bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of impairment/disability due to occupational asthma through a multidimensional approach
Authors: Yacoub M-R. , Lavoie K. , Lacoste G. , Daigle S. , L’Archevêque J. , Ghezzo H. , Lemière C. , Malo J-L.
Published: December 2006

Subjects with occupational asthma (OA) are often left with permanent sequelae after removal from exposure, and assessing their impairment/disability should utilise various tools.

The aim of the present study was to examine whether: 1) assessment of inflammation in induced sputum is relevant to impairment; and 2) use of questionnaires on quality of life and psychological factors can be useful for the evaluation of disability. In total, 40 subjects were prospectively assessed for permanent impairment/disability due to OA 2 yrs after cessation of exposure. Impairment was assessed as follows: 1) need for asthma medication; 2) asthma severity; 3) airway calibre and responsiveness; and 4) degree of inflammation in induced sputum. Disability was assessed according to quality of life and psychological distress.

There was a significant improvement in airway responsiveness and inflammation from diagnosis to the present assessment. Sputum eosinophils ≥2% and neutrophils >60% were present in eight (20%) and 12 (30%) out of all subjects, respectively, one or the other feature being the only abnormalities in 15% of subjects. Quality of life was moderately affected and there was a prevalence of depression and anxiety close to 50%.

In the assessment of subjects with occupational asthma, information on airway inflammation and psychological impacts are relevant to the assessment of impairment/disability, although these findings need further investigation.
Smoking and tuberculosis among silicotic patients
Authors: Leung C. C. , Yew W. W. , Law W. S. , Tam C. M. , Leung M. , Chung Y. W. , Cheung K. W. , Chan K. W. , Fu F.
Published: December 2006

The aim of the present study was to investigate the relationship between smoking and tuberculosis (TB) among high-risk silicotic patients in Hong Kong.

A cohort of 435 silicotic patients tuberculin tested from 1995–2002 was prospectively followed-up until the end of 2005. Baseline characteristics were analysed with respect to positive tuberculin reaction (≥10 mm) at baseline and subsequent development of TB.

Smoking, alcohol use and body mass index were independent predictors of positive tuberculin reaction at baseline in multiple logistic regression analysis. Total cigarette pack-yrs did not demonstrate any significant effect. The annual incidences of TB were 1,841, 2,294 and 4,181 per 100,000 for never-, ex- and current smokers, respectively. On Cox proportional hazard analysis, current smokers have a significantly higher risk of TB than other silicotic patients (adjusted hazard ratio (95% confidence interval (CI)): 1.96 (1.14–3.35)) after controlling for age, alcohol use, tuberculin status, treatment for latent TB infection and other relevant background/disease factors. A significant dose-response relationship was also observed with the daily number of cigarettes currently smoked. Smoking cessation may reduce 32.4% (95% CI: 6.5–54.0) of the risk.

Smoking increases the risk of both tuberculosis infection and subsequent development of the disease among silicotic patients.
Quantitative analysis of cell-type specific gene expression in the green alga Volvox carteri
Authors: Nematollahi Ghazaleh , Kianianmomeni Arash , Hallmann Armin
Published: December 2006

Background

The multicellular alga Volvox carteri possesses only two cell types: mortal, motile somatic cells and potentially immortal, immotile reproductive cells. It is therefore an attractive model system for studying how cell-autonomous cytodifferentiation is programmed within a genome. Moreover, there are ongoing genome projects both in Volvox carteri and in the closely related unicellular alga Chlamydomonas reinhardtii. However, gene sequencing is only the beginning. To identify cell-type specific expression and to determine relative expression rates, we evaluate the potential of real-time RT-PCR for quantifying gene transcript levels.

Results

Here we analyze a diversified pool of 39 target genes by real-time RT-PCR for each cell type. This gene pool contains previously known genes with unknown localization of cellular expression, 28 novel genes which are described in this study for the first time, and a few known, cell-type specific genes as a control. The respective gene products are, for instance, part of photosynthesis, cellular regulation, stress response, or transport processes. We provide expression data for all these genes.

Conclusion

The results show that quantitative real-time RT-PCR is a favorable approach to analyze cell-type specific gene expression in Volvox, which can be extended to a much larger number of genes or to developmental or metabolic mutants. Our expression data also provide a basis for a detailed analysis of individual, previously unknown, cell-type specifically expressed genes.
The major histocompatibility complex (Mhc) class IIB region has greater genomic structural flexibility and diversity in the quail than the chicken
Authors: Hosomichi Kazuyoshi , Shiina Takashi , Suzuki Shingo , Tanaka Masayuki , Shimizu Sayoko , Iwamoto Shigehisa , Hara Hiromi , Yoshida Yutaka , Kulski Jerzy K , Inoko Hidetoshi , Hanzawa Kei
Published: December 2006

Background

The quail and chicken major histocompatibility complex (Mhc) genomic regions have a similar overall organization but differ markedly in that the quail has an expanded number of duplicated class I, class IIB, natural killer (NK)-receptor-like, lectin-like and BG genes. Therefore, the elucidation of genetic factors that contribute to the greater Mhc diversity in the quail would help to establish it as a model experimental animal in the investigation of avian Mhc associated diseases.

