bluuebunny/crossref_metadata_2025 huggingface dataset:
Sulfinylated azadecalins act as functional mimics of a pollen germination stimulant in Arabidopsis pistils
Authors: Qin Yuan , Wysocki Ronald J. , Somogyi Arpad , Feinstein Yelena , Franco Jessica Y. , Tsukamoto Tatsuya , Dunatunga Damayanthi , Levy Clara , Smith Steven , Simpson Robert , Gang David , Johnson Mark A. , Palanivelu Ravishankar
Published: July 2011

Polarized cell elongation is triggered by small molecule cues during development of diverse organisms. During plant reproduction, pollen interactions with the stigma result in the polar outgrowth of a pollen tube, which delivers sperm cells to the female gametophyte to effect double fertilization. In many plants, pistils stimulate pollen germination. However, in Arabidopsis, the effect of pistils on pollen germination and the pistil factors that stimulate pollen germination remain poorly characterized. Here, we demonstrate that stigma, style, and ovules in Arabidopsis pistils stimulate pollen germination. We isolated an Arabidopsis pistil extract fraction that stimulates Arabidopsis pollen germination, and employed ultra‐high resolution electrospray ionization (ESI), Fourier‐transform ion cyclotron resonance (FT‐ICR) and MS/MS techniques to accurately determine the mass (202.126 Da) of a compound that is specifically present in this pistil extract fraction. Using the molecular formula (C10H19NOS) and tandem mass spectral fragmentation patterns of the m/z (mass to charge ratio) 202.126 ion, we postulated chemical structures, devised protocols, synthesized N‐methanesulfinyl 1‐ and 2‐azadecalins that are close structural mimics of the m/z 202.126 ion, and showed that they are sufficient to stimulate Arabidopsis pollen germination in vitro (30 μm stimulated approximately 50% germination) and elicit accession‐specific response. Although N‐methanesulfinyl 2‐azadecalin stimulated pollen germination in three species of Lineage I of Brassicaceae, it did not induce a germination response in Sisymbrium irio (Lineage II of Brassicaceae) and tobacco, indicating that activity of the compound is not random. Our results show that Arabidopsis pistils promote germination by producing azadecalin‐like molecules to ensure rapid fertilization by the appropriate pollen.
Trends of Zambia’s tuberculosis burden over the past two decades
Authors: Kapata Nathan , Chanda‐Kapata Pascalina , O’Grady Justin , Schwank Samana , Bates Mathew , Mukonka Victor , Zumla Alimuddin , Mwaba Peter
Published: July 2011

Objectives  To study trends in Zambia’s TB notification rates between 1990 and 2010 and to ascertain progress made towards TB control.

Methods  Retrospective review of TB notification returns and TB programme reports for the period from 1990 to 2010.

Results  Two distinct TB trend periods were identified: a period of rising trends up to a peak between 1990 and 2004 and a period of moderately declining trends between 2004 and 2010. Treatment outcomes improved over the two decades. Data on trends in paediatric TB, TB in prisoners and TB in pregnant women remain scanty and unreliable owing to poor diagnostic capability. There were no data available on trends on drug‐resistant TB because of the lack of laboratory services to perform drug sensitivity testing.

Conclusions  The period of increasing TB between 1990 and 2000 coincided with an increase in HIV/AIDS. The period of slightly decreasing TB between 2004 and 2010 can be attributed to improved TB care, sustained DOTS implementation and improvement in TB diagnostic services. Newer diagnostics technologies for the rapid diagnosis of active TB cases and for drug‐resistant testing, recently endorsed by the WHO, need to be implemented into the national TB programmes to detect more cases and to provide epidemiological and surveillance data from which to obtain an evidence base for guided investments for TB control. Alignment of TB and HIV services is required to achieve improved management outcomes.
Ehlers–Danlos arthrochalasia type (VIIA–B) – expanding the phenotype: from prenatal life through adulthood
Authors: Klaassens M , Reinstein E , Hilhorst‐Hofstee Y , Schrander JJP , Malfait F , Staal H , ten Have LC , Blaauw J , Roggeveen HCJ , Krakow D , De Paepe A , van Steensel MAM , Pals G , Graham JM , Schrander‐Stumpel CTRM
Published: July 2011

Klaassens M, Reinstein E, Hilhorst‐Hofstee Y, Schrander JJP, Malfait F, Staal H, ten Have LC, Blaauw J, Roggeveen HCJ, Krakow D, De Paepe A, van Steensel MAM, Pals G, Graham JM Jr, Schrander‐Stumpel CTRM. Ehlers–Danlos arthrochalasia types (VIIA–B) – expanding the phenotype: from prenatal life through adulthood.

