bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurokinin 1 receptor‐expressing projection neurons in laminae III and IV of the rat spinal cord have synaptic AMPA receptors that contain GluR2, GluR3 and GluR4 subunits
Authors: Todd Andrew J. , Polgár Erika , Watt Christine , Bailey Mark E.S. , Watanabe Masahiko
Published: February 2009

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPArs), which mediate fast excitatory glutamatergic transmission, are tetramers made from four subunits (GluR1–4 or GluRA–D). Although synaptic AMPArs are not normally detected by immunocytochemistry in perfusion‐fixed tissue, they can be revealed by using antigen retrieval with pepsin. All AMPAr‐positive synapses in spinal cord are thought to contain GluR2, while the other subunits have specific laminar distributions. GluR4 can be alternatively spliced such that it has a long or short cytoplasmic tail. We have reported that <10% of AMPAr‐containing synapses in lamina II have the long form of GluR4, and that these are often arranged in dorsoventrally orientated clusters. In this study, we test the hypothesis that GluR4‐containing receptors are associated with dorsal dendrites of projection neurons in laminae III and IV that express the neurokinin 1 receptor (NK1r). Immunostaining for NK1r was carried out before antigen retrieval, and sections were then reacted to reveal GluR2 and either GluR4 (long form), GluR3 or GluR1. All NK1r‐positive lamina III/IV neurons had numerous GluR2‐immunoreactive puncta in their dendritic plasma membranes, and virtually all (97%) of the puncta tested were labelled (usually strongly) with the GluR4 antibody. Sizes of puncta varied, but many were elongated and they were significantly larger than nearby puncta that were not associated with the NK1r cells. None of the GluR2 puncta on these cells was positive for GluR1, while 85% were GluR3‐immunoreactive. These results show that synaptic AMPArs on the dendrites of the lamina III/IV NK1r projection neurons contain GluR2, GluR3 and GluR4, but not GluR1 subunits.
Anorectal manometry with water‐perfused catheter in healthy adults with no functional bowel disorders
Authors:   Gruppo Lombardo per lo Studio della Motilità Intestinale
Published: February 2009

Anorectal manometry provides an objective assessment of anal sphincter pressure and rectal sensitivity and anorectal reflexes in response to distension. However, its clinical utility is hampered by a lack of standardized protocols and normative data from healthy subjects. Previous studies have used water‐perfused systems in normal subjects, but some adopted a rapid pull‐through technique; others did not evaluate rectal sensations and others did not carefully exclude patients with functional bowel disorders.

Objective  To evaluate anorectal function in healthy adults without functional bowel disorders, using a water‐perfused system with the stationary technique in order to obtain normative values for anorectal manometry.

Method  Fifty‐two healthy volunteers with no Rome II diagnostic criteria for functional bowel disorders, including only nulliparous women, underwent anorectal manometry with a water‐perfused system, according to a standardized protocol.

Results  Maximum squeeze pressure of the anal sphincter as well as the area under the pressure‐time curve during squeeze was significantly lower in women than men (P < 0.01), while sphincter length, resting pressure, volume thresholds for reflex inhibitory recto‐anal and rectal sensations were similar.

Conclusions  This study describes a protocol for stationary anorectal manometry using a water‐perfused system, and a method for analysing the various parameters obtained during the procedure, as recently suggested in the international literature. It supplies normative data obtained in a population of healthy subjects including nulliparous women, with no functional bowel disorders.
Capecitabine plus oxaliplatin vs fluorouracil plus oxaliplatin as first line treatment for metastatic colorectal caner – meta‐analysis of six randomized trials
Authors: Cao Y. , Liao C. , Tan A. , Liu L. , Mo Z. , Gao F.
Published: February 2009

Objective  This meta‐analysis was performed to evaluate the efficacy and safety of capecitabine plus oxaliplatin vs fluorouracil (FU) plus oxaliplatin as first line treatment for metastatic or advanced colorectal cancer.

Method  A total of 2196 patients from six randomized controlled trials were available for analysis, which included 1105 patients in capecitabine plus oxaliplatin group and 1091 patients in FU plus oxaliplatin group. The efficacy data included overall survival (OS), progression‐free survival (PFS), time to treatment failure (TTF), overall response rate (ORR), and the safety data contained specific grade 3 and 4 toxicity such as anaemia, thrombocytopenia, neutropenia, diarrhoea, nausea, asthenia, vomiting, abdominal pain, hand foot syndrome, neuropathy and stomatitis were evaluated.

Results  Pooled analysis of OS (hazards ratio HR = 1.04, 95%CI: 0.95–1.14), PFS (1.08, 0.98–1.18), ORR (odds ratio OR = 0.87, 0.73–1.03) in the capecitabine plus oxaliplatin group shows no statistical significance when compared with those in the FU plus oxaliplatin group. The statistically significant differences in pooled estimates suggest a higher incidence of grade 3/4 thrombocytopenia (OR = 1.87, 1.24–2.81), grade 3/4 hand‐foot syndrome (3.90, 2.13–7.12) in the capecitabine plus oxaliplatin group and grade 3/4 neutropenia (0.20, 0.07–0.53) in the FU plus oxaliplatin group. No statistically significant difference was noted in the incidence of grade 3/4 anaemia, asthenia, diarrhoea, nausea, vomiting, abdominal pain, neuropathy and stomatitis.

