most importantly, inhibition of COX‐1 abolished prolonged neutrophil accumulation in the peritoneal cavity of MMP‐9−/−mice and increased apoptosis of inflammatory leucocytes. Similarly, weaker apoptosis of MMP‐9−/−bone marrow neutrophils treatedin vitrowith zymosan was reversed by COX‐1 inhibition. In conclusion, enhanced COX‐1 expression is responsible for persistent neutrophil presence in the peritoneum of MMP‐9−/−mice because of increased synthesis of anti‐apoptotic PGE2. In non‐transgenic mice, however, inflammatory leucocytes die apoptotically in the late stages of peritonitis as a result of COX‐2‐dependent PGD2activity. Overall, we show a dependence of COX expression on the presence of MMP‐9.
Natural killer cells in infection and inflammation of the lung
Authors: Culley Fiona J.
Published: August 2009

The lungs are a major site of entry of pathogens into the body and thus require rapid and effective innate responses to prevent pathogens establishing infection and to limit their spread. Additionally, the immune response in the lung must be tightly regulated such that pathogens are cleared, but immunopathology and chronic inflammation are prevented. In this review, I consider the role of natural killer (NK) cells in pulmonary infection and inflammation, specifically their contributions to influenza, tuberculosis, asthma and chronic obstructive pulmonary disease (COPD), which are major causes of morbidity and mortality world‐wide. Despite evidence of the importance of NK cells in these diseases, there are still major gaps in our understanding of how their function is regulated in this unique tissue environment. Understanding how different beneficial and detrimental effector functions of NK cells are triggered will be crucial if NK cells are to be exploited therapeutically in respiratory disease.
Increased number and function of natural killer cells in human immunodeficiency virus 1‐positive subjects co‐infected with herpes simplex virus 2
Authors: Long Brian R. , Erickson Ann E. , Chapman Joan M. , Barbour Jason D. , Vu Bien‐Aimee N. , Ho Emily L. , Lanier Lewis L. , Sauer Mariana M. , Carvalho Karina I. , Nixon Douglas F. , Kallas Esper G.
Published: August 2009

Natural killer (NK) cells bridge the interface between innate and adaptive immunity and are implicated in the control of herpes simplex virus 2 (HSV‐2) infection. In subjects infected with human immunodeficiency virus 1 (HIV‐1), the critical impact of the innate immune response on disease progression has recently come into focus. Higher numbers of NK cells are associated with lower HIV‐1 plasma viraemia. Individuals with the compound genotype of killer cell immunoglobulin‐like receptor (KIR) 3DS1 and human leucocyte antigen (HLA)‐Bw4‐80I, or who have alleles of KIR3DL1 that encode proteins highly expressed on the NK cell surface, have a significant delay in disease progression. We studied the effect of HSV‐2 co‐infection in HIV‐1‐infected subjects, and show that HSV‐2 co‐infection results in a pan‐lymphocytosis, with elevated absolute numbers of CD4+ and CD8+ T cells, and NK cells. The NK cells in HSV‐2 co‐infected subjects functioned more efficiently, with an increase in degranulation after in vitro stimulation. The number of NK cells expressing the activating receptors NKp30 and NKp46, and expressing KIR3DL1 or KIR3DS1, was inversely correlated with HIV‐1 plasma viral load in subjects mono‐infected with HIV‐1, but not in subjects co‐infected with HSV‐2. This suggests that HSV‐2 infection mediates changes within the NK cell population that may affect immunity in HIV‐1 infection.
Perturbation of the natural killer cell compartment during primary human immunodeficiency virus 1 infection primarily involving the CD56bright subset
Authors: Mantegani Paola , Tambussi Giuseppe , Galli Laura , Din Chiara Tassan , Lazzarin Adriano , Fortis Claudio
Published: August 2009

