bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional Trade Agreements in East Asia: Will They Be Sustainable?*
Authors: Park Innwon
Published: June 2009

By assessing the sustainability of regional trade agreements (RTAs) for East Asia, we quantitatively evaluate the likely impact of proposed East Asian RTA strategies on the East Asian economies and the world economy with respect to consumption, production, volume of trade and terms of trade effects by applying a multi‐country and multi‐sector computable general equilibrium model. These strategies include: (i) the ASEAN Free Trade Area (AFTA: a being‐left‐alone strategy); (ii) an ASEAN Hub RTA (a hub‐and‐spoke type of overlapping RTA strategy); (iii) the AFTA versus a China–Japan–Korea RTA (a duplicating or competing RTA strategy); and (iv) an ASEAN+3 RTA (an expansionary RTA strategy). We find that an expansionary ASEAN+3 RTA could be a sustainable policy option because the members’ gains would be significantly positive, with more equitably distributed gains between members than when using other strategies. The effect on world welfare would also be positive and the negative effect on nonmembers would not be very strong. More interestingly, if the East Asian countries cooperate with Pacific Basin countries to form an APEC‐level RTA, such as a free trade area of the Asia‐Pacific, the extension of the regional trade bloc might be considered a more desirable policy option than the proposed East Asian RTAs for East Asian economies, even though countries excluded from the free trade area of the Asia Pacific are worse off.
Sources of Growth and Structural Change in the Vietnamese Economy, 1996–2003: A Computable General Equilibrium Analysis*
Authors: Giesecke James A. , Nhi Tran Hoang
Published: June 2009

We use the MONASH‐VN model, a dynamic computable general equilibrium model of the Vietnamese economy, to investigate Vietnam's rapid growth and structural change over the period 1996 to 2003. We do this in two steps. First, we estimate changes in variables representing production technologies, consumer preferences, government policy and other structural features of the economy. Movements in these structural and policy variables are then used to explain the recent history of Vietnam's rapid growth and structural change. We find the most important sources of growth and change to be technical improvements, favorable shifts in foreign demand for Vietnamese goods and employment growth. Other important factors include movement in household preferences away from primary products and towards manufactures and services, expansion in agricultural land supply, and tax reform.
Productivity Spillovers from FDI in Malaysian Manufacturing: Evidence from Micro‐panel Data*
Authors: Khalifah Noor Aini , Adam Radziah
Published: June 2009

Using an establishment‐level panel dataset for the Malaysian manufacturing industries for 2000–2004, we argue that differences in the proxies and degrees of foreign shareholdings in measuring foreign presence lead to opposite signs and/or significance of spillover effects. The results show significant evidence of positive productivity spillovers to local establishments in the same industry, based on a broad measure of foreign presence. However, there is no evidence of positive spillover when employment share is used as a proxy for foreign presence. Furthermore, significant negative spillover effects are related to higher employment shares of wholly foreign‐owned establishments. Although there is no significant difference in labor productivity between wholly foreign‐owned and locally‐owned establishments, both majority and minority foreign‐owned establishments have significantly lower levels of labor productivity than locally‐owned establishments in Malaysia.
7. Multivariate Decomposition for Hazard Rate Models
Authors: Powers Daniel A. , Yun Myeong-Su
Published: June 2009

We develop a regression decomposition technique for hazard rate models, where the difference in observed rates is decomposed into components attributable to group differences in characteristics and group differences in effects. The baseline hazard is specified using a piecewise constant exponential model, which leads to convenient estimation based on a Poisson regression model fit to person-period, or split-episode data. This specification allows for a flexible representation of the baseline hazard and provides a straightforward way to introduce time-varying covariates and time-varying effects. We provide computational details underlying the method and apply the technique to the decomposition of the black-white difference in first premarital birth rates into components reflecting characteristics and effect contributions of several predictors, as well as the effect contribution attributable to race differences in the baseline hazard.
Discordance in HIV‐1 viral loads and antiretroviral drug concentrations comparing semen and blood plasma
Authors: Lorello G , La Porte C , Pilon R , Zhang G , Karnauchow T , MacPherson P
Published: June 2009