The Ehlers–Danlos syndromes (EDS) form a clinically and genetically heterogeneous group of inherited connective‐tissue disorders characterized by joint hypermobility, tissue fragility and skin abnormalities. Six subtypes have been well characterized based on clinical features and molecular genetic abnormalities. The arthrochalasia type EDS (formerly types VIIA and B) is characterized by severe generalized joint hypermobility with multiple dislocations including congenital bilateral dislocation of the hips, muscular hypotonia and distinct dysmorphic features. The diagnosis of the arthrochalasia type EDS is of importance in the neonatal period because of consequences of physical disability in later life. However, the differential diagnosis may be difficult because of overlap with other hypermobility syndromes. In addition, the significant hypotonia may direct the physician toward various neuromuscular diagnoses. As patients become older, the hypotonia decreases and facial features become less distinct. In this report, we describe seven patients at different ages. Timing of diagnosis varied from prenatal life to adult age. The diagnosis of EDS type VII was confirmed by biochemical studies or mutation analysis showing characteristic mutations in COL1A1 and COL1A2. These mutations result in skipping of exon 6, which leads to defective collagen synthesis. For physicians treating patients with EDS type VII, achieving mobility for the patient is the greatest challenge and it may be impossible because of recurrent dislocations of nearly all joints in severe cases.
Liver transplantation in children weighing 5 kg or less: Analysis of the UNOS database
Authors: Arnon Ronen , Annunziato Rachel , Miloh Tamir , Sogawa Hiroshi , Nostrand Kelsey Van , Florman Sander , Suchy Frederick , Kerkar Nanda
Published: July 2011

Arnon R, Annunziato R, Miloh T, Sogawa H, Van Nostrand K, Florman S, Suchy F, Kerkar N. Liver transplantation in children weighing 5 kg or less: Analysis of the UNOS database. Pediatr Transplantation 2011: 15: 650–658. © 2011 John Wiley & Sons A/S.

Abstract:  LT is a major medical and surgical challenge in very small patients. Aim of the study is to determine the outcomes after LT in infants ≤5 kg at transplant in a large cohort of patients. Methods: Infants ≤5 kg who had LT between 10/1987 and 5/2008 were identified from the UNOS database. Risk factors for death and graft loss were analyzed by multivariate logistic regression. Results: Of 11 467 children, 570 (5%) were ≤5 kg at LT. Mean age and weight at LT were 0.11 ± 0.48 yr, 4.32 ± 0.74 kg, respectively. One‐ and five‐yr patient and graft survival were 77.7%, 72.2% and 66.1%, 57.6%, respectively. The primary cause of death was infection (25.9%). Recipient age was a predictor of graft loss. Patient and graft survival have improved over time. Life support at transplant was identified as a risk factor for both death and graft loss (p < 0.02, p < 0.01, respectively). Conclusion: LT recipients ≤5 kg have high mortality and graft loss. Over time, graft survival has improved, although it is still inferior to the overall reported outcomes of pediatric LT. Being on life support at transplant is a significant risk factor for death and graft loss in very small recipients.
Short‐term effect of dietary yeast nucleotide supplementation on small intestinal enzyme activities, bacterial populations and metabolites and ileal nutrient digestibilities in newly weaned pigs*
Authors: Sauer N. , Eklund M. , Roth S. , Rink F. , Jezierny D. , Bauer E. , Mosenthin R.
Published: July 2011

In previous studies, dietary nucleotides have been shown to improve performance in single‐stomached animals by promoting the renewal of small intestine epithelial cells and by influencing the activity and composition of the microbial community in the digestive tract. The present experiment was carried out with 12 barrows weaned at the age of 18 days and fitted with a simple T‐cannula at the distal ileum. To determine short‐term effects of dietary yeast nucleotides, the piglets received a grain‐soybean meal‐based basal diet with or without supplementation of 1 g/kg of a dried yeast product containing free nucleotides. Dietary supplementation with yeast did not affect bacterial numbers in the ileum as well as ileal concentrations of individual short‐chain fatty acids (SCFA), total SCFA and total lactic acid (p > 0.05). Moreover, there was no effect of supplemental yeast nucleotides on ileal α‐amylase, leucine amino peptidase, maltase and lactase activities (p > 0.05), as well as on ileal dry matter, crude protein and crude fibre digestibilities (p > 0.05). In conclusion, short‐term supplementation with dietary yeast nucleotides did not affect microbial metabolite concentrations, bacterial numbers and enzyme activities in the ileal digesta as well as ileal nutrient digestibilities of newly weaned pigs.
Airborne fungus exposure prior to hospitalisation as risk factor for mould infections in immunocompromised patients
Authors: Blum Gerhard , Eschertzhuber Stephan , Auberger Jutta , Ulmer Hanno , Geltner Christian , Gastl Günther , Nachbaur David , Lass‐Flörl Cornelia
Published: July 2011

The aim of this study was to investigate the relationship between fungal exposure prior to hospitalisation and ensuing onset of invasive mould infections (IMI) in patients at risk. Patients admitted to the Department of Haematology, Oncology and Transplant Surgery of the Medical University Innsbruck received a questionnaire regarding fungal exposure prior to hospital stay. Questions inquired heavy fungal exposures up to 5 days before hospitalisation. A total of 234 patients were enrolled in this study. Multiple fungus exposures were associated with the onset of community‐acquired IMI in patients with haematological malignancies. In univariate analysis, haematological malignancies (P = 0.013) and allergy to dust, pollen or moulds (P = 0.015) were significantly associated with fungal infections. In multivariate analysis, logistic regression showed that haematological patients (P = 0.015) and patients with allergy (P = 0.015) were significantly more frequently infected with fungi. Hospital‐independent fungal sources highlight risk‐factors for IMI in severe immunocompromised patients and the rate of community‐acquired IMI does increase.
Measuring ecological niche overlap from occurrence and spatial environmental data
Authors: Broennimann Olivier , Fitzpatrick Matthew C. , Pearman Peter B. , Petitpierre Blaise , Pellissier Loïc , Yoccoz Nigel G. , Thuiller Wilfried , Fortin Marie‐Josée , Randin Christophe , Zimmermann Niklaus E. , Graham Catherine H. , Guisan Antoine
Published: July 2011

Aim Concerns over how global change will influence species distributions, in conjunction with increased emphasis on understanding niche dynamics in evolutionary and community contexts, highlight the growing need for robust methods to quantify niche differences between or within taxa. We propose a statistical framework to describe and compare environmental niches from occurrence and spatial environmental data.