Conclusion  The effect of capecitabine plus oxaliplatin regimen is similar to FU plus oxaliplatin regimen as first line treatment for metastatic colorectal cancer, but it offers advantages of simplicity and convenience to administer.
The Influence of China's Entry into the WTO on its Education System
Authors: DING XIAOHAO , YUE CHANGJUN , SUN YUZE
Published: February 2009

The entry of China in the World Trade Organization (WTO) in 2001 holds a number of promises for educational services. The purpose of this article is to explore both the direct and the indirect influence of China's entry into WTO on its education system. The direct influence mainly refers to the increase in the demand for education overseas and in the number of foreign students studying in China, the cooperation between China and educational institutions overseas, and China's administrative and legal frameworks for education. As to the indirect influence, the article focuses on the impact of economic growth on public and private expenditure on education, of income growth on demand for education and of changes in industrial structure on educational output. On this basis, the article examines the challenges that China's education system will face following its entry into the WTO.
The Education Lending Policy of the European Investment Bank
Authors: TUIJNMAN ALBERT
Published: February 2009

The purpose of this article is to present the latest Education Lending Policy (ELP) of the European Investment Bank (EIB), adopted by the Board of Governors in 2008. It is structured in two parts. The first briefly presents the EIB in general and the evolution of its education lending portfolio in particular. This sets the stage for the second part of the article, which reproduces the Bank's new ELP — only the second such formal education sector policy statement adopted by the institution to date.
Funding Allocation and Staff Management. A Portuguese Example
Authors: ROSA MARIA JOÃO , AMADO DIANA , AMARAL ALBERTO
Published: February 2009

For many years the Portuguese Ministry of Education used a funding formula to allocate the State budget to public higher education institutions. Some of its major objectives were higher enrolments and allocation equity. As the expenditure on salaries was a major component of the budget, the formula was supposed to force convergence to established standard staff/student ratios. This article analyses the evolution of staff numbers in Portuguese public universities to assess how successful the funding formula has been in forcing convergence to standard staff numbers.
Fish venom: pharmacological features and biological significance
Authors: Sivan Gisha
Published: February 2009

Nearly 1200 species of marine fish are venomous and they account for two‐third of the population of venomous vertebrates. Fish venoms are focused as a potential source of pharmacological agents and physiological tools that have evolved to target vital processes in the human body that appear to have more electivity than many drugs. Fish venoms possess cardiovascular, neuromuscular, oedematic and cytolytic activity. Lethal toxins have been isolated and purified, with some having LD50 values comparable to that of snake venoms. Cardiovascular activity seems to be the dominant effect of fish venoms in experimental models. Piscine venom acts both pre‐ and post‐junctionally to produce depolarization of cell membranes. Studies on cytolytic activity of fish venom found that it produces lysis by forming hydrophilic pores in cell membranes which then result in cell lysis. Almost all fish venoms with neuromuscular activity also possesses cytolytic activity, and it is very likely that the two activities are related. Fish venom is known to induce intense and sustained edematogenic response. As piscine venoms have evolved for the same purpose, they show a number of similarities pharmacologically and it seems likely that most of the biological activities of any given toxin can be traced back to its cytolytic activity. A variety of toxins have been isolated from piscine venom. Although there is a complex balance between the components present in the venom of different fish, all of them seem to share similar activity – functionally and pharmacologically as well as structurally.
Age Differences in Future Orientation and Delay Discounting
Authors: Steinberg Laurence , Graham Sandra , O’Brien Lia , Woolard Jennifer , Cauffman Elizabeth , Banich Marie
Published: February 2009

Age differences in future orientation are examined in a sample of 935 individuals between 10 and 30 years using a delay discounting task as well as a new self‐report measure. Younger adolescents consistently demonstrate a weaker orientation to the future than do individuals aged 16 and older, as reflected in their greater willingness to accept a smaller reward delivered sooner than a larger one that is delayed, and in their characterizations of themselves as less concerned about the future and less likely to anticipate the consequences of their decisions. Planning ahead, in contrast, continues to develop into young adulthood. Future studies should distinguish between future orientation and impulse control, which may have different neural underpinnings and follow different developmental timetables.
Multiple Child‐Care Arrangements and Young Children’s Behavioral Outcomes
Authors: Morrissey Taryn W.
Published: February 2009

Nationally, 15% of children younger than 5 years regularly attend more than 1 child‐care arrangement. An association between arrangement multiplicity and children’s behavior problems has been identified, but previous research may be susceptible to measurement or omitted variable bias. This study used within‐child fixed effects models to examine associations between changes in the number of concurrent, nonparental child‐care arrangements and changes in mother‐ and caregiver‐reported behavior among 2‐ and 3‐year‐old children in the National Institute for Child Health and Human Development Study of Early Child Care and Youth Development (N= 850). Increases in the number of arrangements were related to increases in children’s concurrent behavior problems and decreases in prosocial behaviors, particularly among girls and younger children. Implications for policy and research are discussed.
The Development of Children’s Ability to Use Evidence to Infer Reality Status
Authors: Tullos Ansley , Woolley Jacqueline D.
Published: February 2009