Objectives

For individuals not on antiretroviral therapy, the risk of heterosexual transmission of HIV appears negligible when blood plasma (BP) viral loads are <1500 HIV‐1 RNA copies/mL. It is not clear whether this observation can be extrapolated to individuals on highly active antiretroviral therapy (HAART). Because of differential tissue penetration, antiretroviral drug concentrations may be sufficient to maintain an undetectable viral load in the BP yet not achieve adequate levels to suppress HIV in the genital tract. Therefore, we wanted to correlate HIV viral loads and drug concentrations in semen plasma (SP) and BP.

Methods

Thirty‐three men were included. All were on combination antiretroviral therapy with an undetectable BP viral load for at least 1 year. Blood and semen samples were collected within 2 h of each other and tested for HIV RNA by the NucliSens QT (bioMerieux, St Laurent, QC, Canada) method; drug concentrations were determined by liquid chromatography tandem mass spectrometry.

Results

Two of the 33 patients (6.1%) with BP viral loads below detection had time‐matched HIV viral loads in SP ≥700 copies/mL. Both patients were on efavirenz, the SP concentrations of which were ≤10% of the levels in BP and well below the minimal therapeutic drug monitoring target concentration required to suppress HIV.

Conclusions

Because, at least in part, of poor drug penetration into the genital tract, an undetectable HIV viral load in the BP does not guarantee an undetectable viral load in semen. In view of this, caution should be taken in concluding that patients on HAART with suppressed viraemia are sexually non‐infectious.
Brain‐derived neurotrophic factor gene polymorphisms and serum levels in Chinese atopic dermatitis patients
Authors: Ma L , Gao X‐H , Zhao L‐P , Di Z‐H , Mchepange UO , Zhang L , Chen H‐D , Wei H‐C
Published: June 2009

Background  Brain‐derived neurotrophic factor (BDNF) plays an important role in the pathogenesis of atopic dermatitis (AD). Whether BDNF gene polymorphisms are associated with Chinese AD remains totally unknown.

Objective  The aim is to determine if BDNF gene C270T and G196A polymorphisms are associated with Chinese AD, and analyse the clinical relevance of BDNF gene polymorphisms and BDNF serum levels.

Methods  We conducted a case‐control association analysis (160 patients and 169 controls) in Northern Chinese subjects. Genotyping was performed by restriction fragment length polymorphism, and serum levels of BDNF were measured using enzyme‐linked immunosorbent assay.

Results  For C270T, there were significant differences in C/T genotype distribution (P = 0.003) and T allele frequencies (P = 0.004) between AD patients and controls in the whole dataset. Higher C/T genotype frequencies were found in male AD (10.6% vs. 1.1%, P = 0.018) and in intrinsic AD (IAD; 15.79% vs. 2.91%, P = 0.008). No association between G196A polymorphism and AD was observed in the whole cohort, while A allele was much more frequent in AD patients with atopy in first‐degree relatives (65.8% vs. 34.2%, P = 0.038). Serum BDNF levels were correlated with IAD severity as measured by Scoring Atopic Dermatitis index (r = 0.576, P < 0.001).

Conclusion  T allele in C270T may be a risk factor for AD, especially in IAD and male AD. A allele in G196A may be a risk factor in AD patients with atopy in first‐degree relatives. Serum BDNF levels were correlated with the severity of IAD.
Basement membrane changes in lichen planopilaris
Authors: Al‐Refu K , Goodfield M
Published: June 2009

Background  Lichen planopilaris (LPP) is an inflammatory disease that affects the scalp and tends to produce cicatricial alopecia. The inflammatory process frequently results in the disruption of the basal cell of the external root sheath of the hair follicle.

Objectives  To investigate the alterations in the basement membrane zone (BMZ) in LPP by immunohistochemistry.

