bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of Zidovudine-Induced Mitochondrial Toxicity and Myopathy
Authors: Scruggs Erin R. , Dirks Naylor Amie J.
Published: May 2008

Zidovudine (3-azido-3′-deoxythymidine), also referred to as azidothymidine (AZT), has become an integral component in highly active antiretroviral therapy, and has also been used in the treatment of cancer. The clinical effectiveness of AZT is constrained due to its association with increased adverse effects, such as myopathy. There are numerous potential mechanisms that may contribute to AZT-induced myopathy. The first hypothesized mechanism to explain AZT-induced toxicity was mtDNA depletion due to inhibition of DNA polymerase γ. Although mtDNA depletion is present in patients with myopathy, current data suggests that alternative mechanisms may play a more direct role in the myotoxicity. These mechanisms include AZT-induced oxidative stress, direct inhibition of mitochondrial bioenergetic machinery, and mitochondrial depletion of L-carnitine. Furthermore, we hypothesize that apoptosis may play a role in AZT-induced myopathy.
Differential Expression of RUNX Genes in Human Esophageal Squamous Cell Carcinoma: Downregulation of RUNX3 Worsens Patient Prognosis
Authors: Tonomoto Yasuhito , Tachibana Mitsuo , Dhar Dipok Kumar , Onoda Toshinao , Hata Kohkichi , Ohnuma Hideyuki , Tanaka Tsuneo , Nagasue Naofumi
Published: May 2008

Background: The RUNX proteins are a family of transcriptional factors that have essential functions during embryogenesis and development, whereas deregulation in expression of RUNXs is often linked to tumor formation. To date, there has been no study describing the precise expression, prognostic impact and methylation status of RUNXs in esophageal squamous cell carcinoma. Methods: Resected specimens from 61 patients with esophageal SCC were used to identify the expression of RUNX1, RUNX2 and RUNX3 by real-time RT-PCR. Localization of mRNA was done by in situ hybridization, expression of Smad4 was evaluated by immunohistochemistry, and the methylation status of RUNX3 was analyzed by methylation-specific PCR. Results: RUNX3 had a significant impact on patient prognosis with worse survival in the RUNX3-negative group. In early tumors (T1/T2), the prevalence of lymph vessel invasion and the number of metastatic lymph nodes were significantly higher in RUNX3-negative tumors. Furthermore, RUNX3 became a strong prognostic factor only in Smad4-positive tumors. Also, the methylation status of the RUNX3 promoter had a significant correlation with the loss of RUNX3 expression. Conclusion: Downregulation of RUNX3 may play a role in disease progression of esophageal SCC, and hypermethylation of the promoter region might be one of the crucial pathways to silence RUNX3 gene.
Expression of Cdx2 and Claudin-2 in the Multistage Tissue of Gastric Carcinogenesis
Authors: Xin Song , Huixin Chen , Benchang Shen , Aiping Bai , Jinhui Wang , Xiaoyan Li , Yu Wong Benjamin Chun , Minhu Chen
Published: May 2008

In this paper, we investigated Cdx2 and claudin-2 expression in pathological paraffin tissues of sinus ventriculi from gastroscopic biopsy to determine the correlation between the expressions of these 2 genes during gastric carcinogenesis by immunochemical ABC technique. Altogether, we analyzed 108 chronic superficial gastritis, 55 chronic atrophic gastritis, 109 intestinal-type metaplasia, 93 dysplasia and 52 gastric intestinal-type adenocarcinoma samples. Our results indicated that the percentage of Cdx2-positive cases was 0% (0/108) for chronic superficial gastritis, 0% (0/55) for chronic atrophic gastritis, 90.83% (99/109) for intestinal-type metaplasia, 51.61% (48/93) for dysplasia and 61.54% (32/52) for gastric intestinal-type adenocarcinoma, primarily expressed in the cell nucleus and partly in the cytoplasm (p < 0.05); interestingly, the percentage for the intestine-type metaplasia was markedly high. The percentage of claudin-2-positive cases was 0% (0/108) for chronic superficial gastritis, 0% (0/55) for chronic atrophic gastritis, 0% (0/109) for intestinal-type metaplasia, 35.48% (33/93) for dysplasia and 71.15% (37/52) for gastric intestinal-type adenocarcinoma, primarily in the cell membrane and gradually increased in the multistage process of gastric carcinogenesis (p < 0.05). Significant correlations were found between claudin-2 and Cdx2 protein expression in dysplasia and intestine-type adenocarcinoma (r = 0.112, p < 0.05). Thus, there may be a correlation between the expression of claudin-2 and Cdx2 in stages of dysplasia and cancer.
A Novel Variant in the Platelet Endothelial Aggregation Receptor-1 Gene Is Associated With Increased Platelet Aggregability
Authors: Herrera-Galeano J. Enrique , Becker Diane M. , Wilson Alexander F. , Yanek Lisa R. , Bray Paul , Vaidya Dhananjay , Faraday Nauder , Becker Lewis C.
Published: May 2008

Objective—

Platelet endothelial aggregation receptor-1 (PEAR1) is a recently identified platelet transmembrane protein that becomes activated by platelet contact. We looked for novel genetic variants in PEAR1 and studied their association with agonist-induced native platelet aggregation and with the inhibitory effect of aspirin on platelets.