These studies investigate children’s use of scientific reasoning to infer the reality status of novel entities. Four‐ to 8‐year‐olds heard about novel entities and were asked to infer their reality status from 3 types of evidence: supporting evidence, irrelevant evidence, and no evidence. Experiment 1 revealed that children used supporting versus irrelevant and no evidence differentially. Experiment 2 demonstrated that children without initial reality status biases were better at evaluating evidence than were biased children. In conclusion, the ability to infer reality status from evidence develops incrementally between ages 4 and 6, and children perform better when their evaluation is free from bias.
Adolescents’ and Parents’ Evaluations of Helping Versus Fulfilling Personal Desires in Family Situations
Authors: Smetana Judith G. , Tasopoulos‐Chan Marina , Gettman Denise C. , Villalobos Myriam , Campione‐Barr Nicole , Metzger Aaron
Published: February 2009

A sample of 118 predominantly European American families with early and middle adolescents (Mages= 12.32 and 15.18 years) and 1 parent evaluated hypothetical conflicts between adolescents’ and parents’ requests for assistance versus the other’s personal desires. Evaluations differed by level of need, but in low‐need situations, adolescents viewed teens as more obligated to help parents than did parents, whereas parents rated it as more permissible for teens to satisfy personal desires than did teenagers. Justifications for helping focused on concern for others, role responsibilities, and among parents, psychological reasons. Middle adolescents reasoned about role responsibilities more and viewed satisfying personal desires as less selfish than did early adolescents, but satisfying personal desires was seen as more selfish by parents of middle than early adolescents. Implications for adolescent–parent relationships are discussed.
Family, Neighborhood, and Peer Characteristics as Predictors of Child Adjustment: A Longitudinal Analysis of Additive and Mediation Models
Authors: Criss Michael M. , Shaw Daniel S. , Moilanen Kristin L. , Hitchings Julia E. , Ingoldsby Erin M.
Published: February 2009

The purpose of this study was to test direct, additive, and mediation models involving family, neighborhood, and peer factors in relation to emerging antisocial behavior and social skills. Neighborhood danger, maternal depressive symptoms, and supportive parenting were assessed in early childhood. Peer group acceptance was measured in middle childhood, and data on antisocial behavior and social skills were collected when boys were 11 and 12 years old. Results were consistent with an additive effects model of child antisocial behavior. In contrast, peer relationships were stronger predictors of social skills than were family factors. Support for mediation was found in models involving neighborhood danger and supportive parenting. However, only peer group acceptance predicted change in antisocial and prosocial behavior. Implications for family and peer relations as socialization contexts are discussed.
Hunters, ritual, and freedom:dozosacrifice as a technology of the self in theBenkadimovement of Côte d'Ivoire
Authors: Hellweg Joseph
Published: February 2009

This article argues thatdozohunters in Côte d'Ivoire used sacrifice to become unofficial police in the 1990s as part of a security movement they calledBenkadi. Scholars have noted similar transformations of West African hunters into soldiers, park guards, and development agents in the context of political, economic, and ecological changes. Although such changes created the conditions in whichdozos assumed national security roles, these conditions alone fail to explain whydozos became police. I exploredozosacrifice as a ‘technology of the self’ in Foucault's terms to argue thatdozos freely assumed security roles as ethical responsibilities analogous to those implicit in their hunting and occult pursuits. I draw on Frankl and Laidlaw to explain the emotional and practical aspects of such self‐fashioning. The cultural analysis ofdozorituals clarifies the waysdozoagency shaped the impact of political economy and ecology ondozopractice.

L'article affirme que dans les années 1990, les chasseursdozode Côte‐d'Ivoire ont utilisé le sacrifice pour se constituer en police officieuse au sein d'un groupement de sécurité qu'ils ont appeléBenkadi. Les chercheurs ont noté une évolution similaire par laquelle d'autres chasseurs d'Afrique de l'Ouest devenaient soldats, garde‐chasse ou agents de développement, dans le contexte des changements politiques, économiques et écologiques. Bien que ces changements aient créé les conditions dans lesquelles lesdozos se sont chargés de fonctions de sûreté nationale, ces conditions ne suffisent pas à expliquer comment ils en sont venus à constituer une force de l'ordre. L'auteur explore le sacrifice desdozoscomme une «technologie de soi», selon les termes de Foucault, pour avancer qu'ils ont librement endossé des rôles de sûreté impliquant des responsabilités éthiques proches de celles implicitement contenues dans leurs chasses et leurs pratiques occultes. Il invoque Frankl et Laidlaw pour expliquer les aspects émotionnels et pratiques de cet auto‐façonnage. L'analyse culturelle des rituels desdozoséclaircit la manière dont ils ont agi pour donner forme aux effets de l'économie et de l'écologie politiques sur leurs pratiques.
Mortality is influenced by locality in a major HIV/AIDS epidemic
Authors: Druyts EF , Rachlis BS , Lima VD , Harvard SS , Zhang W , Brandson EK , Strathdee SA , Montaner JSG , Hogg RS
Published: February 2009

Objectives

The aim of the study was to compare the risks of death among HIV‐infected patients on highly active antiretroviral therapy (HAART) in two proximate, yet distinct neighbourhoods: a neighbourhood with a high concentration of gay men, and a neighbourhood with a high concentration of injecting drug users.