We investigated the distribution of natural killer (NK) cell subsets, their activating and inhibitory receptors, and their cytolytic potential, in primary human immunodeficiency virus (HIV)‐infected (PHI) individuals at baseline and during 1 year of follow‐up with or without antiretroviral therapy, and compared the results with those obtained in treatment‐naïve, chronically HIV‐infected (CHI) individuals, and HIV‐seronegative (HN) healthy individuals. The proportion of the CD56dim and CD56bright subsets decreased with disease progression, whereas that of the CD56− CD16+ subset increased. In the CD56dim subset, the proportion of cells with natural cytotoxicity receptors (NCRs) decreased with disease progression, and their cytolytic potential was reduced. Conversely, the CD56bright subset was characterized by a high proportion of NCR‐positive, killer cell immunoglobulin‐like receptor (KIR)‐positive NKG2A+ cells in both CHI and PHI individuals, which was associated with an increase in their cytolytic potential. During the 1 year of follow‐up, the PHI individuals with high viraemia levels and low CD4+ T‐cell counts who received highly active antiretroviral therapy (HAART) had a similar proportion of NK subsets to CHI individuals, while patients with low viraemia levels and high CD4+ T‐cell counts who remained untreated had values similar to those of the HN individuals. Our results indicate a marked perturbation of the NK cell compartment during HIV‐1 infection that is multifaceted, starts early and is progressive, primarily involves the CD56bright subset, and is partially corrected by effective HAART.
Nurse‐led peer support group: experiences of women with polycystic ovary syndrome
Authors: Percy Carol A. , Gibbs Tineke , Potter Lj , Boardman Shirine
Published: August 2009

Title.  Nurse‐led peer support group: experiences of women with polycystic ovary syndrome.

Aim.  This paper is a report of a study to explore the experiences of women with polycystic ovary syndrome attending a nurse‐led support group.

Background.  Polycystic ovary syndrome is a common chronic endocrine disorder associated with high levels of psychological distress. It has been argued that healthcare providers should regularly review the psychological health of women with polycystic ovary syndrome, and that nurses can help women to adjust to the condition by providing education and support. Little is known about the means of providing social support for women with the syndrome, or of any benefits for patients.

Method.  Qualitative interviews were conducted with 13 female patients in 2006. The patients attended a support group at a public hospital in the United Kingdom. The data were analysed using deductive and inductive thematic analysis.

Findings.  The group provided both socio‐emotional and informational social support. Participants reported that attending the group helped to reduce isolation, and provided an opportunity for social comparison and accessible and personally relevant information. Participants described the group as having had a major personal impact for them. They reported feeling empowered and direct positive effects on their self‐management behaviours.

Conclusion.  Social support appears to be a key factor mediating the psychosocial impact in women with polycystic ovary syndrome. Healthcare providers should consider running such support groups or referring patients to them. Providing social support may alleviate distress and improve self‐management.
Community health: an evolutionary concept analysis
Authors: Baisch Mary Jo
Published: August 2009

Title. Community health: an evolutionary concept analysis.

Aim. This paper is a report of a concept analysis of community health.

Background. Community health is a term that has been broadly used in both research and practice. Although local communities are invested in community health improvement, this process often occurs without a clear definition of the concept of community health.

Data sources. Data sources included a sample of 537 papers covering the period 1990 to 2004 and representing the disciplines of nursing, public health, medicine and sociology and landmark works concerning community health, six community health assessment instruments and interviews with seven key community health informants.

Review methods. Rodgers’ Evolutionary Method of Concept Analysis was used to design the study and analyse the data. The professional literature was analysed and compared with the use of the concept of community health in community health assessment instruments and by key informants.

Results. Dynamic and contextual, community health is achieved through participatory, community development processes based upon ecological models that address broad determinants of health. The primary focus of this collaborative work is population‐based health promotion and disease prevention.

Conclusion. The definition derived from the concept analysis of community health makes explicit the importance of community‐based participatory action in local health improvement processes. Identification of the attributes of community health will enhance communication across disciplines involved in community health practice, research and education.