Methods and Results—

We genotyped PEAR1 for 10 single nucleotide polymorphisms (SNPs), selected for optimal gene coverage at a density of 4 kb, in 1486 apparently healthy individuals from two generations of families with premature CAD. Subjects had a mean age of 45 years; 62% were white and 38% black. Platelet aggregation to collagen, epinephrine, and ADP was measured in platelet rich plasma, at baseline and after 2 weeks of aspirin (ASA, 81 mg/d), and genotype-phenotype associations were examined separately by ethnicity using multivariable generalized linear models adjusted for covariates. The C allele of SNP rs2768759 [A/C], located in the promoter region of the gene, was common in whites and uncommon in blacks (allele frequency 70.2% versus 17.7%). The C allele was generally associated in both ethnic groups with increased aggregation of native platelets to each agonist. After ASA, the associations were stronger and more consistent and remained significant when post-ASA aggregation was adjusted for baseline aggregation, consistent with a relationship between the C allele and reduced platelet responsiveness to ASA. The PEAR1 SNP explained up to 6.9% of the locus specific genetic variance in blacks and up to 2.5% of the genetic variance in whites after ASA.

Conclusion—

PEAR1 appears to play an important role in agonist-induced platelet aggregation and in the response to ASA in both whites and blacks.
Angiogenic Function of Prostacyclin Biosynthesis in Human Endothelial Progenitor Cells
Authors: He Tongrong , Lu Tong , d'Uscio Livius V. , Lam Chen-Fuh , Lee Hon-Chi , Katusic Zvonimir S.
Published: May 2008

The role of prostaglandin production in the control of regenerative function of endothelial progenitor cells (EPCs) has not been studied. We hypothesized that activation of cyclooxygenase (COX) enzymatic activity and the subsequent production of prostacyclin (PGI
2
) is an important mechanism responsible for the regenerative function of EPCs. In the present study, we detected high levels of COX-1 protein expression and PGI
2
biosynthesis in human EPCs outgrown from blood mononuclear cells. Expression of COX-2 protein was almost undetectable under basal conditions but significantly elevated after treatment with tumor necrosis factor-α. Condition medium derived from EPCs hyperpolarized human coronary artery smooth muscle cells, similar to the effect of the PGI
2
analog iloprost. The proliferation and in vitro tube formation by EPCs were inhibited by the COX inhibitor indomethacin or by genetic inactivation of COX-1 or PGI
2
synthase with small interfering (si)RNA. Impaired tube formation and cell proliferation induced by inactivation of COX-1 were rescued by the treatment with iloprost or the selective peroxisome proliferator–activated receptor (PPAR)δ agonist GW501516 but not by the selective PGI
2
receptor agonist cicaprost. Downregulation of PPARδ by siRNA also reduced angiogenic capacity of EPCs. Iloprost failed to reverse PPARδ siRNA-induced impairment of angiogenesis. Furthermore, transfection of PGI
2
synthase siRNA, COX-1 siRNA, or PPARδ siRNA into EPCs decreased the capillary formation in vivo after transplantation of human EPCs into the nude mice. These results suggest that activation of COX-1/PGI
2
/PPARδ pathway is an important mechanism underlying proangiogenic function of EPCs.
Sensitivity of Global Mixing and Fluxes to Isolated Transport Barriers
Authors: Nakamura Noboru
Published: May 2008

Effects of isolated transport barriers on the global mixing and fluxes of a tracer are investigated, where a barrier is defined as a local minimum in effective diffusivity. An idealized 1D model with a prescribed diffusivity profile, with or without forcing, is used to show that the structure, flux, and decay rates of the tracer are all very sensitive to the barrier geometry, particularly when it is deep and narrow. Although the tracer gradients and the variance dissipation are concentrated to the barrier region, the flux shows a more global response to the barrier, decreasing everywhere. The harmonic mean of effective diffusivity is proposed as a useful first-order predictor of the global transport. This 1D model is used to diagnose the isentropic transport in the upper troposphere and lower stratosphere with offline transport calculations driven by the Met Office winds. The global tracer variance in these calculations decays approximately exponentially, and the time-mean decay rate and tracer structure are well captured by the gravest 1D eigenmode with the time-averaged effective diffusivity. However, the decay rate and the flux of the full solution are 15%–20% smaller than those of the eigenmode because of a negative temporal correlation between the effective diffusivity and the gradient. The vertical and decadal variations of the decay rates are consistent with the corresponding variations in the harmonic mean effective diffusivity. To the extent that the global mixing is sensitive to the local barrier properties, and to the extent that the latter are sensitive to the errors in advecting winds and model numerics, modeling of global atmospheric transport remains a challenge. This may explain, at least partially, the disparate model estimates reported in the literature.
Vortex-Driven Sensitivity in Deformation Flow
Authors: Liu Zhiyuan , Roebber Paul J.
Published: May 2008