Methods

We compared the clinical and socioeconomic characteristics of HIV‐infected patients from the two neighbourhoods entering the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program from 1 September 1997 to 30 November 2005, using contingency table statistics. Cox survival models and Kaplan–Meier methods were used to estimate the cumulative mortality rates.

Results
We found significant differences between patients from the two neighbourhoods for all socioeconomic variables. Patients in the neighbourhood with a high concentration of injecting drug users were more likely to be female, have a history of injecting drug use, have a less HIV‐experienced physician and be less adherent. Patients in the neighbourhood with a high concentration of gay men were more likely to have AIDS. Mortality was significantly higher for patients in the neighbourhood with a high concentration of injecting drug users [hazard ratio (HR) 3.01; 95% confidence interval (CI) 1.73, 5.24].

Conclusions

A threefold increase was observed in the risk of death among HIV‐infected individuals on HAART in the neighbourhood with a high concentration of injecting drug users relative to the neighbourhood with a high concentration of gay men. The implications of this study should be assessed in similar HIV/AIDS epicentres.
Effects of ritonavir‐boosted darunavir vs. ritonavir‐boosted atazanavir on lipid and glucose parameters in HIV‐negative, healthy volunteers
Authors: Tomaka F , Lefebvre E , Sekar V , Van Baelen B , Vangeneugden T , Vandevoorde A , Diego Miralles G
Published: February 2009

Background

Darunavir (TMC114) is a new HIV protease inhibitor (PI).

Design

This Phase I, randomized, open‐label trial compared the effects of darunavir plus low‐dose ritonavir (RTV) (darunavir/RTV) with those of atazanavir/RTV on lipid and glucose parameters.

Methods

Forty‐nine HIV‐negative, healthy male volunteers received RTV 100 mg once a day (qd) for 7 days, followed by either darunavir/RTV 800/100 mg qd (n=25) or atazanavir/RTV 300/100 mg qd (n=24) for 21 days. Mean changes in fasting lipid and glucose parameters at day 28 were calculated using post‐RTV alone (day 7) and baseline (day −1) values as references. Short‐term safety, tolerability and RTV pharmacokinetic parameters were evaluated.

Results

After 7 days of RTV treatment, the mean triglyceride concentration increased by approximately 30 mg/dL in both groups, changes in other lipid and glucose parameters were relatively small. Mean concentrations of lipids and glucose over the treatment period were mostly similar between the treatment groups. Mean changes from day 7 to day 28 for the darunavir/RTV and atazanavir/RTV groups, respectively, were −3.6 and −0.5 mg/dL for high‐density lipoprotein cholesterol; 5.0 and 5.3 mg/dL for low‐density lipoprotein cholesterol; 4.9 and 1.2 mg/dL for total cholesterol; 6.4 and 14.0 mg/dL for triglycerides; −1.7 and −2.4 mg/dL for glucose; and −1.4 and 0.3 mg/dL for insulin. No grade 3 or 4 lipid or glucose laboratory abnormalities were reported. Treatment‐emergent hyperbilirubinaemia was reported for all volunteers (including five grade 4 cases) during atazanavir/RTV treatment.

Conclusions

Co‐administration of darunavir or atazanavir with low‐dose RTV resulted in minor and similar changes in lipid and glucose parameters in HIV‐negative healthy volunteers.
Climate warming and reproduction in Chinese alligators
Authors: Zhang F. , Li Y. , Guo Z. , Murray B. R.
Published: February 2009

The Chinese alligatorAlligator sinensisis a critically endangered species endemic to China, and one of the most endangered crocodilian species in the world. Like many other reptiles, important aspects of alligator biology such as foraging, timing of hibernation, breeding and the sex ratio of offspring are all affected by temperature variation. We examined the effects of long‐term temperature change on oviposition dates and clutch sizes of the Chinese alligator in a semi‐natural facility in southern China. Our study focused on two captive generations including an old breeding generation captured from the wild and a generation composed of their F1 offspring. Median oviposition date shifted to earlier in the year and mean clutch size was larger for both generations as the monthly mean air temperature in April increased over the 19 years of data collection. We observed a mean advance in oviposition date of 10 days for the old breeding generation from 1987 to 2005 and 8 days for both generations from 1991 to 2005. Correspondingly, clutch sizes for the two generations also increased during this period. There were no differences in median oviposition dates and clutch sizes between the two generations from 1991 to 2005. Our results suggest that Chinese alligators have responded to increasing global temperatures. Our findings also suggest that recent increasing global temperatures have the potential to have a substantial effect on Chinese alligator populations in the wild, thus prompting an urgent need for field monitoring of the effects of global warming on this endangered alligator species.
Adenosine A2A receptors enhance GABA transport into nerve terminals by restraining PKC inhibition of GAT‐1
Authors: Cristóvão‐Ferreira Sofia , Vaz Sandra H. , Ribeiro Joaquim A. , Sebastião Ana M.
Published: February 2009