Methods  Skin biopsies from six patients with LPP plus six normal controls were studied by immunohistochemistry with antibodies to the following BMZ components: cytokeratin 5, cytokeratin 14, BP230 (bullous pemphigoid), BP180, plectin, laminin 5, collagen IV and collagen VII.

Results  The localization and staining of the hemidesmosome, laminin and collagen components were strikingly different in the inflamed follicular epithelium when compared to the uninvolved follicles or interfollicular epithelium in active LPP lesions. The hemidesmosome‐associated complexes were weakly expressed and discontinuous in involved hair follicles. The expression of laminin‐5, type IV collagen and type VII collagen was disrupted and not linear along the BMZ with finger‐like projections of the staining protruding into the dermis. The expression of the intermediate filaments was normal.

Conclusion  These alterations in the BMZ in LPP may explain the abnormal healing at follicular level which leads to irreversible hair loss and scarring in this condition.
Prevalence of myocardial infarction in patients with psoriasis in central China
Authors: Xiao J , Chen L‐H , Tu Y‐T , Deng X‐H , Tao J
Published: June 2009

Objective  To explore whether the prevalence of myocardial infarction (MI) was higher in psoriatics than in patients without psoriasis, and whether major cardiovascular risk factors were associated with psoriasis in central China.

Methods  Data were collected at Medical Records Section of Affiliated Union Hospital, Tongji Hospital, Wuhan Iron and Steel Company General Hospital and No. 1 Hospital of Wuhan between 1999 and 2007. Patients with psoriasis were classified as severe if they ever received a systemic therapy. And patients were classified as having risk factors if they received codes for diabetes, hypertension, hyperlipidemia, or smoking. Controls without psoriasis were randomly selected from the Physical Examination Centre in the Affiliated Union Hospital. Analysis was performed by using conditional logistic regression, and adjustments were made for age and sex.

Results  There were 45 MIs (2.96%) within the control population and 97 (6.00%) and 118 (8.01%) MIs within the mild and severe psoriasis groups, respectively. Respective odds ratio (OR) and 95% confidence interval (95% CI) of cardiovascular risk factors in those with mild psoriasis than controls were as follows: obesity (OR, 1.41; 95% CI, 1.08–1.85), diabetes (OR, 1.45; 95% CI, 1.11–1.91), hypertension (OR, 1.39; 95% CI, 1.04–1.85), hyperlipidemia (OR, 1.37; 95% CI, 1.06–1.78) and smoking (OR, 1.35; 95% CI, 1.01–1.80). Patients with severe psoriasis had higher adjusted odds of obesity (OR, 1.51; 95% CI, 1.15–1.98), diabetes (OR, 1.69; 95% CI, 1.32–2.17), hypertension (OR, 1.41; 95% CI, 1.06–1.88), hyperlipidemia (OR, 1.43; 95% CI, 1.11–1.84), and smoking (OR, 1.57; 95% CI, 1.20–2.05) than patients with mild psoriasis and controls. After adjusting for systemic therapies and cardiovascular risk factors (obesity, diabetes, hypertension, hyperlipidemia and smoking) in addition to age and sex, for patients with mild or severe psoriasis, the OR of having an MI was 1.72 (95% CI, 1.29–2.30) and 2.01 (95% CI, 1.45–2.79), respectively.

Conclusions  The prevalence of MI is higher in mild andsevere psoriasis than in patients without psoriasis in central China. In addition, MI and major cardiovascular risk factors (e.g. diabetes, hypertension, hyperlipidemia and smoking) are associated with psoriasis in central China.
Urinary biomarker of oxidative stress in patients with psoriasis vulgaris and atopic dermatitis
Authors: Nakai K , Yoneda K , Maeda R , Munehiro A , Fujita N , Yokoi I , Moriue J , Moriue T , Kosaka H , Kubota Y
Published: June 2009

Background  The involvement of oxidative stress in the pathogenesis of various skin disorders has been suggested for decades. However, few clinical studies have assessed oxidative stress in skin diseases. The easiest and least invasive method to assess oxidative stress in patients may be the measurement of oxidation products in urine.