A sensitivity mechanism for the interaction of two vortices in a two-dimensional deformation background flow is explored. A nonlinear model describing the vortex interaction up to a critical merging distance is developed. This model shows that in a confluent or diffluent background flow, two vortices can obtain a global minimum distance by counterclockwise turning and a local minimum distance by clockwise turning about each other. In a major portion of the phase space, the global minimum distance is smaller than the local minimum distance. Therefore, vortex merger is more likely to occur during the process in which the two vortices approach their global smallest distance. Analysis of the governing equations shows that there exists a “most sensitive line” of initial vortex positions. When an initial state is on one side of the most sensitive line, the two vortices can obtain their global smallest distance and thus have a higher chance for merger. Conversely, when an initial state is on the other side relative to the most sensitive line, the two vortices can only obtain their local smallest distance. Consequently, they have a lower chance for merger. When an initial state is close to the most sensitive line, a very small initialization error can put this initial state on the wrong side of the most sensitive line, and the forecast evolution of the pair of vortices may be very different from the observed evolution. Numerical simulations that support these theoretical results are shown.
Detection and Attribution of Temperature Changes in the Mountainous Western United States
Authors: Bonfils Céline , Santer Benjamin D. , Pierce David W. , Hidalgo Hugo G. , Bala Govindasamy , Das Tapash , Barnett Tim P. , Cayan Daniel R. , Doutriaux Charles , Wood Andrew W. , Mirin Art , Nozawa Toru
Published: May 2008

Large changes in the hydrology of the western United States have been observed since the mid-twentieth century. These include a reduction in the amount of precipitation arriving as snow, a decline in snowpack at low and midelevations, and a shift toward earlier arrival of both snowmelt and the centroid (center of mass) of streamflows. To project future water supply reliability, it is crucial to obtain a better understanding of the underlying cause or causes for these changes. A regional warming is often posited as the cause of these changes without formal testing of different competitive explanations for the warming. In this study, a rigorous detection and attribution analysis is performed to determine the causes of the late winter/early spring changes in hydrologically relevant temperature variables over mountain ranges of the western United States. Natural internal climate variability, as estimated from two long control climate model simulations, is insufficient to explain the rapid increase in daily minimum and maximum temperatures, the sharp decline in frost days, and the rise in degree-days above 0°C (a simple proxy for temperature-driven snowmelt). These observed changes are also inconsistent with the model-predicted responses to variability in solar irradiance and volcanic activity. The observations are consistent with climate simulations that include the combined effects of anthropogenic greenhouse gases and aerosols. It is found that, for each temperature variable considered, an anthropogenic signal is identifiable in observational fields. The results are robust to uncertainties in model-estimated fingerprints and natural variability noise, to the choice of statistical downscaling method, and to various processing options in the detection and attribution method.
Does an Increase in Air Quality Models’ Resolution Bring Surface Ozone Concentrations Closer to Reality?
Authors: Valari Myrto , Menut Laurent
Published: May 2008

A persistent challenge for small-scale air quality modeling is the assessment of health impact and population exposure studies. Despite progress in computation and in the quality of model input (i.e., high-resolution information on land use and emission patterns), the uncertainty associated with input parameters cannot be eliminated. The aim of this paper is to study different sources of uncertainty that affect model results as the resolution increases. Mesoscale chemistry transport simulations at different resolutions are used and modeled 03 concentrations are compared with surface measurements. The case study consists of CHIMERE model simulations over the city of Paris. It is shown that the principal source of noise in model results is the resolution of the input emission fluxes. The O3 concentrations modeled with simulations forced by several horizontal resolutions of input emission data (from Δx = 48 km to Δx = 6 km) indicate that model results do not improve monotonously with resolution, but that after a certain point discrepancies become larger. Based on this result and as an alternative to the deterministic downscaling that resolves explicitly the finer scale (beyond the 1-km range), the authors propose a subgrid-scale approach that uses a statistical description of spatial scales finer than model resolution. As an example, the subgrid variability of modeled O3 concentration has been quantified, when modeled dry deposition processes occur over subgrid surfaces (land use fractions). The implementation of this modified calculation gives access to subgrid fluxes and subgrid surface concentrations instead of the mean values provided by the commonly used model calculation.
Single- and Dual-Doppler Analysis of a Tornadic Vortex and Surrounding Storm-Scale Flow in the Crowell, Texas, Supercell of 30 April 2000
Authors: Marquis James , Richardson Yvette , Wurman Joshua , Markowski Paul
Published: May 2008

Fine-resolution single- and dual-Doppler data were collected in the tornadic region of a supercell storm intercepted by two Doppler-on-Wheels radars on 30 April 2000 near Crowell, Texas. Eleven dual-Doppler analyses characterize the 2D and 3D near-surface wind fields associated with a tornado during a 13-min period. An interesting evolution of the low-level rotation is observed. Initially concentric “tornado” (∼500 m wide) and “tornado–cyclone” (∼2 km wide) radar velocity couplets make a transition into a solitary intermediate-sized (∼750 m wide) circulation that widens and makes a further transition into a two-celled multiple-vortex structure with an asymmetric distribution of vertical vorticity. The asymmetry and eventual disruption of the multiple-vortex structure may have been partially controlled by locally strong outflow winds that affect the convergence fields in its vicinity. A smaller (∼500 m wide) tornado embedded in a broad area of rotation is subsequently observed. The dual-Doppler wind fields are also used to characterize aspects of the storm-scale flow. Locally surging outflow winds result in a double rear-flank gust front structure. The tornado and tornado–cyclone are completely surrounded by outflow at all observation times and air parcels traced within the inflow to the storm rise along the gust front rather than enter the tornado near the ground.
A Case Study of Severe Winter Convection in the Midwest
Authors: Pettegrew Brian P. , Market Patrick S. , Wolf Raymond A. , Holle Ronald L. , Demetriades Nicholas W. S.
Published: May 2008