Neurotransmitter transporters are regulated by phosphorylation but little is known about endogenous substances and receptors that regulate this process. Adenosine is an ubiquitous neuromodulator operating G‐protein coupled receptors, which affect the activity of several kinases. We therefore evaluated the influence of adenosine upon the GABA transporter 1 (GAT‐1) mediated GABA uptake into hippocampal synaptosomes. Removal of endogenous adenosine (adenosine deaminase, 1 U/mL) decreased GABA uptake, an effect mimicked by blockade of A2A receptors (2‐(2‐furanyl)‐7‐(2‐phenylethyl)‐7H‐pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]pyrimidin‐5‐amine, 50 nM) but not A1 or A2B receptors. A2A receptor activation (4‐[2‐[[6‐amino‐9‐(N‐ethyl‐β‐d‐ribofuranuronamidosyl)‐9H‐purin‐yl]amino]ethyl]benzenepropanoic acid hydrochloride, 3–100 nM) enhanced GABA uptake by increasing the transporter Vmax without change of KM. This was mimicked by adenylate cyclase activation (forskolin, 10 μM) and prevented by protein kinase A (PKA) inhibition (N‐[2‐(p‐bromocinnamylamino) ethyl]‐5‐isoquinolinesulfonamide dihydrochloride, 1 μM), whichper sedid not influence GABA transport. Blockade of protein kinase C (PKC) (2‐[1‐(3‐dimethylaminopropyl)indol‐3‐yl]‐3‐(indol‐3‐yl) maleimide, 1 μM) facilitated GABA transport whereas PKC activation (4‐β‐phorbol‐didecanoate, 250 nM) inhibited it. PKA blockade did not affect the facilitatory action of the PKC inhibitor or the inhibitory action of the PKC activator. However, when adenylate cyclase was activated neither activation nor inhibition of PKC affected GABA uptake. It is concluded that A2A receptors, through activation of the adenylate cyclase/cAMP/PKA transducing pathway facilitate GAT‐1 mediated GABA transport into nerve endings by restraining tonic PKC‐mediated inhibition.
Opposite effects of anandamide andn‐arachidonoyl dopamine in the regulation of prostaglandin E2and 8‐iso‐PGF2αformation in primary glial cells
Authors: Navarrete Carmen M. , Fiebich Bernd L. , De Vinuesa Amaya García , Hess Sandra , De Oliveira Antonio C. P. , Candelario‐Jalil Eduardo , Caballero Francisco J. , Calzado Marco A. , Muñoz Eduardo
Published: February 2009

It is widely accepted that neuroinflammation is a key player in various pathological events associated with brain injury. More specifically, glial activation and the subsequent release of pro‐inflammatory cytokines, reactive oxygen species (ROS), and prostaglandins play a role of paramount importance in cerebral damage. In this study, we examined the role of two endocannabinoids, anandamide (AEA) andN‐arachidonoyldopamine (NADA) in the regulation of prostaglandin E2(PGE2) synthesis in primary glial cells. We show that NADA is a potent inhibitor of PGE2synthesis in lipopolysaccharide (LPS) stimulated cells, without modifying the expression or enzymatic activity of COX‐2 and the production of prostaglandin D2. We also show that NADA has the ability to prevent the free radical formation in primary microglial cells. The key findings of this investigation are our observation that AEA and NADA have opposite effects on glial cells and, most importantly, the first description of NADA as a potential antioxidative and anti‐inflammatory agent acting through a mechanism that involves reduction in the synthesis of microsomal prostaglandin E synthase in LPS‐activated microglia. These findings provide new mechanistic insights into the anti‐inflammatory activities of NADA in the CNS and its potential to design novel therapeutic strategies to manage neuroinflammatory diseases.
Neural cells secrete a unique repertoire of proteins
Authors: Schubert David , Herrera Federico , Cumming Robert , Read Jessica , Low William , Maher Pamela , Fischer Wolfgang H.
Published: February 2009

Proteins that are released from cells consist of those in the extracellular matrix, as well as extracellular signaling and adhesion molecules. The majority of these extracellular proteins are, however, unknown. To determine their identity, we have used a proteomics approach to define proteins released from neurons, astrocytes and neural precursor cells. Using two‐dimensional gels and liquid chromatography/mass spectrometry technology, it is shown that while astrocytes release a relatively small number of proteins, neurons and neuronal precursor cells release a larger number of proteins with more functional diversity. Although there is overlap between the different cell types, the exact composition of the extracellular protein pool is unique for each cell population. The various subsets of extracellular neural proteins include those involved in cellular Redox regulation and chaperones. In addition, many proteolytic enzymes are found outside of the cell. These data show that the extracellular space within the nervous system has a more diverse protein composition than previously thought.
Toll‐like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning
Authors: Pradillo Jesús M. , Fernández‐López David , García‐Yébenes Isaac , Sobrado Mónica , Hurtado Olivia , Moro María A. , Lizasoain Ignacio
Published: February 2009