Objective  This study aims to assess oxidative stress in psoriasis and atopic dermatitis patients.

Methods  Urine samples were collected from 29 psoriasis patients (25 males and 4 females), 21 atopic dermatitis patients (14 males and 7 females) and 20 healthy controls (16 males and 4 females). The severity and extent of psoriasis and atopic dermatitis was assessed by their area and severity index. We measured nitrate as a metabolite of nitric oxide, malondialdehyde as a major lipid oxidation product, and 8‐hydroxydeoxyguanosine (8‐OHdG) as a DNA oxidation marker.

Results  Urinary nitrate and 8‐OHdG levels, but not malondialdehyde, were significantly higher in psoriasis patients than those in healthy controls. On the contrary, only urinary nitrate level was significantly higher in atopic dermatitis patients than those in healthy controls. The severity and extent of both psoriasis and atopic dermatitis significantly correlated with urinary nitrate level and malondialdehyde level, but it did not correlate with urinary 8‐OHdG level.

Conclusions  Measurement of these three urinary oxidative products is non‐invasive. Above all, measurement of urinary nitrate may be most useful in the clinical assessment of oxidative stress in both psoriasis and atopic dermatitis patients. There is a possibility that urinary 8‐OHdG level may indicate the different pathogenesis between psoriasis and atopic dermatitis.
Guidelines for the laboratory diagnosis of Chlamydia trachomatis infections in East European countries
Authors: Domeika M , Savicheva A , Sokolovskiy E , Frigo N , Brilene T , Hallén A , Unemo M , Ballard RC , Ward M ,   EE SRH Network
Published: June 2009

The present guidelines aim to provide comprehensive information regarding the laboratory diagnosis of infections caused by Chlamydia trachomatis in East European countries. These recommendations contain important information for laboratory staff working with sexually transmitted infections (STIs) and/or STI‐related issues. Individual East European countries may be required to make minor national adjustments to these guidelines as a result of lack of accessibility to some reagents or equipment, or laws in a specific country.
Somatostatin receptor scintigraphy in primary cutaneous T‐ and B‐cell lymphomas
Authors: Valencak J , Trautinger F , Raderer M , Chott A , Der‐Petrossian M , Ivancic‐Brandenberger E , Knobler R , Kurtaran A , Hoffmann M
Published: June 2009

Background  Monitoring and repeated staging is of substantial importance in many patients with primary cutaneous T‐cell lymphomas (CTCL). For primary cutaneous B‐cell lymphomas (CBCL), extensive initial staging is the mainstay for correct diagnosis.

Aim  To evaluate the value of somatostatin receptor scintigraphy using the radiolabeled somatostatin analog 111In‐pentetreotide in comparison to conventional imaging methods for the staging of patients with primary CTCL and primary CBCL.

Methods  Twenty‐two patients (15 patients with histologically verified CTCL and 7 patients with histologically verified CBCL) were included. Stage of disease was established by physical examination, laboratory screening, skin inspection, palpation of superficial lymph nodes, sonography and computed tomography (CT) in patients with advanced clinical stage. Focally elevated tracer uptake of 111In‐pentetreotide was compared to common imaging modalities, physical aspect and digital photographs of the respective skin lesions.

Results  Of the 15 patients with CTCL, only 4 (27%) showed positive scintigraphic results, but not in all sites of lymphomatous involvement. None of the five patients with mycosis fungoides in stage I, nor any of the four patients with Sézary syndrome, had a positive 111In‐ pentetreotide scan. Of the seven patients with CBCL three positive scintigraphic results (43%) could be obtained: in two patients with a follicular center lymphoma and one patient with a diffuse large B‐cell lymphoma – leg type, but again not in all apparent sites of lymphoma.