Between 2100 UTC 11 February 2003 and 0200 UTC 12 February 2003, a line of thunderstorms passed swiftly through parts of eastern Iowa and into north-central Illinois. Although this storm somewhat resembled a warm season, line-type mesoscale convective system, it was unique in that the thunderstorm winds exceeded the severe criterion (50 kt; 25.7 m s−1) during a snowburst. While the parent snowband deposited only 4 cm of snow, it did so in a short period and created a treacherous driving situation because of the ensuing near-whiteout conditions caused by strong winds that reached the National Weather Service severe criteria, as the line moved across central Illinois. Such storms in the cold season rarely occur and are largely undocumented; the present work seeks to fill this void in the existing literature.

While this system superficially resembled a more traditional warm season squall line, deeper inspection revealed a precipitation band that failed to conform to that paradigm. Radar analysis failed to resolve any of the necessary warm season signatures, as maximum reflectivities of only 40–45 dBZ reached no higher than 3.7 km above ground level. The result was low-topped convection in a highly sheared environment. Moreover, winds in excess of 50 kt (25.7 m s−1) occurred earlier in the day without thunderstorm activity, upstream of the eventual severe thundersnow location. Perhaps of greatest importance is the fact that the winds in excess of the severe criterion were more the result of boundary layer mixing, and largely coincident with the parent convective line. This event was a case of forced convection, dynamically linked to its parent cold front via persistent frontogenesis and the convective instability associated with it; winds sufficient for a severe thunderstorm warning, while influenced by convection, resulted from high momentum mixing downward through a dry-adiabatic layer.
Day Reporting Center Completion
Authors: Craddock Amy
Published: May 2008

This study of 14 day reporting centers demonstrated that findings from analyses that take into account the clustering of clients into programs differ from those that ignore it. The multilevel analysis found that a higher likelihood of completion is associated with being older, White/non-Hispanic, having a current “other” offense, and having emotional problems. Probationers were less likely to complete if they had drug or alcohol problems, primarily criminal companions, and poor living situations. The more time spent in the program and the more contact hours received in employment services were also positively associated with completion. Although a substantial proportion of the variation in the likelihood of completion was found to be due to program-level factors, no specific program characteristics were significant.
Applying Deeper Learning and Confucian Values in Enhancing School Effectiveness
Authors: Ho Li-An , Lin Chin-Yen , Kuo Tsung-Hsien , Kuo Yen-Ku , Kuo Yen-Lin
Published: May 2008

The study investigates how school teachers' personal background influences their deeper learning capacity and the school effectiveness. Furthermore, the study examines the correlation between teachers' learning capacity and school effectiveness. Four sets of analyses are performed: t tests, one-way ANOVAs, Pearson correlations, and stepwise regression analyses. The research targets a single top-ranking urban junior high school that has the highest admission rates for senior high schools in Taiwan. Data were collected from 192 school teachers, drawn from various grade levels. Results show that (a) personal background does affect teachers' deeper learning capacity and school effectiveness and (b) deeper learning capacity has a strong correlation with school effectiveness.
The Right of Access to Information: opportunities and challenges for civil society and good governance in South Africa
Authors: Arko-Cobbah Albert
Published: May 2008

The right of access to information has been accepted by South Africa as a sine qua non for a democratic state pursuing the values of accountability, transparency, openness and responsiveness in the affairs of government institutions. The article seeks to articulate this view, pointing out that South Africa's recognition of this right was informed by the apartheid system of government that was buttressed by the institutionalized violence of state repression through certain obnoxious legislation like the Internal Security Act. Thus, post-apartheid South Africa, through the 1996 Constitution and other legislation like the Promotion of Access to Information Act, has empowered civil society to ensure government accountability. Despite the fact that the country's access to information legislation is fretted with shortcomings, which this paper expounds, it is acknowledged that a commendable landmark has been made in the political history of the country.
Canadian Libraries on the Agenda: their accomplishments and directions
Authors: Evans Gwynneth , Savard Réjean
Published: May 2008

The authors present an analysis of Canadian libraries in the light of the current president's theme: Libraries on the Agenda. Claudia Lux chose this theme with colleagues to emphasize the role of libraries in the information society and to encourage them to contribute to all sectors of society and to national development. The article is based on the review of a number of studies and on reports and research found in and beyond library literature. Canada is a very large country and its society is quite diverse. This article explains the major trends affecting all libraries in Canada: funding, digitization of collections, consortial arrangements for electronic collections, education, etc. The authors then review the situation in the various types of libraries; national, academic, public, school and special libraries. They conclude the paper with a reflection on leadership and the observation that Canadian libraries are on the agenda and active.
Personnel Demonstration Projects and Human Resource Management Innovation
Authors: Thompson James R.
Published: May 2008

The Personnel Demonstration Project (PDP) provision of the Civil Service Reform Act (CSRA) of 1978 was intended to promote innovative human resource management (HRM) practices and policies. The early experience in this regard was not encouraging. However, during the second 15 years of its existence, the Personnel Demonstration Project authority has been critical to the diffusion of two important human resource management policy innovations, paybanding and category rating. This analysis explores the policymaking dynamic through which this diffusion has occurred.
Student Internet Purchases
Authors: Norum Pamela S.
Published: May 2008