It has been demonstrated that a short ischemic event (ischemic preconditioning, IPC) results in a subsequent resistance to severe ischemia (ischemic tolerance, IT). We have recently demonstrated the role of innate immunity and in particular of toll‐like receptor (TLR) 4 in brain ischemia. Several evidences suggest that TLR4 might also be involved in IT. Therefore, we have now used an in vivo model of IPC to investigate whether TLR4 is involved in IT. A 6‐min temporary bilateral common carotid arteries occlusion was used for focal IPC and it was performed on TLR4‐deficient mice (C57BL/10ScNJ) and animals that express TLR4 normally (C57BL/10ScSn). To assess the ability of IPC to induce IT, permanent middle cerebral artery occlusion was performed 48 h after IPC. Stroke outcome was evaluated by determination of infarct volume and assessment of neurological scores. IPC caused neuroprotection as shown by a reduction in infarct volume and better outcome in mice expressing TLR4 normally. TLR4‐deficient mice showed less IPC‐induced neuroprotection than wild‐type animals. Western blot analysis of tumor necrosis factor alpha (TNF‐α), inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) showed an up‐regulation in the expression of these proteins in both substrains of mice measured 18, 24 and 48 h after IPC, being higher in mice with TLR4. Similarly, nuclear factor‐kappa B (NF‐κB) activation was observed 18, 24 and 48 h after IPC, being more intense in TLR4‐expressing mice. These data demonstrate that TLR4 signalling is involved in brain tolerance as shown by the difference in the percentage of neuroprotection produced by IPC between ScSn and ScNJ (60% vs. 18%). The higher expression of TNF‐α, iNOS and cyclooxygenase‐2 and NF‐κB activation in mice expressing TLR4 is likely to participate in this endogenous neuroprotective effect.
Conservation of Epiphyte Diversity in an Andean Landscape Transformed by Human Land Use
Authors: KÖSTER NILS , FRIEDRICH KAROLINE , NIEDER JÜRGEN , BARTHLOTT WILHELM
Published: February 2009

Abstract:  Epiphytes are diverse and important elements of tropical forests, but as canopy‐dwelling organisms, they are highly vulnerable to deforestation. To assess the effect of deforestation on epiphyte diversity and the potential for epiphyte conservation in anthropogenically transformed habitats, we surveyed the epiphytic vegetation of an Ecuadorian cloud forest reserve and its surroundings. Our study was located on the western slopes of the Andes, a global center of biodiversity. We sampled vascular epiphytes of 110 study plots in a continuous primary forest; 14 primary forest fragments; isolated remnant trees in young, middle‐aged, and old pastures; and young and old secondary forests. It is the first study to include all relevant types of habitat transformation at a single study site and to compare epiphyte diversity at different temporal stages of fragmentation. Epiphyte diversity was highest in continuous primary forest, followed by forest fragments and isolated remnant trees, and lowest in young secondary forests. Spatial parameters of habitat transformation, such as fragment area, distance to the continuous primary forest, or distance to the forest edge from inside the forest, had no significant effect on epiphyte diversity. Hence, the influence of dispersal limitations appeared to be negligible or appeared to operate only over very short distances, whereas microclimatic edge effects acted only in the case of completely isolated trees, but not in larger forest fragments. Epiphyte diversity increased considerably with age of secondary forests, but species assemblages on isolated remnant trees were impoverished distinctly with time since isolation. Thus, isolated trees may serve for recolonization of secondary forests, but only for a relatively short time. We therefore suggest that the conservation of even small patches of primary forest within agricultural landscape matrices is essential for the long‐term maintenance of the high epiphyte diversity in tropical cloud forests.
Primary autoimmune neutropenia in children in Taiwan
Authors: Wang Lin‐Yen , Wang Chang‐Ling , Chu Chen‐Chung , Lee Hui‐Lin , Ho Hsin‐Tsung , Liang Der‐Cherng , Liu Hsi‐Che , Lin Marie
Published: February 2009

BACKGROUND: Autoimmune neutropenia in children is caused by granulocyte‐specific autoantibodies. These antibodies react to the patient's own neutrophils but disappear when the neutropenia spontaneously remits. This study reviewed our experience with autoimmune neutropenia in children and investigated possible associations with HLA‐DR and HLA‐DQ alleles.

STUDY DESIGN AND METHODS: From 1993 to 2006, our laboratory received 155 blood samples from children with neutropenia. Of these samples, 55 had granulocyte‐specific autoantibodies on the indirect granulocyte immunofluorescence test. As the children had no other disorders associated with neutropenia, they were diagnosed with primary autoimmune neutropenia. HLA‐DRB1 and ‐DQB1 allele typing was performed in 31 cases, and the results were compared with those of 190 normal healthy unrelated Taiwanese controls.

RESULTS: The mean ages of onset and resolution of neutropenia were 9.8 months (median, 9.0 months; range, 4‐28 months) and 22.5 months (median, 20.0 months; range, 13‐44 months), respectively. The male‐to‐female ratio was 1.2:1. The mean absolute neutrophil count was 190 per µL (standard deviation, 213/µL). Most patients (74%) had antibodies against HNA‐1a. Autoimmune neutropenia in children in Taiwan was significantly associated with HLA‐DQB1*0503 (odds ratio, 6.48; p = 0.0002; pc = 0.003) allele.