Conclusions  Based on our results, we do not recommend the use of somatostatin receptor scintigraphy for routine staging of patients with CTCL and CBCL. As our series includes only 22 patients, and the number of patients with rarer variants of CTCL was rather small, it might be too premature to abandon SST‐R in the staging of patients with cutaneous lymphomas.
Study on association between polymorphism of HLA‐DRB1 alleles and Behçet's disease
Authors: Shang Y‐B , Zhai N , Li J‐P , Han S‐X , Ren Q‐S , Song F‐J , Chen H‐D
Published: June 2009

Background  Behçet's disease (BD) is known to be associated with human leucocyte antigen (HLA)‐B*51 in many ethnic groups. However, the association of HLA class II gene with BD has been described to be different according to different countries and regions.

Objective  This study aims to investigate the association between polymorphism of HLA‐DRB1 alleles and BD.

Methods  Forty patients with BD and 100 healthy controls were typed for HLA‐DRB1 alleles by the LABTypeTM SSO method.

Results  The frequency of HLA‐DRB1*14 was significantly higher in BD patients than in controls (P < 0.05), while the frequency of HLA‐DRB1*15 was markedly lower in BD patients (P < 0.05). Regarding clinical manifestations, the frequency of HLA‐DRB1*15 was significantly decreased in BD patients with genital ulcerations compared with controls (P < 0.05); the frequency of HLA‐DRB1*14 was significantly increased in BD patients with erythema nodosum–like lesions and in BD patients with folliculitis‐like lesions when compared to controls (P < 0.05, respectively). Moreover, the frequency of HLA‐DRB1*14 was significantly increased in BD patients under 20 years of age at the onset of disease (P < 0.01), while the frequency of HLA‐DRB1*15 was significantly decreased in them (P < 0.05), compared with controls.

Conclusion  The results suggested that HLA‐DRB1 alleles might play an important role in the onset and clinical manifestations of BD.
A comparative view of the evolution of grasses under domestication
Authors: Glémin Sylvain , Bataillon Thomas
Published: June 2009

Crop grasses were among the first plants to be domesticated c. 12 000 yr ago, and they still represent the main staple crops for humans. During domestication, as did many other crops, grasses went through dramatic genetic and phenotypic changes. The recent massive increase in genomic data has provided new tools to investigate the genetic basis and consequences of domestication. Beyond the genetics of domestication, many aspects of grass biology, including their phylogeny and developmental biology, are also increasingly well studied, offering a unique opportunity to analyse the domestication process in a comparative way. Taking such a comparative point of view, we review the history of domesticated grasses and how domestication affected their phenotypic and genomic diversity. Considering recent theoretical developments and the accumulation of genetic data, we revisit more specifically the role of mating systems in the domestication process. We close by suggesting future directions for the study of domestication in grasses.

Contents

Summary
273

I.
Introduction
274

II.
A brief history of domestication in grasses
275

III.
Domestication genes
278

IV.
Models of the domestication process
280

V.
Evolutionary consequences of domestication for grass genomes
281

VI.
Mating systems and the evolutionary dynamics of domestication in grasses
284

VII.
Conclusion
286

Acknowledgements
287

References
287
Characterization of milk coagulating properties from the extract of Withania coagulans
Authors: NAZ SHEHLA , MASUD TARIQ , NAWAZ MALIK ADIL
Published: June 2009

Plant aspartic proteinases (APs) from Withania coagulans were extracted by using NaCl (0.85%) and were characterized by pH, temperature stability, rennet strength and CaCl2 supplementation. Additionally, the milk‐clotting enzyme was partially purified by fractional precipitation with ammonium sulphate and acetone followed by column chromatography of the most active fraction, giving specific activity of 12 307.6 U/mg. The maximum enzyme activity was observed at 4.25 pH and 37°C, which suggested its use in making cheese requiring moderate temperatures (Mozerella, Cheddar). The enzymatic activity increases as the concentration of CaCl2 increases and decreases with the increase of temperature. SDS analysis showed the presence of a single unique band having a molecular weight of 66 KDa.
Long‐term treatment with fluoxetine induces desensitization of 5‐HT4receptor‐dependent signalling and functionality in rat brain
Authors: Vidal Rebeca , Valdizán Elsa M. , Mostany Ricardo , Pazos Angel , Castro Elena
Published: June 2009