Since the onset of the Internet shopping format, e‐commerce sales have soared, and Generation Y consumers, the first generation to grow up with the Internet, have turned into young adults. As part of Generation Y, college students represent a lucrative market for businesses selling a wide array of goods and services, and they are extremely computer savvy. The purpose of this study was to empirically analyze online buying behavior among college students. Based on an economic framework, factors affecting the online purchase of nine different merchandise categories were examined. Data were analyzed from 4,688 students enrolled in a major Midwestern university. Logistic analysis revealed that variations in the effect of age, gender, income, car ownership, ability to identify a secure Internet site, and compulsive buying behavior existed between the merchandise categories. This study has implications for educators, marketers, and policy makers.
Centre—Right Parties and Political Outcomes in East Central Europe
Authors: Vachudova Milada Anna
Published: May 2008

The emergence of moderate centre—right parties in East Central Europe after 1989 was closely related to the strength and nature of organized opposition during the late communist period. Where such opposition was strong enough to take power, it went on to become the ideological, organizational and elite base for one or more moderate right parties. Where it was weak, moderate right parties were eclipsed by what I call `independence right' and `communist nationalist' parties that dominated the party system using nationalism and other forms of right-wing discourse. Identifying what kind of party dominates this discourse helps explain the very different political outcomes that followed regime change in 1989, including the different structures of party competition and the diverging quality of democracy. Over time, however, political change and the exigencies of qualifying for European Union (EU) membership empowered the centre—right, prompting most `independence right' and `communist nationalist' parties to become mainstream left-wing or right-wing parties. But the EU is now playing another role in party politics in the region, as those conservative centre—right parties that vow to protect the country from integration have become somewhat more powerful compared to their liberal counterparts.
From the Politics of State-Building To Programmatic Politics
Authors: Haughton Tim , Fisher Sharon
Published: May 2008

The post-federal experience was important in shaping the structure of party competition in Central and Eastern Europe in the 1990s, particularly on the centre—right. The cases of Slovakia and Croatia demonstrate not only how and why appeals relating to national autonomy/statehood became salient in some states in the region, but also why dominant parties stressing such themes were unable to lock in their support. Strategic crafting, particularly in the absence of consensus over continuation of the federation, appears key in explaining the rise of dominant parties in the two cases. Nonetheless, where appeals to the nation were combined with illiberalism and were received unfavourably by strategically important international clubs, public support for such parties declined. Following removal from power, these dominant parties undertook bouts of reinvention, attempting to rebrand themselves as mainstream European centre—right parties with mixed results.
Searching for the Right Organization
Authors: Enyedi Zsolt , Linek Lukáš
Published: May 2008

The article examines four centre—right parties in East-Central Europe in order to assess the impact of ideology on party organization and revisit the thesis of organizational weakness in the region. The data collected indicate that, together with electoral success, inherited resources and national context, ideology does indeed shape the style of organization. Centre—right parties, as opposed to leftist parties, tend to be less bureaucratized, have fewer staff members, a simpler structure, more individualized leadership and the `party-in-public-office' tends also to have a more elevated role. Parties that have more individualistic ideologies tends also to have `lighter' organization and weaker embeddedness, while parties subscribing to a more collectivist and corporatist type of conservatism have developed more complex party organization and rely more heavily on affiliate organizations. Analysis of temporal changes uncovers a degree of organizational vitality that is surprising given that the literature on both centre—right and on post-communist politics points towards organizational weakness.
Undocumented Migrants
Authors: Krause Monika
Published: May 2008

The number of people without rights of residence or work in the territory of Western Europe's nation states is growing. In official representations of political life this group is commonly 'symbolically eliminated' or taken up by an increasingly hostile discourse on 'illegal immigrants' and 'international terrorism'. This article explores what a rereading of the work of Hannah Arendt can contribute to the analytical task of giving an alternative meaning to the presence of this group. Arendt opens up new ways of thinking and acting in view of the present situation. She shows us the rightless migrant as subject to a very specific form of domination - total domination. With Arendt we can see the migrant also as an emblematic philosophical figure, whose status exposes the contradiction of state-centred citizenship and the discourse of human rights. Lastly, the migrant comes into view as a potential political actor; protests by sans papiers become visible as sites of active citizenship.
Resistance to second-line injectables and treatment outcomes in multidrug-resistant and extensively drug-resistant tuberculosis cases
Authors: Migliori G. B. , Lange C. , Centis R. , Sotgiu G. , Mütterlein R. , Hoffmann H. , Kliiman K. , De Iaco G. , Lauria F. N. , Richardson M. D. , Spanevello A. , Cirillo D. M. , TBNET Study Group
Published: May 2008

No information is currently available on the influence of injectable second-line drugs on treatment outcomes of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) patients.

To investigate this issue, a large series of MDR- and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation (Archangels Oblast) between 1999 and 2006 were analysed. All study sites performed drug susceptibility testing for first- and second-line anti-TB drugs, laboratory quality assurance and treatment delivery according to World Health Organization recommendations.

Out of 4,583 culture-confirmed cases, 240 MDR- and 48 XDR-TB cases had a definitive outcome recorded (treatment success, death, failure). Among MDR- and XDR-TB cases, capreomycin resistance yielded a higher proportion of failure and death than capreomycin-susceptible cases. Resistance to capreomycin was independently associated with unfavourable outcome (logistic regression analysis: odds ratio 3.51).