CONCLUSION: In Taiwan, autoimmune neutropenia in children is associated with HLA‐DQB1*0503. The autoantibody in autoimmune neutropenia is most commonly anti‐HNA‐1a.
Models for Bounded Systems with Continuous Dynamics
Authors: Cangelosi Amanda R. , Hooten Mevin B.
Published: February 2009

Summary Models for natural nonlinear processes, such as population dynamics, have been given much attention in applied mathematics. For example, species competition has been extensively modeled by differential equations. Often, the scientist has preferred to model the underlying dynamical processes (i.e., theoretical mechanisms) in continuous time. It is of both scientific and mathematical interest to implement such models in a statistical framework to quantify uncertainty associated with the models in the presence of observations. That is, given discrete observations arising from the underlying continuous process, the unobserved process can be formally described while accounting for multiple sources of uncertainty (e.g., measurement error, model choice, and inherent stochasticity of process parameters). In addition to continuity, natural processes are often bounded; specifically, they tend to have nonnegative support. Various techniques have been implemented to accommodate nonnegative processes, but such techniques are often limited or overly compromising. This article offers an alternative to common differential modeling practices by using a bias‐corrected truncated normal distribution to model the observations and latent process, both having bounded support. Parameters of an underlying continuous process are characterized in a Bayesian hierarchical context, utilizing a fourth‐order Runge–Kutta approximation.
Chop‐Lump Tests for Vaccine Trials
Authors: Follmann Dean , Fay Michael P. , Proschan Michael
Published: February 2009

Summary This article proposes new tests to compare the vaccine and placebo groups in randomized vaccine trials when a small fraction of volunteers become infected. A simple approach that is consistent with the intent‐to‐treat principle is to assign a score, say W, equal to 0 for the uninfecteds and some postinfection outcome X > 0 for the infecteds. One can then test the equality of this skewed distribution of W between the two groups. This burden of illness (BOI) test was introduced by Chang, Guess, and Heyse (1994, Statistics in Medicine 13, 1807–1814). If infections are rare, the massive number of 0s in each group tends to dilute the vaccine effect and this test can have poor power, particularly if the X's are not close to zero. Comparing X in just the infecteds is no longer a comparison of randomized groups and can produce misleading conclusions. Gilbert, Bosch, and Hudgens (2003, Biometrics 59, 531–541) and Hudgens, Hoering, and Self (2003, Statistics in Medicine 22, 2281–2298) introduced tests of the equality of X in a subgroup—the principal stratum of those “doomed” to be infected under either randomization assignment. This can be more powerful than the BOI approach, but requires unexaminable assumptions. We suggest new “chop‐lump” Wilcoxon and t‐tests (CLW and CLT) that can be more powerful than the BOI tests in certain situations. When the number of volunteers in each group are equal, the chop‐lump tests remove an equal number of zeros from both groups and then perform a test on the remaining W's, which are mostly >0. A permutation approach provides a null distribution. We show that under local alternatives, the CLW test is always more powerful than the usual Wilcoxon test provided the true vaccine and placebo infection rates are the same. We also identify the crucial role of the “gap” between 0 and the X's on power for the t‐tests. The chop‐lump tests are compared to established tests via simulation for planned HIV and malaria vaccine trials. A reanalysis of the first phase III HIV vaccine trial is used to illustrate the method.
Forcing Function Diagnostics for Nonlinear Dynamics
Authors: Hooker Giles
Published: February 2009

Summary This article investigates the problem of model diagnostics for systems described by nonlinear ordinary differential equations (ODEs). I propose modeling lack of fit as a time‐varying correction to the right‐hand side of a proposed differential equation. This correction can be described as being a set of additive forcing functions, estimated from data. Representing lack of fit in this manner allows us to graphically investigate model inadequacies and to suggest model improvements. I derive lack‐of‐fit tests based on estimated forcing functions. Model building in partially observed systems of ODEs is particularly difficult and I consider the problem of identification of forcing functions in these systems. The methods are illustrated with examples from computational neuroscience.
Bayesian Variable Selection with Joint Modeling of Categorical and Survival Outcomes: An Application to Individualizing Chemotherapy Treatment in Advanced Colorectal Cancer
Authors: Chen Wei , Ghosh Debashis , Raghunathan Trivellore E. , Sargent Daniel J.
Published: February 2009

Summary Colorectal cancer is the second leading cause of cancer related deaths in the United States, with more than 130,000 new cases of colorectal cancer diagnosed each year. Clinical studies have shown that genetic alterations lead to different responses to the same treatment, despite the morphologic similarities of tumors. A molecular test prior to treatment could help in determining an optimal treatment for a patient with regard to both toxicity and efficacy. This article introduces a statistical method appropriate for predicting and comparing multiple endpoints given different treatment options and molecular profiles of an individual. A latent variable‐based multivariate regression model with structured variance covariance matrix is considered here. The latent variables account for the correlated nature of multiple endpoints and accommodate the fact that some clinical endpoints are categorical variables and others are censored variables. The mixture normal hierarchical structure admits a natural variable selection rule. Inference was conducted using the posterior distribution sampling Markov chain Monte Carlo method. We analyzed the finite‐sample properties of the proposed method using simulation studies. The application to the advanced colorectal cancer study revealed associations between multiple endpoints and particular biomarkers, demonstrating the potential of individualizing treatment based on genetic profiles.
Multiple adverse outcomes over 30 years following adolescent substance misuse treatment
Authors: Hodgins S. , Larm P. , Molero‐Samuleson Y. , Tengström A. , Larsson A.
Published: February 2009

Objective:  To compare outcomes over 30 years experienced by individuals who as adolescents entered substance misuse treatment and a general population sample.