Location Europe, North America and South America.

Methods The framework applies kernel smoothers to densities of species occurrence in gridded environmental space to calculate metrics of niche overlap and test hypotheses regarding niche conservatism. We use this framework and simulated species with pre‐defined distributions and amounts of niche overlap to evaluate several ordination and species distribution modelling techniques for quantifying niche overlap. We illustrate the approach with data on two well‐studied invasive species.

Results We show that niche overlap can be accurately detected with the framework when variables driving the distributions are known. The method is robust to known and previously undocumented biases related to the dependence of species occurrences on the frequency of environmental conditions that occur across geographical space. The use of a kernel smoother makes the process of moving from geographical space to multivariate environmental space independent of both sampling effort and arbitrary choice of resolution in environmental space. However, the use of ordination and species distribution model techniques for selecting, combining and weighting variables on which niche overlap is calculated provide contrasting results.

Main conclusions The framework meets the increasing need for robust methods to quantify niche differences. It is appropriate for studying niche differences between species, subspecies or intra‐specific lineages that differ in their geographical distributions. Alternatively, it can be used to measure the degree to which the environmental niche of a species or intra‐specific lineage has changed over time.
The Big Chill: Interpersonal Coldness and Emotion‐Labeling Skills
Authors: Moeller Sara K. , Robinson Michael D. , Wilkowski Benjamin M. , Hanson Devin M.
Published: July 2011

Interpersonally cold (relative to warm) individuals may be less skilled in inferring the emotional states of others, a factor that should contribute to their poorer social relationships. Systematic support for this hypothesis was obtained in 4 studies (total N = 434 undergraduates) involving diverse emotion‐ and affect‐decoding tasks. Specifically, relatively cold individuals exhibited lower accuracy in decoding emotional facial expressions (Study 1), in labeling the emotions of others from audio and video clips (Study 2), in predicting the emotions of others from social scenario descriptions (Study 3), and in the normative accuracy of their word evaluations (Study 4). Altogether, the results demonstrate that cold individuals appear broadly deficient in linking emotion and affect to relevant environmental stimuli. Implications of the findings for understanding the nature and correlates of interpersonal coldness are discussed.
Trait Means and Desirabilities as Artifactual and Real Sources of Differential Stability of Personality Traits
Authors: Wood Dustin , Wortman Jessica
Published: July 2011

Using data from 3 personality trait inventories and 7 samples, we show that trait items that have means near the scale midpoint and that vary more in their perceived desirability (e.g., items related to dominance, creativity, traditionalism, and organization) tend to be more stable over time, whereas items with means near the scale maximum or minimum and that vary less in their perceived desirability (e.g., items related to agreeableness, intellect, and reliability) tend to be less stable. Our findings indicate that items with means near the scale maximum or minimum have lower stabilities primarily due to having lower measurement dependability (i.e., short‐term stabilities unlikely to reflect true change). However, items varying more in their desirability are more stable even after accounting for measurement dependability, consistent with the view that trait stability is facilitated in part by individuals actively working to develop in the direction they find desirable.
The Role of Perfectionism in Daily Self‐Esteem, Attachment, and Negative Affect
Authors: Dunkley David M. , Berg Jody‐Lynn , Zuroff David C.
Published: July 2011

This study of university students (64 men, 99 women) examined the role of self‐critical (SC) and personal standards (PS) higher order dimensions of perfectionism in daily self‐esteem, attachment, and negative affect. Participants completed questionnaires at the end of the day for 7 consecutive days. Trait and situational influences were found in the daily reports of self‐esteem, attachment, and affect. In contrast to PS perfectionism, SC perfectionism was strongly related to aggregated daily reports of low self‐esteem, attachment fears (fear of closeness, fear of dependency, fear of loss), and negative affect as well as instability indexes of daily self‐esteem, attachment, and negative affect. Multilevel modeling indicated that both SC and PS perfectionists were emotionally reactive to decreases in self‐esteem, whereas only SC perfectionists were emotionally reactive to increases in fear of closeness with others. These results demonstrate the dispositional and moderating influences of perfectionism dimensions on daily self‐esteem, attachment, and negative affect.
OVERSTATING VALUES: MEDICAL FACTS, DIVERSE VALUES, BIOETHICS AND VALUES‐BASED MEDICINE
Authors: PARKER MALCOLM
Published: July 2011