In the treatment of patients with multidrug-resistant and extensively drug-resistant tuberculosis, resistance to the injectable drug capreomycin was an independent predictor for therapy failure in this cohort. AsMycobacterium tuberculosisdrug resistance is increasing worldwide, there is an urgent need for novel interventions in the fight against tuberculosis.
Risk factors for death among tuberculosis cases: analysis of European surveillance data
Authors: Lefebvre N. , Falzon D.
Published: May 2008

The proportion of tuberculosis (TB) patients in the European Union (EU) who die remains high (8% overall). The aim of the present study was to quantify the risk of dying associated with demographic and clinical factors.

Case-based data on 39,566 TB patients notified by 15 EU countries during 2002–2004 were analysed using logistic regression.

It was observed that advancing age and resistance to isoniazid and rifampicin were the strongest determinants of death, while male sex, European origin, pulmonary site of disease and previous anti-TB treatment were weaker predictors. Risk varied between reporting countries, presumably reflecting differences in patient profiles, reporting practices and programme effectiveness.

In conclusion, earlier suspicion, diagnosis and treatment may reduce deaths, particularly among the elderly. Special attention is needed to avert the development and transmission of multidrug-resistant tuberculosis.
Pulmonary hypertension in interstitial lung disease: Fig. 1—
Authors: Behr J. , Ryu J. H.
Published: May 2008

In the lungs, parenchymal and vascular remodelling share pathomechanisms that may explain the relatively high prevalence (30–40%) of pulmonary hypertension (PH) in interstitial lung disease (ILD) patients. Notably, PH significantly contributes to exercise limitation and dismal prognosis of ILD patients. The absence of specific clinical symptoms commonly leads to delayed diagnosis. Besides clinical judgment and out-of-proportion reduction in diffusing capacity, severe hypoxaemia or exercise oxygen desaturation, echocardiography and biomarkers such as B-type natriuretic peptide (BNP) and N-terminal pro-hormone BNP are potentially helpful tools in identifying PH. However, right heart catheterisation is still necessary to confirm the diagnosis. Management of PH in ILD comprises treatment of the underlying disease process and long-term oxygen therapy. Affected patients should be listed for lung transplantation without delay, when appropriate. However, due to age and comorbidities only a minority of ILD patients will be eligible for lung transplantation. In the absence of satisfactory therapies for many ILDs, and considering the clinical burden of PH in affected patients, specific vasomodulatory therapies presently approved for PAH may be promising options for ILD patients. Consequently, there is an urgent need for adequately designed clinical trials to assess the effectiveness of specific PH therapy in the context of ILDs.
Comparison of DNA histograms by standard flow cytometry and image cytometry on sections in Barrett's adenocarcinoma
Authors: Huang Qin , Yu Chenggong , Zhang Xiaoqi , Goyal Raj K
Published: May 2008

Background

The purpose of this study was to compare DNA histograms obtained by standard flow cytometry (FC) and high fidelity image cytometry on sections (ICS) in normal gastrointestinal mucosa and Barrett's adenocarcinoma (BAC).

Methods

Archival formalin-fixed paraffin-embedded tissue blocks of 10 normal controls from 10 subjects and 42 BAC tissues from 17 patients were examined. DNA FC was performed using standard techniques and ICS was carried out by Automated Cellular Imaging System (ACIS). DNA ploidy histograms were classified into diploid with peak DNA index (DI) at 0.9–1.1, and aneuploid with peak DI > 1.1. DI values of aneuploid peaks were determined. Additionally, for DNA ICS, heterogeneity index (HI) representing DNA content heterogeneity, and histograms containing cells with DI > G2 were also identified.

Results

All control samples were diploid by both FC and ICS analyses. In BAC, FC showed diploid peaks in 29%, diploid peaks with additional aneuploid or tetraploid peaks in 57%, and 14% of the samples, respectively. In contrast, ICS showed aneuploid peaks in all the cases with peak DI > 1.25; 37 cases had peak DI between 1.25 and 2.25; and 5 cases had peak DI > 2.25. HI values (mean ± SD) were 11.3 ± 1.1 in controls and 32.4 ± 8.5 in BAC (p < 0.05). Controls had no G2 exceeding cells. However, 19/37 (51%) of the cases with primary peak DI < 2.25 had cells exceeding 9N.

Conclusion

ICS detects DNA aneuploidy in all BAC samples while FC missed the diagnosis of aneuploidy in 29%. In addition, ICS provides more information on HI and G2 exceeding rates.
Exposure from the Chernobyl accident had adverse effects on erythrocytes, leukocytes, and, platelets in children in the Narodichesky region, Ukraine: A 6-year follow-up study
Authors: Stepanova Eugenia , Karmaus Wilfried , Naboka Marina , Vdovenko Vitaliy , Mousseau Tim , Shestopalov Viacheslav M , Vena John , Svendsen Erik , Underhill Dwight , Pastides Harris
Published: May 2008

Background

After the Chernobyl nuclear accident on April 26, 1986, all children in the contaminated territory of the Narodichesky region, Zhitomir Oblast, Ukraine, were obliged to participate in a yearly medical examination. We present the results from these examinations for the years 1993 to 1998. Since the hematopoietic system is an important target, we investigated the association between residential soil density of137Caesium (137Cs) and hemoglobin concentration, and erythrocyte, platelet, and leukocyte counts in 1,251 children, using 4,989 repeated measurements taken from 1993 to 1998.