Aims and approaches

The main aim here was to characterize the genetic and genomic features of the transcribed major quail MhcIIB (CojaIIB) region that is located between the Tapasin and BRD2 genes, and to compare our findings to the available information for the chicken MhcIIB (BLB). We used four approaches in the study of the quail MhcIIB region, (1) haplotype analyses with polymorphic loci, (2) cloning and sequencing of the RT-PCR CojaIIB products from individuals with different haplotypes, (3) genomic sequencing of the CojaIIB region from the individuals with the different haplotypes, and (4) phylogenetic and duplication analysis to explain the variability of the region between the quail and the chicken.

Results

Our results show that the Tapasin-BRD2 segment of the quail Mhc is highly variable in length and in gene transcription intensity and content. Haplotypic sequences were found to vary in length between 4 to 11 kb. Tapasin-BRD2 segments contain one or two major transcribed CojaIIBs that were probably generated by segmental duplications involving c-type lectin-like genes and NK receptor-like genes, gene fusions between two CojaIIBs and transpositions between the major and minor CojaIIB segments. The relative evolutionary speed for generating the MhcIIBs genomic structures from the ancestral BLB2 was estimated to be two times faster in the quail than in the chicken after their separation from a common ancestor. Four types of genomic rearrangement elements (GRE), composed of simple tandem repeats (STR), were identified in the MhcIIB genomic segment located between the Tapasin-BRD2 genes. The GREs have many more STR numbers in the quail than in the chicken that displays strong linkage disequilibrium.

Conclusion

This study suggests that the Mhc classIIB region has a flexible genomic structure generated by rearrangement elements and rapid SNP accumulation probably as a consequence of the quail adapting to environmental conditions and pathogens during its migratory history after its divergence from the chicken.
Regional age-related changes in neuronal nitric oxide synthase (nNOS), messenger RNA levels and activity in SAMP8 brain
Authors: Colas Damien , Gharib Abdallah , Bezin Laurent , Morales Anne , Guidon Gérard , Cespuglio Raymond , Sarda Nicole
Published: December 2006

Background

Nitric oxide (NO) is a multifunctional molecule synthesized by three isozymes of the NO synthase (NOSs) acting as a messenger/modulator and/or a potential neurotoxin. In rodents, the role of NOSs in sleep processes and throughout aging is now well established. For example, sleep parameters are highly deteriorated in senescence accelerated-prone 8 (SAMP8) mice, a useful animal model to study aging or age-associated disorders, while the inducible form of NOS (iNOS) is down-regulated within the cortex and the sleep-structures of the brainstem. Evidence is now increasing for a role of iNOS and resulting oxidative stress but not for the constitutive expressed isozyme (nNOS). To better understand the role of nNOS in the behavioural impairments observed in SAMP8 versus SAMR1 (control) animals, we evaluated age-related variations occurring in the nNOS expression and activity and nitrites/nitrates (NOx-) levels, in three brain areas (n = 7 animals in each group). Calibrated reverse transcriptase (RT) and real-time polymerase chain reaction (PCR) and biochemical procedures were used.

Results

We found that the levels of nNOS mRNA decreased in the cortex and the hippocampus of 8- vs 2-month-old animals followed by an increase in 12-vs 8-month-old animals in both strains. In the brainstem, levels of nNOS mRNA decreased in an age-dependent manner in SAMP8, but not in SAMR1. Regional age-related changes were also observed in nNOS activity. Moreover, nNOS activity in hippocampus was found lower in 8-month-old SAMP8 than in SAMR1, while in the cortex and the brainstem, nNOS activities increased at 8 months and afterward decreased with age in SAMP8 and SAMR1. NOx- levels showed profiles similar to nNOS activities in the cortex and the brainstem but were undetectable in the hippocampus of SAMP8 and SAMR1. Finally, NOx- levels were higher in the cortex of 8 month-old SAMP8 than in age-matched SAMR1.

Conclusion

Concomitant variations occurring in NO levels derived from nNOS and iNOS at an early age constitute a major factor of risk for sleep and/or memory impairments in SAMP8.
The impact of rheumatoid arthritis on foot function in the early stages of disease: a clinical case series
Authors: Turner Deborah E , Helliwell Philip S , Emery Paul , Woodburn James
Published: December 2006

Background

Foot involvement occurs early in rheumatoid arthritis but the extent to which this impacts on the structure and function leading to impairment and foot related disability is unknown. The purpose of this study was to compare clinical disease activity, impairment, disability, and foot function in normal and early rheumatoid arthritis (RA) feet using standardised clinical measures and 3D gait analysis.

Methods

Twelve RA patients with disease duration ≤2 years and 12 able-bodied adults matched for age and sex underwent 3D gait analysis to measure foot function. Disease impact was measured using the Leeds Foot impact Scale (LFIS) along with standard clinical measures of disease activity, pain and foot deformity. For this small sample, the mean differences between the groups and associated confidence intervals were calculated using the t distribution

Results

Moderate-to-high foot impairment and related disability were detected amongst the RA patients. In comparison with age- and sex-matched controls, the patients with early RA walked slower (1.05 m/s Vs 1.30 m/s) and had a longer double-support phase (19.3% Vs 15.8%). In terminal stance, the heel rise angle was reduced in the patients in comparison with normal (-78.9° Vs -85.7°). Medial arch height was lower and peak eversion in stance greater in the RA patients. The peak ankle plantarflexion power profile was lower in the patients in comparison with the controls (3.4 W/kg Vs 4.6 W/kg). Pressure analysis indicated that the RA patients had a reduced lesser toe contact area (7.6 cm2
Vs 8.1 cm2), elevated peak forefoot pressure (672 kPa Vs 553 kPa) and a larger mid-foot contact area (24.6 cm2
Vs 19.4 cm2).