Fulford has argued that (1) the medical concepts illness, disease and dysfunction are inescapably evaluative terms, (2) illness is conceptually prior to disease, and (3) a model conforming to (2) has greater explanatory power and practical utility than the conventional value‐free medical model. This ‘reverse’ model employs Hare's distinction between description and evaluation, and the sliding relationship between descriptive and evaluative meaning. Fulford's derivative ‘Values Based Medicine’ (VBM) readjusts the imbalance between the predominance of facts over values in medicine. VBM allegedly responds to the increased choices made available by, inter alia, the progress of medical science itself. VBM attributes appropriate status to evaluative meaning, where strong consensus about descriptive meaning is lacking. According to Fulford, quasi‐legal bioethics, while it can be retained as a kind of deliberative framework, is outcome‐based and pursues ‘the right answer’, while VBM approximates a democratic, process‐oriented method for dealing with diverse values, in partnership with necessary contributions from evidence‐based medicine (EBM). I support the non‐cognitivist underpinnings of VBM, and its emphasis on the importance of values in medicine. But VBM overstates the complexity and diversity of values, misrepresents EBM and VBM as responses to scientific and evaluative complexity, and mistakenly depicts ‘quasi‐legal bioethics’ as a space of settled descriptive meaning. Bioethical reasoning can expose strategies that attempt to reduce authentic values to scientific facts, illustrating that VBM provides no advantage over bioethics in delineating the connections between facts and values in medicine.
STIGMATIZATION AND PUBLIC HEALTH ETHICS
Authors: COURTWRIGHT ANDREW
Published: July 2011

Encouraged by the success of smoking denormalization strategies as a tobacco‐control measure, public health institutions are adopting a similar approach to other health behaviors. For example, a recent controversial ad campaign in New York explicitly aimed to denormalize HIV/AIDS amongst gay men. Authors such as Scott Burris have argued that efforts like this are tantamount to stigmatization and that such stigmatization is unethical because it is dehumanizing. Others have offered a limited endorsement of denormalization/stigmatization campaigns as being justified on consequentialist grounds; namely, that the potential public health benefits outweigh any stigmatizing side effects. In this paper, I examine and reject the blanket condemnation of stigmatization efforts in public health. I argue that the moral status of such efforts are best evaluated within a contractualist, as opposed to a consequentialist, framework. Contractualism in public health ethics asks whether a particular stigmatizing policy could be justified to reasonable individuals who do not know whether they will be affected by that policy. Using this approach, I argue that it is sometimes permissible for public health institutions to engage in health‐related stigmatization.
GETTING MORAL ENHANCEMENT RIGHT: THE DESIRABILITY OF MORAL BIOENHANCEMENT
Authors: PERSSON INGMAR , SAVULESCU JULIAN
Published: July 2011

We respond to a number of objections raised by John Harris in this journal to our argument that we should pursue genetic and other biological means of morally enhancing human beings (moral bioenhancement). We claim that human beings now have at their disposal means of wiping out life on Earth and that traditional methods of moral education are probably insufficient to achieve the moral enhancement required to ensure that this will not happen. Hence, we argue, moral bioenhancement should be sought and applied. We argue that cognitive enhancement and technological progress raise acute problems because it is easier to harm than to benefit. We address objections to this argument. We also respond to objections that moral bioenhancement: (1) interferes with freedom; (2) cannot be made to target immoral dispositions precisely; (3) is redundant, since cognitive enhancement by itself suffices.
The rise and decline of European parliaments, 1188–17891
Authors: VAN ZANDEN JAN LUITEN , BURINGH ELTJO , BOSKER MAARTEN
Published: July 2011

This article quantifies the activities of medieval and early modern parliaments. It traces the long‐term evolution of this European institution, and offers a first pass at analysing its impact on long‐term economic development. Starting in Spain in the twelfth century, parliaments gradually spread over the Latin west between 1200 and 1500. In the early modern period, parliaments declined in influence in southern and central Europe and further gained in importance in the Netherlands and Britain, resulting in an institutional ‘Little Divergence’ between 1500 and 1800. We discuss the background of this phenomenon in detail. Moreover, by analysing the effects of parliamentary activity on city growth we find that these differences in institutional development help to explain the economic divergence between north‐western and southern and central Europe.
Child day‐labourers in agriculture: evidence from farm accounts, 1740–18501
Authors: BURNETTE JOYCE
Published: July 2011

While child labour has always been an important part of the industrial revolution story, there is little quantitative evidence about the number of child workers in the 1740–1850 period. This article estimates trends in the percentage of the agricultural day‐labouring workforce that were children. By using the wage level to identify child workers, it is possible to estimate child labour for a large sample of English farms. It is found that girls were rarely employed as day‐labourers, while boys were employed about as frequently as women. The percentage of boys in the day‐labour workforce increased until the 1820s and then declined.
Cultural and linguistic validation of acne‐QoL in French
Authors: Tan J. , O’Toole A. , Zhang X. , Dreno B. , Poulin Y.
Published: July 2011

Background  Acne‐Quality of Life (acne‐QoL) is a facial acne‐specific quality‐of‐life instrument developed in English.

Objective  Our objective was to translate and validate acne‐QoL in French and to establish the reliability and responsivity of this measure.

Methods  Acne‐QoL was translated into French (acne‐QoLfr) in accordance with international methodological recommendations. The validated French version of the Cardiff Acne Disability Index (CADIfr) was used as a comparator. Acne patients in Quebec (n = 20) and France (n = 14) completed the acne‐QoLfr and CADIfr on three occasions over 3 months (day 0, day 2–3, day 60–90).

Results  A total of 34 patients were recruited. Pearson’s correlation for total acne‐QoLfr scores at day 0 and day 2–3 was 0.77. Of the four domains comprising the acne‐QoLfr, correlations were highest for symptoms (0.85) and lowest for the role‐emotional domain (0.66). At day 60–90, total acne‐QoLfr scores increased by a mean of 19.7 points, reflecting improved quality‐of‐life with acne therapy and demonstrating responsivity of the instrument.