Methods

Soil contamination measurements from 38 settlements were used as exposures. Blood counts were conducted using the same auto-analyzer in all investigations for all years. We used linear mixed models to compensate for the repeated measurements of each child over the six year period. We estimated the adjusted means for all markers, controlling for potential confounders.

Results

Data show a statistically significant reduction in red and white blood cell counts, platelet counts and hemoglobin with increasing residential137Cs soil contamination. Over the six-year observation period, hematologic markers did improve. In children with the higher exposure who were born before the accident, this improvement was more pronounced for platelet counts, and less for red blood cells and hemoglobin. There was no exposure×time interaction for white blood cell counts and not in 702 children who were born after the accident. The initial exposure gradient persisted in this sub-sample of children.

Conclusion

The study is the first longitudinal analysis from a large cohort of children after the Chernobyl accident. The findings suggest persistent adverse hematological effects associated with residential137Cs exposure.
Novel PKC signaling is required for LPS-induced soluble Flt-1 expression in macrophages
Authors: Lee Ming-Cheng , Wei Shu-Chen , Tsai-Wu Jyy-Jih , Wu C H Herbert , Tsao Po-Nien
Published: May 2008

In vitro activation of macrophages by LPS induces rapid release of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 receptor (sFlt-1), which are thought to be the effectors to cause sepsis. However, the signal pathway that controls the VEGF and sFlt-1 expressions in LPS-activated macrophages remains unclear. In this study, we demonstrated that phosphorylation of protein kinase C (PKC)δ played a key role in the VEGF and sFlt-1 signaling pathway of LPS-activated macrophages. PKC is a family of serine-threonine kinases, which are classified into three major groups based on homology and cofactor requirements: conventional PKCs, novel PKCs, and atypical PKCs. In the murine RAW264.7 cells, as well as in primary human monocytes/macrophages, pretreatment with a general PKC inhibitor GF109203X or with a novel PKCδ inhibitor rottlerin or overexpression of a kinase-inactive form of PKCδ (K376R) eliminated LPS-induced sFlt-1 expression and augmented LPS-induced VEGF expression at the protein and the transcription levels. In contrast, Gö6976, an inhibitor for the conventional PKCs, or myristoylated PKCζ pseudosubstrate peptide, an inhibitor for the atypical PKCs, failed to exert the same effects. These data suggest that PKCδ signaling is involved in LPS-induced sFlt-1 expression and serves as a negative mediator in LPS-induced VEGF expression in macrophages. A novel strategy controlling the LPS-induced PKC pathways, especially the PKCδ isoform, may be developed based on this study.
Estrogen Receptor (ER) β Modulates ERα Responses to Estrogens in the Developing Rat Ventromedial Nucleus of the Hypothalamus
Authors: Gonzales Keith L. , Tetel Marc J. , Wagner Christine K.
Published: May 2008

The mechanisms by which estradiol exerts specific actions on neural function are unclear. In brain the actions of estrogen receptor (ER) α are well documented, whereas the functions of ERβ are not yet fully elucidated. Here, we report that ERβ inhibits the activity of ERα in an anatomically specific manner within the neonatal (postnatal d 7) brain. Using selective agonists we demonstrate that the selective activation of ERα in the relative absence of ERβ activation induces progesterone receptor expression to a greater extent than estradiol alone in the ventromedial nucleus, but not the medial preoptic nucleus, despite high ERα expression. Selective activation of ERβ attenuates the ERα-mediated increase in progesterone receptor expression in the ventromedial nucleus but has no effect in medial preoptic nucleus. These results suggest that ERα/ERβ interactions may regulate the effects of estrogens on neural development and reveal the neonatal brain as a unique model in which to study the specificity of steroid-induced gene expression.
Aquaporin 1 Is Important for Maintaining Secretory Granule Biogenesis in Endocrine Cells
Authors: Arnaoutova Irina , Cawley Niamh X. , Patel Nimesh , Kim Taeyoon , Rathod Trushar , Loh Y. Peng
Published: May 2008

Aquaporins (AQPs), a family of water channels expressed in epithelial cells, function to transport water in a bidirectional manner to facilitate transepithelial fluid absorption and secretion. Additionally, AQP1 and AQP5 are found in pancreatic zymogen granules and synaptic vesicles and are involved in vesicle swelling and exocytosis in exocrine cells and neurons. Here, we show AQP1 is in dense-core secretory granule (DCSG) membranes of endocrine tissue: pituitary and adrenal medulla. The need for AQP1 in endocrine cell function was examined by stable transfection of AQP1 antisense RNA into AtT20 cells, a pituitary cell line, to down-regulate AQP1 expression. These AQP1-deficient cells showed more than 60% depletion of DCSGs and significantly decreased DCSG protein levels, including proopiomelanocotin/pro-ATCH and prohormone convertase 1/3, but not non-DCSG proteins. Pulse-chase studies revealed that whereas DCSG protein synthesis was unaffected, approximately 50% of the newly synthesized proopiomelanocortin was degraded within 1 h. Low levels of ACTH were released upon stimulation, indicating that the small number of DCSGs that were made in the presence of the residual AQP1 were functionally competent for exocytosis. Analysis of anterior pituitaries from AQP1 knockout mice showed reduced prohormone convertase 1/3, carboxypeptidase E, and ACTH levels compared to wild-type mice demonstrating that our results observed in AtT20 cells can be extended to the animal model. Thus, AQP1 is important for maintaining DCSG biogenesis and normal levels of hormone secretion in pituitary endocrine cells.
The Xenopus laevis Isoform of G Protein-Coupled Receptor 3 (GPR3) Is a Constitutively Active Cell Surface Receptor that Participates in Maintaining Meiotic Arrest in X. laevis Oocytes
Authors: Deng James , Lang Stephanie , Wylie Christopher , Hammes Stephen R.
Published: May 2008