Conclusion

Analysis detected small but clinically important changes in foot function in a small cohort of RA patients with disease duration <2 years. These were accompanied by active joint disease and impairment and disability.
Neck ligament strength is decreased following whiplash trauma
Authors: Tominaga Yasuhiro , Ndu Anthony B , Coe Marcus P , Valenson Arnold J , Ivancic Paul C , Ito Shigeki , Rubin Wolfgang , Panjabi Manohar M
Published: December 2006

Background

Previous clinical studies have documented successful neck pain relief in whiplash patients using nerve block and radiofrequency ablation of facet joint afferents, including capsular ligament nerves. No previous study has documented injuries to the neck ligaments as determined by altered dynamic mechanical properties due to whiplash. The goal of the present study was to determine the dynamic mechanical properties of whiplash-exposed human cervical spine ligaments. Additionally, the present data were compared to previously reported control data. The ligaments included the anterior and posterior longitudinal, capsular, and interspinous and supraspinous ligaments, middle-third disc, and ligamentum flavum.

Methods

A total of 98 bone-ligament-bone specimens (C2–C3 to C7-T1) were prepared from six cervical spines following 3.5, 5, 6.5, and 8 g rear impacts and pre- and post-impact flexibility testing. The specimens were elongated to failure at a peak rate of 725 (SD 95) mm/s. Failure force, elongation, and energy absorbed, as well as stiffness were determined. The mechanical properties were statistically compared among ligaments, and to the control data (significance level: P < 0.05; trend: P < 0.1). The average physiological ligament elongation was determined using a mathematical model.

Results

For all whiplash-exposed ligaments, the average failure elongation exceeded the average physiological elongation. The highest average failure force of 204.6 N was observed in the ligamentum flavum, significantly greater than in middle-third disc and interspinous and supraspinous ligaments. The highest average failure elongation of 4.9 mm was observed in the interspinous and supraspinous ligaments, significantly greater than in the anterior longitudinal ligament, middle-third disc, and ligamentum flavum. The average energy absorbed ranged from 0.04 J by the middle-third disc to 0.44 J by the capsular ligament. The ligamentum flavum was the stiffest ligament, while the interspinous and supraspinous ligaments were most flexible. The whiplash-exposed ligaments had significantly lower (P = 0.036) failure force, 149.4 vs. 186.0 N, and a trend (P = 0.078) towards less energy absorption capacity, 308.6 vs. 397.0 J, as compared to the control data.

Conclusion

The present decreases in neck ligament strength due to whiplash provide support for the ligament-injury hypothesis of whiplash syndrome.
Plasma organochlorine concentrations and bone ultrasound measurements: a cross-sectional study in peri-and postmenopausal Inuit women from Greenland
Authors: Côté Suzanne , Ayotte Pierre , Dodin Sylvie , Blanchet Claudine , Mulvad Gert , Petersen Henning S , Gingras Suzanne , Dewailly Éric
Published: December 2006

Background

Inuit women are highly exposed through their traditional seafood based diet to organochlorine compounds, some of them displaying endocrine disrupting properties. We hypothesized that this exposure might be related to bone characteristics that are altered in osteoporosis, because hormone deficiency is a known risk factor for the disease.

Methods

We measured quantitative ultrasound parameters (QUS) at the right calcaneum of 153 peri- and postmenopausal Inuit women (49–64 year old) from Nuuk, Greenland, and investigated the relation between these parameters and plasma organochlorine concentrations. We used high-resolution gas chromatography with electron capture detection to analyze plasma samples for 14 polychlorinated biphenyls (PCB) congeners and 11 chlorinated pesticides and metabolites. We analysed morning urine samples for cadmium, a potential confounder, by atomic absorption spectrometry. We used a validated questionnaire to document dietary and lifestyle habits as well as reproductive and medical histories.

Results

Concentrations of PCB 153, a surrogate of exposure to most organochlorines present in plasma samples, were inversely correlated to QUS parameters in univariate analyses (p < 0.001). However, PCB 153 concentrations were not associated with QUS values in multivariate analyses that comprised potential confounding factors such as age, body weight, former oral contraceptive use and current hormone replacement therapy (HRT) use, which were all significant predictors of bone stiffness (total R2 = 0.39; p < 0.001).

Conclusion

Overall we found little evidence that organochlorines exposure is related to osteoporosis in Greenlandic Inuit women, but the hypothesis that exposure to dioxin-like compounds might be linked to decreased bone quality and osteoporosis deserves further attention.
Comparison of tissue pressure and ablation time between the LeVeen and cool-tip needle methods
Authors: Nakamuta Makoto , Kohjima Motoyuki , Morizono Shusuke , Yoshimoto Tsuyoshi , Miyagi Yuzuru , Sakai Hironori , Enjoji Munechika , Kotoh Kazuhiro
Published: December 2006

Background

Radio frequency ablation (RFA) has been accepted clinically as a useful local treatment for hepatocellular carcinoma (HCC). However, intrahepatic recurrence after RFA has been reported which might be attributable to increase in intra-tumor pressure during RFA. To reduce the pressure and ablation time, we developed a novel method of RFA, a multi-step method in which a LeVeen needle, an expansion-type electrode, is incrementally and stepwise expanded. We compared the maximal pressure during ablation and the total ablation time among the multi-step method, single-step method (a standard single-step full expansion with a LeVeen needle), and the method with a cool-tip electrode. Finally, we performed a preliminary comparison of the ablation times for these methods in HCC cases.