Conclusion  Acne‐QoLfr is a linguistically and culturally validated tool for facial acne that is both reliable and responsive.
Sexually transmitted infections in pregnant adolescents: prevalence and association with maternal and foetal morbidity
Authors: Borges‐Costa J. , Matos C. , Pereira F.
Published: July 2011

Background  Pregnant adolescents have a high incidence of sexually transmitted infections and higher risk of adverse birth outcome.

Objectives  To assess the prevalence of sexually transmitted infections in pregnant adolescents and the associations between these infections and adverse birth outcome.

Methods  A prospective study with a face‐to‐face interview to pregnant adolescents was followed by first‐void urine and cervical swabs collection for polymerase chain reaction testing for Chlamydia trachomatis and Neisseria gonorrhoeae. After child delivery, clinical files were also reviewed for serological and microbiological results for other infections and data concerning maternal–foetal morbidity. A 5% level of significance was used.

Results  The inclusion criteria were fulfilled by 204 pregnant adolescents, and the prevalence of C. trachomatis was 11.8% and of N. gonorrhoeae was 4.9%, with the majority being asymptomatic. No antibodies for syphilis or human immunodeficiency virus were found. Maternal morbidity occurred in 3.4%, prematurity was observed in 11.8% of the newborns and low birth weight in 9.8%. Statistically significant associations were observed between maternal morbidity and the presence of gonorrhoea, younger adolescents and severe prematurity and between infection with C. trachomatis and/or N. gonorrhoea and low birth weight.

Conclusions  Sexually transmitted infections are frequently asymptomatic and cause maternal–foetal morbidity. The opportunity that pregnancy offers for screening and counselling should not therefore be missed, especially in adolescents.
Fertility and prenatal attitudes towards pregnancy in women with eating disorders: results from the Avon Longitudinal Study of Parents and Children
Authors: Easter A , Treasure J , Micali N
Published: July 2011

Please cite this paper as: Easter A, Treasure J, Micali N. Fertility and prenatal attitudes towards pregnancy in women with eating disorders: results from the Avon Longitudinal Study of Parents and Children. BJOG 2011;118:1491–1498.

Objective  To study the effects of eating disorders (EDs) on fertility and attitudes to pregnancy.

Design  A longitudinal prospective birth cohort.

Setting  Avon area, UK.

Sample  A cohort of 14 663 women who enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). Singleton and live births were included across four groups of women: lifetime anorexia nervosa (AN; n = 171); lifetime bulimia nervosa (BN; n = 199), lifetime anorexia nervosa and bulimia nervosa (AN + BN; n = 82); and the general population (n = 10 636).

Methods  Fertility problems, conception time and attitudes to pregnancy were investigated in women with AN, BN and AN + BN, compared with the remaining sample (general population).

Main outcome measures  Having seen a doctor for fertility problems, time taken to conceive (>12 months, and >6 months), unplanned pregnancies, and attitudes to pregnancy at 12 and 18 weeks of gestation.

Results  Women with AN (OR 1.6, 95% CI 1.1–2.5; P < 0.021) and women with AN + BN (OR 1.9, 95% CI 1.1–3.4; P < 0.020) were more likely to have seen a doctor for lifetime fertility problems, and women with AN + BN were also more likely to take longer than 6 months to conceive (OR 1.9, 95% CI 1.0–3.5; P < 0.04), and to have conceived the current pregnancy with fertility treatment. Unplanned pregnancies were more common in the AN group compared with the general population. All ED groups more frequently experienced negative feelings upon discovering their pregnancy, which remained higher in the AN + BN group at 18 weeks of gestation.

Conclusions  Lifetime EDs are associated with fertility problems, unplanned pregnancies and negative attitudes to pregnancy. Health professionals should be aware of EDs when assessing fertility and providing treatment for this.
The Alzheimer’s therapeutic PBT2 promotes amyloid‐β degradation and GSK3 phosphorylation via a metal chaperone activity
Authors: Crouch Peter J. , Savva Maria S. , Hung Lin W. , Donnelly Paul S. , Mot Alexandra I. , Parker Sarah J. , Greenough Mark A. , Volitakis Irene , Adlard Paul A. , Cherny Robert A. , Masters Colin L. , Bush Ashley I. , Barnham Kevin J. , White Anthony R.
Published: July 2011

J. Neurochem. (2011) 119, 220–230.

Impaired metal ion homeostasis causes synaptic dysfunction and treatments for Alzheimer’s disease (AD) that target metal ions have therefore been developed. The leading compound in this class of therapeutic, PBT2, improved cognition in a clinical trial with AD patients. The aim of the present study was to examine the cellular mechanism of action for PBT2. We show PBT2 induces inhibitory phosphorylation of the α‐ and β‐isoforms of glycogen synthase kinase 3 and that this activity is dependent on PBT2 translocating extracellular Zn and Cu into cells. This activity is supported when Aβ:Zn aggregates are the source of extracellular Zn and adding PBT2 to Aβ:Zn preparations promotes Aβ degradation by matrix metalloprotease 2. PBT2‐induced glycogen synthase kinase 3 phosphorylation appears to involve inhibition of the phosphatase calcineurin. Consistent with this, PBT2 increased phosphorylation of other calcineurin substrates, including cAMP response element binding protein and Ca2+/calmodulin‐dependent protein kinase. These data demonstrate PBT2 can decrease Aβ levels by sequestering the Zn that promotes extracellular formation of protease resistant Aβ:Zn aggregates, and that subsequent intracellular translocation of the Zn by PBT2 induces cellular responses with synapto‐trophic potential. Intracellular translocation of Zn and Cu via the metal chaperone activity of PBT2 may be an important mechanism by which PBT2 improves cognitive function in people with AD.
Crx broadly modulates the pineal transcriptome
Authors: Rovsing Louise , Clokie Samuel , Bustos Diego M. , Rohde Kristian , Coon Steven L. , Litman Thomas , Rath Martin F. , Møller Morten , Klein David C.
Published: July 2011