Oocytes are held in meiotic arrest in prophase I until ovulation, when gonadotropins trigger a subpopulation of oocytes to resume meiosis in a process termed “maturation.” Meiotic arrest is maintained through a mechanism whereby constitutive cAMP production exceeds phosphodiesterase-mediated degradation, leading to elevated intracellular cAMP. Studies have implicated a constitutively activated Gαs-coupled receptor, G protein-coupled receptor 3 (GPR3), as one of the molecules responsible for maintaining meiotic arrest in mouse oocytes. Here we characterized the signaling and functional properties of GPR3 using the more amenable model system of Xenopus laevis oocytes. We cloned the X. laevis isoform of GPR3 (XGPR3) from oocytes and showed that overexpressed XGPR3 elevated intraoocyte cAMP, in large part via Gβγ signaling. Overexpressed XGPR3 suppressed steroid-triggered kinase activation and maturation of isolated oocytes, as well as gonadotropin-induced maturation of follicle-enclosed oocytes. In contrast, depletion of XGPR3 using antisense oligodeoxynucleotides reduced intracellular cAMP levels and enhanced steroid- and gonadotropin-mediated oocyte maturation. Interestingly, collagenase treatment of Xenopus oocytes cleaved and inactivated cell surface XGPR3, which enhanced steroid-triggered oocyte maturation and activation of MAPK. In addition, human chorionic gonadotropin-treatment of follicle-enclosed oocytes triggered metalloproteinase-mediated cleavage of XGPR3 at the oocyte cell surface. Together, these results suggest that GPR3 moderates the oocyte response to maturation-promoting signals, and that gonadotropin-mediated activation of metalloproteinases may play a partial role in sensitizing oocytes for maturation by inactivating constitutive GPR3 signaling.
LINGUISTIC RUIN? LOL! INSTANT MESSAGING AND TEEN LANGUAGE
Authors: Tagliamonte Sali A. , Denis Derek
Published: May 2008

This article presents an analysis of Instant Messaging (IM), a one-to-one synchronous medium of computer-mediated communication. Innumerable articles in the popular press suggest that increasing use of IM by teens is leading to a breakdown in the English language. The analyses presented here are based on a unique corpus involving 72 teenagers and over a million words of natural, unmonitored IM. In addition, a corpus of speech from the same teenagers is examined for comparison. Targeting well-known IM features and four areas of grammar, we show that IM is firmly rooted in the model of the extant language. It reflects the same structured heterogeneity (variation) and the same dynamic, ongoing processes of linguistic change that are currently under way in contemporary varieties of English. At the same time, IM is a unique new hybrid register, exhibiting a fusion of the full range of variants from the speech community—formal, informal, and highly vernacular.
ACOUSTIC CHARACTERISTICS OF UTAH'SCARD-CORDMERGER
Authors: Bowie David
Published: May 2008

Several claims have been put forward to explain the character of Utah's card-cord merger, in which is variably produced as . Instances of words containing from the running speech of a Utahn who variably exhibits the merger were rated by a panel of speakers on whether they were produced as or , allowing utterances to be classified as merged (into ), unmerged, or intermediate. Merged and unmerged instances were not found to be separated cleanly when taking just F1 and F2 into consideration, but looking at F1, F2, and F3 simultaneously resulted in a clean split between those categories, with the intermediate cases falling along the border between them. Further, the formant values did not match up with any simple articulatory explanation for the merger and its attendant distinction. Not only does this demonstrate that Utah's card-cord merger is the result of the simultaneous manipulation of multiple articulatory features, it raises the possibility that clear separation between phonetic categories could be found in other cases that might generally be expected to have some overlap.
The Question of Arab Solidarity in the 1948 War: Political Interests versus Military Considerations
Authors: Yitzhak Ronen
Published: May 2008

Ronen Yitzhak is professor of history at Western Galilee College, Israel.
The Post-9/11 American Conundrum: How to Win the War of Ideas in the World of Islam
Authors: Ahrari Ehsan
Published: May 2008

Ehsan Ahrari is professor of security studies (counterterrorism) at the Asia Pacific Center for Security Studies in Honolulu, Hawaii. The views expressed are those of the author alone and do not reflect those of the Asia Pacific Center for Security Studies or any other department or agency of the US government.
The Kurdistan Workers' Party Turns against the European Union
Authors: Uslu Emrullah
Published: May 2008

Emrullah Uslu is a doctoral candidate at the Middle East Center, University of Utah. He has worked as a policy analyst for the Turkish National Police.