Results

A block of pig liver sealed in a rigid plastic case was used as a model of an HCC tumor with a capsule. The multi-step method with the LeVeen electrode resulted in the lowest pressure as compared with the single-step or cool-tip methods. There was no significant difference in the ablation time between the multi-step and cool-tip ablation methods, although the single-step methods had longer ablation times than the other ablation procedures. In HCC cases, the multi-step method had a significantly shorter ablation time than the single-step or cool-tip methods.

Conclusion

We demonstrated that the multi-step method was useful to reduce the ablation time and to suppress the increase in pressure. The multi-step method using a LeVeen needle may be a clinically applicable procedure for RFA.
Effect of long-term exposure of SH-SY5Y cells to morphine: a whole cell proteomic analysis
Authors: Neasta Jérémie , Uttenweiler-Joseph Sandrine , Chaoui Karima , Monsarrat Bernard , Meunier Jean-Claude , Moulédous Lionel
Published: December 2006

Background

Opiate addiction reflects plastic changes that endurably alter synaptic transmission within relevant neuronal circuits. The biochemical mechanisms of these adaptations remain largely unknown and proteomics-based approaches could lead to a broad characterization of the molecular events underlying adaptations to chronic drug exposure.

Results

Thus, we have started proteomic analyses of the effects of chronic morphine exposure in a recombinant human neuroblastoma SH-SY5Y clone that stably overexpresses the μ-opioid receptor. Cells were treated with morphine for 6, 24 and 72 hours, the proteins were separated by 2-D gel electrophoresis and stained with Coomassie blue, and the protein map was compared with that obtained from untreated cells. Spots showing a statistically significant variation were selected for identification using mass spectrometric analyses.

Conclusion

A total of 45 proteins were identified, including proteins involved in cellular metabolism, cytoskeleton organization, vesicular trafficking, transcriptional and translational regulation, and cell signaling.
CHKA and PCYT1Agene polymorphisms, choline intake and spina bifida risk in a California population
Authors: Enaw James O Ebot , Zhu Huiping , Yang Wei , Lu Wei , Shaw Gary M , Lammer Edward J , Finnell Richard H
Published: December 2006

Background

Neural tube defects (NTDs) are among the most common of all human congenital defects. Over the last two decades, accumulating evidence has made it clear that periconceptional intake of folic acid can significantly reduce the risk of NTD affected pregnancies. This beneficial effect may be related to the ability of folates to donate methyl groups for critical physiological reactions. Choline is an essential nutrient and it is also a methyl donor critical for the maintenance of cell membrane integrity and methyl metabolism. Perturbations in choline metabolism in vitro have been shown to induce NTDs in mouse embryos.

Methods

This study investigated whether single nucleotide polymorphisms (SNPs) in human choline kinase A (CHKA) gene and CTP:phosphocholine cytidylytransferase (PCYT1A) gene were risk factors for spina bifida. Fluorescence-based allelic discrimination analysis was performed for the two CHKA intronic SNPs hCV1562388 (rs7928739) and hCV1562393, and PCYT1A SNP rs939883 and rs3772109. The study population consisted of 103 infants with spina bifida and 338 non-malformed control infants who were born in selected California counties in the period 1989–1991.

Results

The CHKA SNP hCV1562388 genotypes with at least one C allele were associated with a reduced risk of spina bifida (odds ratio = 0.60, 95%CI = 0.38–0.94). The PCYT1A SNP rs939883 genotype AA was associated with a twofold increased risk of spina bifida (odds ratio = 1.89, 95% CI = 0.97–3.67). These gene-only effects were not substantially modified by analytic consideration to maternal periconceptional choline intake.

Conclusion

Our analyses showed genotype effects of CHKA and PCYT1A genes on spina bifida risk, but did not show evidence of gene-nutrient interactions. The underlying mechanisms are yet to be resolved.
Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage
Authors: Heslet Lars , Nielsen Jorn Dalsgaard , Levi Marcel , Sengeløv Henrik , Johansson Pär I
Published: December 2006

Introduction

Diffuse alveolar hemorrhage (DAH) is a serious pulmonary complication seen in patients with autoimmune disorders and patients treated with chemotherapy or after hematopoietic stem cell transplantation. The clinical management of DAH is complex and the condition has a high mortality rate. Tissue factor is expressed in the lung alveoli during inflammation and therefore pulmonary administration of human recombinant activated factor VIIa (rFVIIa) could be a rational treatment option.

Methods

Six patients with acute, bronchoscopically confirmed DAH from a single intensive care unit university hospital center were included in the study of acute DAH in critically ill patients. The patients were treated with intrapulmonary administration of 50 μg/kg rFVIIa in 50 ml of sodium chloride by bronchoalveolar lavage (BAL) with 25 ml in each of the main bronchi, which was repeated after 24 hours in case of treatment failure.

Results

An excellent response, defined as complete and sustained hemostasis after a single dose of rFVIIa, was seen in three patients. A good response, meaning that sustained hemostasis was achieved by a repeated rFVIIa administration, was seen in the remaining three patients. In one of these patients, the BAL treatment was repeated twice; in another patient, the second dose of rFVIIa was administered by nebulizer after extubation after the initial BAL. The hemostatic effect was statistically significant (p = 0.031). The oxygenation capacity, as reflected by the PaO2/FiO2 (arterial oxygen pressure/inspiratory fractional oxygen content) ratio, increased significantly (p = 0.024) in all six patients following the local rFVIIa therapy.