J. Neurochem. (2011) 119, 262–274.

Cone‐rod homeobox (Crx) encodes Crx, a transcription factor expressed selectively in retinal photoreceptors and pinealocytes, the major cell type of the pineal gland. In this study, the influence of Crx on the mammalian pineal gland was studied by light and electron microscopy and by use of microarray and qRTPCR technology, thereby extending previous studies on selected genes (Furukawa et al. 1999). Deletion of Crx was not found to alter pineal morphology, but was found to broadly modulate the mouse pineal transcriptome, characterized by a > 2‐fold down‐regulation of 543 genes and a > 2‐fold up‐regulation of 745 genes (p < 0.05). Of these, one of the most highly up‐regulated (18‐fold) was Hoxc4, a member of the Hox gene family, members of which are known to control gene expression cascades. During a 24‐h period, a set of 51 genes exhibited differential day/night expression in pineal glands of wild‐type animals; only eight of these were also day/night expressed in the Crx−/− pineal gland. However, in the Crx−/− pineal gland 41 genes exhibited differential night/day expression that was not seen in wild‐type animals. These findings indicate that Crx broadly modulates the pineal transcriptome and also influences differential night/day gene expression in this tissue. Some effects of Crx deletion on the pineal transcriptome might be mediated by Hoxc4 up‐regulation.
Regulation of angiotensinogen by angiotensin II in mouse primary astrocyte cultures
Authors: O’Callaghan E. L. , Bassi J. K. , Porrello E. R. , Delbridge L. M. D. , Thomas W. G. , Allen A. M.
Published: July 2011

J. Neurochem. (2011) 119, 18–26.

Astrocytes are the major source of angiotensinogen in the brain and play an important role in the brain renin‐angiotensin system. Regulating brain angiotensinogen production alters blood pressure and fluid and electrolyte homeostasis. In turn, several physiological and pathological manipulations alter expression of angiotensinogen in brain. Surprisingly, little is known about the factors that regulate astrocytic expression of angiotensinogen. There is evidence that angiotensinogen production in both hepatocytes and cardiac myocytes can be positively regulated via the angiotensin type 1 receptor, but this effect has not yet been studied in astrocytes. Therefore, the aim of this project was to establish whether angiotensin II modulates angiotensinogen production in brain astrocytes. Primary astrocyte cultures, prepared from neonatal C57Bl6 mice, expressed angiotensinogen measured by immunocytochemistry and real‐time PCR. Using a variety of approaches we were unable to identify angiotensin receptors on cultured astrocytes. Exposure of cultured astrocytes to angiotensin II also did not affect angiotensinogen expression. When astrocyte cultures were transduced with the angiotensin type 1A receptor, using adenoviral vectors, angiotensin II induced a robust down‐regulation (91.4% ± 1.8%, p < 0.01, n = 4) of angiotensinogen gene expression. We conclude that receptors for angiotensin II are present in extremely low levels in astrocytes, and that this concurs with available data in vivo. The signaling pathways activated by the angiotensin type 1A receptor are negatively coupled to angiotensinogen expression and represent a powerful pathway for decreasing expression of this protein, potentially via signaling pathways coupled to Gαq/11.
Optical and biometric characteristics of anisomyopia in human adults
Authors: Tian Yibin , Tarrant Janice , Wildsoet Christine F
Published: July 2011

Citation information: Tian Y, Tarrant J & Wildsoet CF. Optical and biometric characteristics of anisomyopia in human adults. Ophthalmic Physiol Opt 2011, 31, 540–549. doi: 10.1111/j.1475‐1313.2011.00858.x

Purpose:  To investigate the role of higher order optical aberrations and thus retinal image degradation in the development of myopia, through the characterization of anisomyopia in human adults in terms of their optical and biometric characteristics.

Methods:  The following data were collected from both eyes of 15 young adult anisometropic myopes and 16 isometropic myopes: subjective and objective refractive errors, corneal power and shape, monochromatic optical aberrations, anterior chamber depth, lens thickness, vitreous chamber depth, and best corrected visual acuity. Monochromatic aberrations were analyzed in terms of their higher order components, and further analyzed in terms of 31 optical quality metrics. Interocular differences for the two groups (anisomyopes vs isomyopes) were compared and the relationship between measured ocular parameters and refractive errors also analyzed across all eyes.

Results:  As expected, anisomyopes and isomyopes differed significantly in terms of interocular differences in vitreous chamber depth, axial length and refractive error. However, interocular differences in other optical properties showed no significant intergroup differences. Overall, higher myopia was associated with deeper anterior and vitreous chambers, higher astigmatism, more prolate corneas, and more positive spherical aberration. Other measured optical and biometric parameters were not significantly correlated with spherical refractive error, although some optical quality metrics and corneal astigmatism were significantly correlated with refractive astigmatism.