Method:  All 1992 individuals seen at the only clinic for substance misusing adolescents in Stockholm from 1968 to 1971 were compared to 1992 individuals randomly selected from the Swedish population, matched for sex, age and birthplace. Death, hospitalization for physical illness related to substance misuse, hospitalization for mental illness, substance misuse, criminal convictions and poverty were documented from national registers.

Results:  Relative risks of death, physical illness, mental illness, substance misuse, criminal convictions and poverty were significantly elevated in the clinic compared to the general population sample. After adjustment for substance misuse in adulthood, the risks of death, physical and mental illness, criminality and poverty remained elevated.

Conclusion:  Adolescents who consult for substance misuse problems are at high risk for multiple adverse outcomes over the subsequent 30 years.
Lux vs. wavelength in light treatment of Seasonal Affective Disorder
Authors: Anderson J. L. , Glod C. A. , Dai J. , Cao Y. , Lockley S. W.
Published: February 2009

Objective:  Published dosing guidelines for treatment of Seasonal Affective Disorder (SAD) refer to photopic lux, which is not appropriate for short‐wavelength light. Short wavelengths are most potent for many non‐visual responses to light. If SAD therapy were similarly mediated, standards utilizing lux risk overestimating necessary dose. We investigated antidepressant responses to light using two light‐emitting diode (LED) sources, each emitting substantial short‐wavelength light, but <2500 lux.

Method:  A randomized, double‐blind trial investigated 3‐week 45 min/day out‐patient treatment with blue‐appearing (goLITE®) or blue‐enriched white‐appearing light in 18 moderately‐depressed adults (12F, 49.1 ± 9.5 years). Equivalent numbers of photons within the short‐wavelength range were emitted, but the white source emitted twice as many photons overall and seven‐fold more lux.

Results:  Depression ratings (SIGH‐ADS; http://www.cet.org) decrease averaged 82% (SD = 17%) from baseline (P < 0.0001) in both white‐ and blue‐light groups. Both sources were well tolerated.

Conclusion:  Short‐wavelength LED light sources may be effective in SAD treatment at fewer lux than traditional fluorescent sources.
Subcrestal placement of two‐part implants
Authors: Welander Maria , Abrahamsson Ingemar , Berglundh Tord
Published: February 2009

Objective: The aim of the present experiment was to study the healing around two‐part implants that were placed in a subcrestal position.

Material and methods: Five mongrel dogs, about 2 years old, were included. The mandibular premolars and the first, second and third maxillary premolars were extracted. Three months later two test and two control implants (OsseoSpeed™, 3.5 mm × 8 mm) were placed in one side of the mandible. The implants were placed in such a way that the implant margin was located 2 mm apical to the bone crest. In the test implants, the surface modification extended to the implant margin and, thus, included the shoulder part of the implant. Regular abutments with a turned surface (Zebra™) were connected to the control implants, while experimental abutments with a modified surface (TiOblast™) were connected to the test implants. A plaque control program that included cleaning of implants and teeth every second day was initiated. Four months later the dogs were euthanized and biopsies were obtained and prepared for histological analysis.

Results: The marginal bone level at the test implants was identified in a more coronal position than that at the control implants. In 40% of the test implants, the bone‐to‐implant contact extended coronal of the abutment/fixture (A/F) border, i.e. in contact with the abutment part of the implant. The connective tissue portion of the peri‐implant mucosa that was facing the test abutments contained a higher density of collagen and a smaller proportion of fibroblasts than that at the control sites.

Conclusion: It is suggested that osseointegration may occur coronal to the A/F interface of two‐part implants. Such a result, however, appears to depend on the surface characteristics of the implant components.
Ultrastructural study of tissues surrounding replanted teeth and dental implants
Authors: Shioya Kazuhiro , Sawada Takashi , Miake Yasuo , Inoue Sadayuki , Yanagisawa Takaaki
Published: February 2009

Objectives: The aim of this study was to describe the ultrastructure of the dentogingival border at replanted teeth and implants.

Material and methods: Wistar rats (8 weeks old) were divided into groups for replantation and implantation experiments. In the former, the upper right first molars were extracted and then immediately replanted. In the latter, pure titanium implants were used. All tissues were fixed, demineralized and embedded in epoxy resin for ultrastructural observations.

Results: One week after replantation, the junctional epithelium was lost, and the oral sulcular epithelium covered the enamel surface. The amount of the epithelium increased in 2 weeks, and resembled the junctional epithelium, and the internal basal lamina and hemidesmosomes were formed in 4 weeks. One week after implantation, peri‐implant epithelium was formed, and in 2 and 4 weeks, this epithelium with aggregated connective tissue cells were observed. In 8 weeks, the peri‐implant epithelium receded, and aligned special cells with surrounding elongated fibroblasts and bundles of collagen fibers appeared to seal the implant interface.

Conclusion: In replantation of the tooth, the internal basal lamina remained at the surface of the enamel of the replanted tooth, which is likely to be related to regeneration of the junctional epithelium and the attachment apparatus at the epithelium–tooth interface. Following implantation, a layer of cells with characteristics of connective tissue cells, but no junctional epithelium and attachment apparatus, was formed to seal the site of the implant.