Conclusion

Symptomatic therapy of DAH after intrapulmonary administration of one or more doses of rFVIIa was found to have a good to excellent hemostatic effect in six consecutive patients with DAH. The intrapulmonary administration of rFVIIa seemed to have a high benefit-to-risk ratio. Larger series should confirm the safety of this approach.
Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: subgroup analysis from two randomized trials
Authors: Rizoli Sandro B , Boffard Kenneth D , Riou Bruno , Warren Brian , Iau Philip , Kluger Yoram , Rossaint Rolf , Tillinger Michael ,   the NovoSeven® Trauma Study Group
Published: December 2006

Introduction

We conducted a post-hoc analysis on the effect of recombinant factor VIIa (rFVIIa) on coagulopathic patients from two randomized, placebo-controlled, double-blind trials of rFVIIa as an adjunctive therapy for bleeding in patients with severe trauma.

Methods

Blunt and penetrating trauma patients were randomly assigned to rFVIIa (200 + 100 + 100 μg/kg) at 0, 1, and 3 hours after transfusion of 8 units of red blood cells (RBCs) or to placebo. Subjects were monitored for 48 hours post-dosing and followed for 30 days. Coagulopathy was retrospectively defined as transfusion of fresh frozen plasma (FFP) (>1 unit of FFP per 4 units of RBCs), FFP in addition to whole blood, and transfusion of platelets and/or cryoprecipitate.

Results

Sixty rFVIIa-treated and 76 placebo subjects were retrospectively identified as being coagulopathic. No significant differences were noted in baseline characteristics. The rFVIIa-treated coagulopathic subgroup consumed significantly less blood product: RBC transfusion decreased by 2.6 units for the whole study population (P = 0.02) and by 3.5 units among patients surviving more than 48 hours (P < 0.001). Transfusion of FFP (1,400 versus 660 ml, P < 0.01), platelet (300 versus 100 ml, P = 0.01), and massive transfusions (29% versus 6%, P < 0.01) also dropped significantly. rFVIIa reduced multi-organ failure and/or acute respiratory distress syndrome in the coagulopathic patients (3% versus 20%, P = 0.004), whereas thromboembolic events were equally present in both groups (3% versus 4%, P = 1.00).

Conclusion

Coagulopathic trauma patients appear to derive particular benefit from early adjunctive rFVIIa therapy.
Multiple independent evolutionary solutions to core histone gene regulation
Authors: Mariño-Ramírez Leonardo , Jordan I King , Landsman David
Published: December 2006

Background

Core histone genes are periodically expressed along the cell cycle and peak during S phase. Core histone gene expression is deeply evolutionarily conserved from the yeast Saccharomyces cerevisiae to human.

Results

We evaluated the evolutionary dynamics of the specific regulatory mechanisms that give rise to the conserved histone regulatory phenotype. In contrast to the conservation of core histone gene expression patterns, the core histone regulatory machinery is highly divergent between species. There has been substantial evolutionary turnover of cis-regulatory sequence motifs along with the transcription factors that bind them. The regulatory mechanisms employed by members of the four core histone families are more similar within species than within gene families. The presence of species-specific histone regulatory mechanisms is opposite to what is seen at the protein sequence level. Core histone proteins are more similar within families, irrespective of their species of origin, than between families, which is consistent with the shared common ancestry of the members of individual histone families. Structure and sequence comparisons between histone families reveal that H2A and H2B form one related group whereas H3 and H4 form a distinct group, which is consistent with the nucleosome assembly dynamics.

Conclusion

The dissonance between the evolutionary conservation of the core histone gene regulatory phenotypes and the divergence of their regulatory mechanisms indicates a highly dynamic mode of regulatory evolution. This distinct mode of regulatory evolution is probably facilitated by a solution space for promoter sequences, in terms of functionally viable cis-regulatory sites, that is substantially greater than that of protein sequences.
Three-dimensional morphology and gene expression in the Drosophilablastoderm at cellular resolution II: dynamics
Authors: Keränen Soile VE , Fowlkes Charless C , Luengo Hendriks Cris L , Sudar Damir , Knowles David W , Malik Jitendra , Biggin Mark D
Published: December 2006

Background

To accurately describe gene expression and computationally model animal transcriptional networks, it is essential to determine the changing locations of cells in developing embryos.

Results

Using automated image analysis methods, we provide the first quantitative description of temporal changes in morphology and gene expression at cellular resolution in whole embryos, using the Drosophila blastoderm as a model. Analyses based on both fixed and live embryos reveal complex, previously undetected three-dimensional changes in nuclear density patterns caused by nuclear movements prior to gastrulation. Gene expression patterns move, in part, with these changes in morphology, but additional spatial shifts in expression patterns are also seen, supporting a previously proposed model of pattern dynamics based on the induction and inhibition of gene expression. We show that mutations that disrupt either the anterior/posterior (a/p) or the dorsal/ventral (d/v) transcriptional cascades alter morphology and gene expression along both the a/p and d/v axes in a way suggesting that these two patterning systems interact via both transcriptional and morphological mechanisms.