Conclusions:  An optical cause for anisomyopia related to increased higher order aberrations is not supported by our data. Corneal shape changes and increased astigmatism in more myopic eyes may be a by‐product of the increased anterior chamber growth in these eyes; likewise, the increased positive spherical aberration in more myopic eyes may be a product of myopic eye growth.
Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review
Authors: Dwyer Jeremy P. , Sarwar Shahzad , Egan Brian , Nolan Niamh , Hegarty John
Published: July 2011

Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56‐year‐old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.
Role of stress‐induced NKG2D ligands in liver diseases
Authors: Kahraman Alisan , Fingas Christian D. , Syn Wing‐Kin , Gerken Guido , Canbay Ali
Published: July 2011

Cell death by apoptosis is a prominent feature in a variety of liver diseases. It is likely that apoptosis is the initial cellular response to hepatocyte and biliary injury, which then leads to the initiation of cellular and cytokine cascades culminating in hepatocyte death with subsequent fibrosis and cirrhosis. This sequence of events is of paramount clinical importance. Recently, soluble forms of the major histocompatibility complex class I‐related chains A and closely related B (MIC A and B) were reported to be increased in patients with a variety of liver diseases. MIC A and B are cell surface glycoproteins that function as indicators for cellular stress and thus activate circulating cytotoxic natural killer (NK) cells. The interaction between MIC A and B with their cognate receptor natural killer group 2 member D (NKG2D) culminates in enhanced liver cell death, which is mediated in part by apoptotic mechanisms. The present overview focuses on the role of the stress‐induced NKG2D ligands MIC A and B in diverse liver diseases. Critical insights into these complex relations may help to promote rationally based therapies in liver diseases. Importantly, we hope that this overview will help to stimulate further studies into mechanisms by which stress ligands mediate cell death and its sequale.
Aquaporin‐1 associated with hepatic arterial capillary proliferation on hepatic sinusoid in human cirrhotic liver
Authors: Yokomori Hiroaki , Oda Masaya , Yoshimura Kazunori , Kaneko Fumihiko , Hibi Toshifumi
Published: July 2011

Background

Aquaporins (AQPs) are key regulators not only of water transport in the cytoplasm but also of angiogenesis. Although AQPs in the normal hepatobiliary system have been studied in mammals, little is known about the localization and changes of AQPs in the hepatic microvascular system including sinusoids in cirrhotic liver, which might contribute to portal hypertension.

Aims

We designed this study to examine the localization of AQP1 in human cirrhotic liver.

Methods

Surgical wedge biopsy specimens were obtained from non‐cirrhotic portions of human livers (normal control) and from cirrhotic livers (LC) (Child A‐LC and Child C‐LC). Immunostaining, Western blotting, in situ hybridization (ISH) and laser‐captured microdissection (LCM) were conducted.

Results

In control liver tissue, AQP1 was localized mainly in the portal venules, hepatic arterioles and bile ducts in the portal tract, although AQP1 was detected only slightly in the sinusoids. In cirrhotic liver tissue, AQP1 expression was evident, aberrantly observed on periportal sinusoidal endothelial cells corresponding to the capillarized sinusoids, on the proliferated arterial capillaries opening into the sinusoid in the generating hepatic nodule and on proliferated bile ductules at the peripheral edge of nodules and fibrotic septa. In cirrhotic liver, overexpression of AQP1 at protein and mRNA levels was demonstrated, respectively, using Western blot and ISH. AQP‐1 of mRNA level in sinusoid was confirmed using LCM.

Conclusions

Aberrant expressions of AQP1 in periportal sinusoidal regions in human cirrhotic liver indicate the proliferation of arterial capillaries directly connected to the sinusoids, contributing to microvascular resistance in cirrhosis.
Pharmacological Treatment of Neuropathic Cancer Pain: A Comprehensive Review of the Current Literature
Authors: Vadalouca Athina , Raptis Efklidis , Moka Eleni , Zis Panagiotis , Sykioti Panagiota , Siafaka Ioanna
Published: July 2011

Abstract:  Neuropathic cancer pain (NCP), commonly encountered in clinical practice, may be cancer‐related, namely resulting from nervous system tumor invasion, surgical nerve damage during tumor removal, radiation‐induced nerve damage and chemotherapy‐related neuropathy, or may be of benign origin, unrelated to cancer. A neuropathic component is evident in about 1/3 of cancer pain cases. Although from a pathophysiological perspective NCP may differ from chronic neuropathic pain (NP), such as noncancer‐related pain, clinical practice, and limited publications have shown that these two pain entities may share some treatment modalities. For example, co‐analgesics have been well integrated into cancer pain‐management strategies and are often used as First‐Line options for the treatment of NCP. These drugs, including antidepressants and anticonvulsants, are recommended by evidence‐based guidelines, whereas, others such as lidocaine patch 5%, are supported by randomized, controlled, clinical data and are included in guidelines for restricted conditions treatment. The vast majority of these drugs have already been proven useful in the management of benign NP syndromes. Treatment decisions for patients with NP can be difficult. The intrinsic difficulties in performing randomized controlled trials in cancer pain have traditionally justified the acceptance of drugs already known to be effective in benign NP for the management of malignant NP, despite the lack of relevant high quality data. Interest in NCP mechanisms and pharmacotherapy has increased, resulting in significant mechanism‐based treatment advances for the future. In this comprehensive review, we present the latest knowledge regarding NCP pharmacological management.
Current Considerations for the Treatment of Severe Chronic Pain: The Potential for Tapentadol
Authors: Pergolizzi Joseph , Alegre Cayetano , Blake David , Alén Jaime Calvo , Caporali Roberto , Casser Hans‐Raimund , Correa‐Illanes Gerardo , Fernandes Pedro , Galilea Eugenio , Jany Richard , Jones Anthony , Mejjad Othmane , Morovic‐Vergles Jadranka , Oteo Álvaro Ángel , Radrigán Araya Francisco J. , Simões Maria Eugénia C. , Uomo Generoso
Published: July 2011