Conclusion

Our work establishes a new strategy for measuring temporal changes in the locations of cells and gene expression patterns that uses fixed cell material and computational modeling. It also provides a coordinate framework for the blastoderm embryo that will allow increasingly accurate spatio-temporal modeling of both the transcriptional control network and morphogenesis.
Neuronal Differentiation Is Accompanied by Increased Levels of SNAP‐25 Protein in Fetal Rat Primary Cortical Neurons
Authors: BAILEY JASON A. , LAHIRI DEBOMOY K.
Published: December 2006

Abstract:  Alzheimer's disease (AD) is accompanied by progressive memory loss and decline in general cognitive abilities. Neuropathological hallmarks include amyloid plaque formation, neurofibrillary tangles, and neuronal and synaptic loss. To improve research models in AD, we have characterized several aspects of the primary rat neuronal cell culture model, which relate directly to the study of neuroexocytosis, neuronal plasticity, and amyloidosis. We have attempted to isolate and assess the neuronal enrichment of a primary cortical cell culture by morphological and molecular techniques, following progress of these cultured cells for up to 18 days in culture to identify the optimum timeframe for the manipulation and data collection in these cells. We observed maximum neuronal differentiation around day 15, which was in decline by day 18, thus, the critical window for manipulations in these cultures seems to be between days 12–15. The substantial increase in neuritic length and density was apparent at very early time points and peaked at day 15. In parallel to morphological assessments, we measured levels of a group of selected neuronally important proteins, including cytoskeletal and synaptic proteins. Change in the levels of cell‐associated APP and synaptophysin were not as dramatic as that of SNAP‐25 or secreted APP. Notably, this increased differentiation is accompanied by a dramatic increase in levels of SNAP‐25 protein, which peaked at day 15 and declined thereafter. These results suggest that this neuronal population contains quantifiable presynaptic terminals. Thus, the establishment and molecular characterization of this neuronal model would have many implications in neuroscience research including synaptic differentiation and neuronal plasticity and for the evaluation of pharmacological interventions in the disease process.
SFK–STAT Pathway: An Alternative and Important Way to Malignancies
Authors: HAYAKAWA FUMIHIKO , NAOE TOMOKI
Published: December 2006

Abstract:  Signal transducers and activators of transcription (STAT) proteins play a crucial role in mediating signals from a diverse spectrum of cytokine receptors. STAT is thought to be activated by JAK family kinases (JFK) in many cytokine receptor signal pathways; however, recent studies have demonstrated an alternative pathway to activate STAT by Src family kinases (SFK) in growth factor receptor signal. We also observed STAT5 phosphorylation by Lyn, a member of SFK, in our two recent studies. We introduce these studies and review the literature of STAT activation by SFK and aberrant activation of STAT by oncogenic signals.
Psychological, Neuroimaging, and Biochemical Studies on Functional Association between Impulsive Behavior and the 5‐HT2A Receptor Gene Polymorphism in Humans
Authors: NOMURA MICHIO , NOMURA YASUYUKI
Published: December 2006

Abstract:  It has been suggested that impulsive behavior is caused by dysfunctional serotonergic 5‐HT neurotransmission in the central nervous system (CNS). Brain neuroimaging studies have shown that behavioral inhibition is linked to the activation of cortex sites such as the ventral frontal cortex. Positron emission tomography (PET) imaging with [18F]altanserin to characterize 5‐HT2A receptor binding revealed a reduction in 5‐HT2A binding in the ventral frontal cortex in women who had recovered from impulsive diseases. These clinical, neuroimaging, and pharmacological studies appear to support the hypothesis that functional alteration of neurotransmission due to genetic polymorphisms of the 5‐HT receptors may be involved in impulsive behavior modulation. Following evaluation by a self‐reporting measure, it was proposed that a polymorphism in the promoter of the 5‐HT2A receptor gene is the underlying cause of impulsive behavior; however, this hypothesis is not convincing. We examined whether the polymorphism in the 5‐HT2A receptor gene promoter is involved in impulsive aggression by evaluating a behavioral task (Go/No‐go task) in normal volunteers. The polymorphism of the 5‐HT2A receptor gene promoter in lymphocytes from 71 volunteers was analyzed by using PCR. Impulsivity was defined as the number of commission errors (responding when one should not) recorded during a Go/No‐go task; a larger number of commission errors indicate greater difficulty in inhibiting impulsive behavior. The subjects of the A‐1438A allele group for the 5‐HT2A receptor gene made more commission errors under the punishment‐reward (PR)
condition in a Go/No‐go task than those in the G‐1438G group. In the present review, we discuss and suggest the possible involvement of the A‐1438A polymorphism of the 5HT2A receptor gene promoter in impulsive behavior. This hypothesis was evaluated by using a behavioral task measure that could directly reveal impulsive behavioral traits in humans.
Molecular Mechanisms of Axon Specification and Neuronal Disorders
Authors: YOSHIMURA TAKESHI , ARIMURA NARIKO , KAIBUCHI KOZO
Published: December 2006

Abstract:  A cardinal feature of neurons is the morphological polarity of neurons with serious functional implications. Typically, a neuron has a single axon and several dendrites. Neuronal polarity is essential for the unidirectional signal flow from somata or dendrites to axons in neurons. The initial event in establishing a polarized neuron is the specification of a single axon. Although researchers are accumulating a catalog of structural, molecular, and functional differences between axons and dendrites, we are only now beginning to understand the molecular mechanisms involved in the establishment of neuronal polarity. We have described recent advances in the understanding of cellular events in the early development of an axon and dendrites. Several groups, including ours, reported that the phosphatidylinositol 3‐kinase (PI3‐kinase)/Akt (also called protein kinase B)/glycogen synthase kinase‐3β (GSK‐3β)/collapsin response mediator protein‐2 (CRMP‐2) pathway is important for axon specification and elongation. Recent studies have revealed the roles that Rho family small GTPases, the Par complex, and cytoskeleton‐related proteins play in the initial events of neuronal polarization downstream of PI3‐kinase. We discuss the roles of polarity‐regulating molecules and the potential mechanisms underlying the specification of an axon and dendrites. Polarity‐regulating molecules participate in various neuronal disorders. In this review, the signal transduction of GSK‐3β and CRMP‐2 is introduced as a new target for the treatment of Alzheimer's disease (AD) and nerve injury. These findings may help clarify causes of and treatments aimed at reversing AD and nerve injury.
Brain Keratan Sulfate and Glial Scar Formation
Authors: ZHANG HAOQIAN , UCHIMURA KENJI , KADOMATSU KENJI
Published: December 2006

Abstract:  In response to injury to the central nervous system (CNS), reactive astrocytes appear and accumulate in the wounded area, leading to glial scar formation. Glial scar is the physical barrier to axonal regeneration of injured neurons. Chondroitin sulfate proteoglycans are inhibitory to axon outgrowth and are upregulated in reactive astrocytes upon CNS injury. It is known that keratan sulfate proteoglycans (KSPGs) are also augmented after CNS injury and act as inhibitory cues. We give a brief overview of CNS injury and cover our recent data regarding the relationship between glial scar formation and KS. KS expression in the developing brain is detectable with 5D4, a KS‐specific monoclonal antibody. These 5D4 immunoreactivities are eliminated in mice deficient in N‐acetylglucosamine 6‐O‐sulfotransferase‐1. In adult mice, brain injury apparently upregulates mRNA expression of N‐acetylglucosamine 6‐O‐sulfotransferase‐1 as well as 5D4‐reactive KS in the wounded area. Intriguingly, the expression of 5D4‐reactive KS and reactive astrocyte accumulation in the wounded area are dramatically diminished in the sulfotransferase‐deficient mice. Consequently, the deficient mice exhibit a marked reduction in scar formation and enhancement of neuronal regeneration after brain injury. Thus, N‐acetylglucosamine 6‐O‐sulfotransferase‐1 plays indispensable roles in brain KS biosynthesis and glial scar formation after brain injury.
Girdin, a Novel Actin‐Binding Protein, and Its Family of Proteins Possess Versatile Functions in the Akt and Wnt Signaling Pathways
Authors: ENOMOTO ATSUSHI , PING JIANG , TAKAHASHI MASAHIDE
Published: December 2006

Abstract:  Girdin (GIRDers of actIN filament, also reported as APE, GIV, or HkRP1) is a novel protein expressed ubiquitously in mammals and was recently identified as a binding partner of the serine/threonine kinase Akt. We found that Girdin is an actin‐binding protein involved in both the remodeling of the actin cytoskeleton and in cell motility. Recent studies have uncovered new and varied functions of Girdin. For example, it prolongs the activation of Akt and regulates DNA replication in response to insulin signaling. Girdin also associates with heterotrimeric G proteins and dynamin (a large GTPase), which are involved in membrane transport. We found that Akt phosphorylates Girdin in response to growth factors such as epidermal growth factor (EGF) in fibroblasts. Furthermore, phosphorylated Girdin accumulates at the leading edge of migrating cells, suggesting its role in Akt‐dependent cell migration or tumor invasion. To date, two paralogues of Girdin have been identified in mammals. One of them, Daple (also named HkRP2), is a binding partner and regulator of Dishevelled, an important cytoplasmic component of the Wnt signaling pathway. Another is a protein encoded by FLJ00354 (also named HkRP3), which has not been functionally characterized. These members are assumed to be dimers with large polypeptide chains (220–250 kDa) that associate at their central long coiled‐coil domains. The amino acid sequences of the members show about 32–46% overall identity, with the greatest variation toward the carboxyl terminal domains that specify the binding partners. Here we propose roles for this family of proteins in diverse cellular processes.
Biosignals Modulated by Tumor‐Associated Carbohydrate Antigens
Authors: FURUKAWA KOICHI , HAMAMURA KAZUNORI , AIXINJUELUO WEI , FURUKAWA KEIKO
Published: December 2006

Abstract:  Based on the remodeling of glycosphingolipids on the human tumor cell lines with manipulation of glycosyltransferase genes, roles of sugar moieties in tumor‐associated carbohydrate antigens have been analyzed. Two main topics, that is, the roles of ganglioside GD3 in human malignant melanomas and those of GD2 in small cell lung cancer (SCLC) were reported. GD3 enhances tyrosine phosphorylation of two adaptor molecules, p130Cas and paxillin, resulting in the increased cell growth and invasion in melanoma cells. GD2 also enhances the proliferation and invasion of SCLC cells. GD2 also mediates apoptosis with anti‐GD2 monoclonal antibodies (mAbs) via dephosphorylation of the focal adhesion kinase. These approaches have promoted further understanding of mechanisms by which gangliosides modulate malignant properties of human cancer, and the results obtained here propose novel targets for cancer therapy.
Disrupted‐in‐Schizophrenia‐1 (DISC1)
Authors: SAWAMURA NAOYA , SAWA AKIRA
Published: December 2006