Abstract  Studies suggest that around 20% of adults in Europe experience chronic pain, which not only has a considerable impact on their quality of life but also imposes a substantial economic burden on society. More than one‐third of these people feel that their pain is inadequately managed. A range of analgesic drugs is currently available, but recent guidelines recommend that NSAIDs and COX‐2 inhibitors should be prescribed cautiously. Although the short‐term efficacy of opioids is good, adverse events are common and doses are frequently limited by tolerability problems. There is a perceived need for improved pharmacological treatment options.

Currently, many treatment decisions are based solely on pain intensity. However, chronic pain is multifactorial and this apaproach ignores the fact that different causative mechanisms may be involved. The presence of more than one causative mechanism means that chronic pain can seldom be controlled by a single agent. Therefore, combining drugs with different analgesic actions increases the probability of interrupting the pain signal, but is often associated with an increased risk of drug/drug interactions, low compliance and increased side effects.

Tapentadol combines μ‐opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule, with both mechanisms contributing to its analgesic effects. Preclinical testing has shown that μ‐opioid agonism is primarily responsible for analgesia in acute pain, whereas noradrenaline reuptake inhibition is more important in chronic pain. In clinical trials in patients with chronic pain, the efficacy of tapentadol was similar to that of oxycodone, but it produced significantly fewer gastrointestinal side‐effects and treatment discontinuations. Pain relief remained stable throughout a 1‐year safety study. Thus, tapentadol could possibly overcome some of the limitations of currently available analgesics for the treatment of chronic pain.
Measuring Functioning in People with Fibromyalgia (FM) Based on the International Classification of Functioning, Disability and Health (ICF)—A Psychometric Analysis
Authors: Prodinger Birgit , Salzberger Thomas , Stucki Gerold , Stamm Tanja , Cieza Alarcos
Published: July 2011

Objectives:  Instruments to assess functioning in patients with FM vary considerably in their content and are often symptom‐specific. This study aimed to examine whether it is feasible to construct a psychometric‐sound clinical instrument to measure functioning in FM based on the Brief ICF‐Core‐Set for chronic widespread pain (CWP).

Methods:  Two hundred and fifty six people with FM completed the Brief ICF‐Core‐Set. The Rasch model was used for analysis. Once ordering of response options of ICF categories was ensured, the following properties were studied: fit of the ICF categories to the Rasch model, the targeting between ICF categories and a person’s abilities, unidimensionality, and reliability.

Results:  Six ICF categories were rescored due to disordered thresholds. Five ICF categories were removed due to high model‐misfit and differential item functioning (DIF) for gender. Scores from 46 participants were excluded due to extreme scores. The ICF categories included display consistency with an underlying unidimensional construct, are free of DIF for age, disease duration and gender, display excellent overall reliability, and cover a range of functioning difficulties.

Conclusions:  This study illustrates that it is possible to measure functioning as a unidimensional construct based on selected ICF categories from the components body functions, as well as activities and participation of the Brief ICF‐Core‐Set for CWP in patients with FM.
Is Spinal Cord Stimulation an Effective Treatment Option for Discogenic Pain?
Authors: Vallejo Ricardo , Manuel Zevallos L. , Lowe Jessica , Benyamin Ramsin
Published: July 2011

Introduction:  In a prospective observational study conducted in an urban pain management center, we evaluated whether spinal cord stimulation (SCS) is effective in relieving discogenic pain of IDD origin.

Methods:  Thirteen patients with intractable discogenic low back pain were enrolled. Four patients never underwent permanent implantation due to insurance denial, medical reasons or failed trial and served as a control group. Nine patients underwent SCS implantation (treatment group). All patients were followed for 12 months and assessed at each interval for pain (NRS), disability (ODI), and opioid use.

Results:  Nine patients completed the SCS trial with > 50% pain relief. The pretrial NRS score was 7.8 ± 0.5 mm in treated patients vs. 6.5 ± 1.7 mm in control patients. At 3, 6 and 12 months, the NRS was reduced to 2.9 ± 0.7 mm, 1.7 ± 0.5 mm, and 2.9 ± 0.5 mm, respectively in treated patients. NRS was unchanged in the control patients (6.5 ± 1.9 mm). The ODI score prior to the SCS trial in treated patients was 53.1 ± 3.4% vs. 54.0 ± 20.5 in control patients. At 3, 6 and 12 months the ODI scores were 39.0 ± 8.0%, 38.7 ± 4.6%, and 41.1 ± 3.9%, respectively in the treated patients, and 48.5 ± 29.5 at 12 months in control patients. In 6 patients receiving opioids prior to the SCS trial, average consumption was reduced by 69% (P = 0.036) over 12 months of therapy as compared with a 54% increase in the control patients. SCS usage was stable over the 12‐month study.

Conclusions:  The current study indicates that SCS may provide effective pain relief, improve disability, and reduce opioid usage in patients with discogenic pain.