Abstract:  Here we overview Disrupted‐in‐Schizophrenia‐1 (DISC1), a promising lead in studying the pathophysiology of major mental conditions. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. Different from several other susceptibility genes for schizophrenia, such as neuregulin‐1 and dysbindin, there are two independent pedigrees in which genetic variations of DISC1 directly segregate with major mental conditions. This uniqueness has facilitated neurobiology of DISC1, which may hopefully lead to an important breakthrough in understanding of pathophysiology of major mental conditions. DISC1 is a multifunctional protein that plays a role in neurodevelopment and cell signaling. In autopsied brains from patients with psychosis and substance abuse, change in subcellular distribution of DISC1 is observed. DISC1 interacts with phosphodiesterase (PDE) 4B that degrades cyclic AMP (cAMP), which may be a regulatory molecule for working memory in the prefrontal cortex. Knockdown expression of DISC1 in developing cerebral cortex in mouse brains leads to changes that resemble, at least in part, the pathology found in patients with schizophrenia. These results support involvement of DISC1 in the pathophysiology of major mental conditions, including schizophrenia, in several mechanisms.
FAK Signaling in Neoplastic Disorders
Authors: MON NAING NAING , ITO SATOKO , SENGA TAKESHI , HAMAGUCHI MICHINARI
Published: December 2006

Abstract:  Focal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase, is frequently overexpressed in various tumors and its expression shows good correlation with the progression of tumor. FAK is involved in a diverse range of critical cellular events including spreading, proliferation, migration, and invasion. In addition to these cellular functions, we found that FAK signaling played a critical role in the production of matrix metalloproteinases (MMP) such as MMP‐2 and MMP‐9 and subsequently activated tumor invasion. Moreover, we found that tumor necrosis factor‐α (TNF‐α), a proinflammatory cytokine that acts as an endogenous tumor promoter, activated FAK signaling and enhanced tumor invasion. Since the tumor microenvironment that is largely orchestrated by cytokines is a critical component of tumor progression, these results suggest the importance of FAK as a signaling molecule involved in tumorigenesis. Here, we review the general structure and binding partners of FAK, its regulatory mechanism, and expression in tumors. By summarizing our recent studies, we focus on the critical role of FAK that links cancer with inflammation.
Emergency Department Overcrowding: Analysis of the Factors of Renege Rate
Authors: Asaro Phillip V. , Lewis Lawrence M. , Boxerman Stuart B.
Published: December 2006

Background

Reneging (i.e., leaving without being seen) is an important outcome of emergency department (ED) overcrowding. The input‐throughput‐output conceptualization of ED patient flow is helpful in understanding and measuring the impact of various factors on this outcome.

Objectives

To quantify the impact of input and output factors on ED renege rate.

Methods

The authors used patient‐level and system‐level data from multiple sources in their institution to build logistic regression models, with reneging as the dependent variable. This approach provides the impact of each input and output factor on renege rate expressed as an odds ratio (OR).

Results

The OR for reneging attributable to the difference between the 80th and 20th percentile values for inpatient bed utilization is 1.05. Comparing 80th and 20th percentile values for boarded ED admits as of 7 am, the OR is 1.73; for daily ED arrivals, the OR is 2.00; and for admission percentage, the OR is 1.12. The OR for evening versus morning patient arrival time is 3.9 and for patient arrival on a Monday versus a Sunday is 2.7. The OR for reneging for a patient presenting on Monday evening versus Sunday morning is 10.5.

Conclusions

The effects of ED input and output factors on renege rate are significant and quantifiable. At least some of the variation in these factors and subsequently their effects are predictable, suggesting that further refinement in the management of ED and inpatient resources could affect improvement in ED renege rate. Continued efforts at quantifying the effects are warranted.
Polycomb/Trithorax response elements and epigenetic memory of cell identity
Authors: Ringrose Leonie , Paro Renato
Published: December 2006

Polycomb/Trithorax group response elements (PRE/TREs) are fascinating chromosomal pieces. Just a few hundred base pairs long, these elements can remember and maintain the active or silent transcriptional state of their associated genes for many cell generations, long after the initial determining activators and repressors have disappeared. Recently, substantial progress has been made towards understanding the nuts and bolts of PRE/TRE function at the molecular level and in experimentally mapping PRE/TRE sites across whole genomes. Here we examine the insights, controversies and new questions that have been generated by this recent flood of data.
The structure of PTSD symptoms: A test of alternative models using confirmatory factor analysis
Authors: Elklit Ask , Shevlin Mark
Published: December 2006

Objectives. This study aimed to examine the structure of self‐reported post‐traumatic stress disorder (PTSD) symptoms.

Design. Based on previous factor analytic findings and the DSM‐IV formulation, six confirmatory factor models were specified and estimated that reflected different symptom clusters.

Methods. The analyses were based on responses from 1116 participants who had suffered whiplash injuries and screened for full or subclinical PTSD using the Harvard Trauma Questionnaire.

Results. A correlated four‐factor model with re‐experiencing, avoidance, dysphoria and arousal factors fitted the data very well. Correlations with criteria measures showed that these factors were associated with other trauma related variables in a theoretically predictable way and showed evidence of unique predictive utility.

Conclusions. These results concur with previous research findings using different trauma populations but do not reflect the current DSM‐IV symptom groupings.