The mode of action of antidepressant drugs may be related to mechanisms of monoamines receptor adaptation, including serotonin 5‐HT4receptor subtypes. Here we investigated the effects of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine for 21 days (5 and 10 mg/kg, p.o., once daily) on the sensitivity of 5‐HT4receptors by using receptor autoradiography, adenylate cyclase assays and extracellular recording techniques in rat brain. Fluoxetine treatment decreased the density of 5‐HT4receptor binding in the CA1 field of hippocampus as well as in several areas of the striatum over the doses of 5–10 mg/kg. In a similar way, we found a significant lower response to zacopride‐stimulated adenylate cyclase activity in the fluoxetine 10 mg/kg/day treated group. Furthermore, post‐synaptic 5‐HT4receptor activity in hippocampus‐measured as the excitatory action of zacopride in the pyramidal cells of CA1 evoked by Schaffer collateral stimulation was attenuated in rats treated with both doses of fluoxetine. Taken together, these results support the concept that a net decrease in the signalization pathway of 5‐HT4receptors occurs after chronic selective serotonin reuptake inhibitor treatment: this effect may underlie the therapeutic efficacy of these drugs.
Low‐dose simultaneous delivery of adenovirus encoding hepatocyte growth factor and vascular endothelial growth factor in dogs enhances liver proliferation without systemic growth factor elevation
Authors: Atta Hussein M. , Al‐Hendy Ayman , Salama Salama A. , Shaker Olfat G. , Hammam Olfat A.
Published: June 2009

Background: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) gene transfer proved to enhance liver regeneration. However, elevation of their plasma levels may induce potentially serious distant effects such as tumorigenesis or proliferative retinopathy.

Aims: This study was performed to examine whether simultaneous administration of low‐dose adenovirus encoding HGF and VEGF genes in dogs will stimulate liver proliferation but without inducing liver toxicity or systemic elevation of HGF and VEGF levels.

Methods: Adult dogs received an intravenous injection of low‐dose adenoviral vectors encoding human HGF and VEGF (HGF/VEGF), β‐galactosidase (lacZ) or phosphate‐buffered saline (PBS). Liver proliferation was measured using the proliferating cell nuclear antigen (PCNA) immunostaining labelling index. HGF and VEGF plasma concentrations and transaminases were repeatedly measured. Transgene expression was evaluated using reverse‐transcription polymerase chain reaction.

Results: Human HGF and VEGF expressions were detected only in the liver of HGF/VEGF dogs at day 2 after injection but declined at sacrifice (day 7). No expression was detected in the liver of the lacZ or PBS groups. Plasma levels of HGF and VEGF were not statistically different from those in the lacZ group (P=0.81, P=0.22 respectively). The PCNA labelling index was five‐fold higher in the HGF/VEGF group compared with the lacZ group (P<0.01). No immunostaining was detected in the PBS group. Transaminases were only elevated (P<0.01) in the lacZ group compared with the other groups.

Conclusions: We showed that simultaneous administration of low‐dose adenoviral vectors encoding human HGF and VEGF genes can induce transgene expression and liver proliferation without liver toxicity or systemic growth factor elevation.
Polymorphism of OAS‐1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication
Authors: Li Chang‐Zheng , Kato Naoya , Chang Jin‐Hai , Muroyama Ryosuke , Shao Run‐Xuan , Dharel Narayan , Sermsathanasawadi Radsamee , Kawabe Takao , Omata Masao
Published: June 2009

Background: Progression of disease after hepatitis C virus (HCV) infection differs among individuals, indicating a possibility of participation of host genetic factors. 2′‐5′‐oligoadenylate synthetase 1 (OAS‐1), an important component of the innate immune system, has an antiviral function, and may therefore have a certain relationship with progression of disease.

Aim: To evaluate single nucleotide polymorphisms (SNPs) of OAS‐1 and its relationship with the disease status of HCV infection.

Methods: Six SNPs of OAS‐1 were selected and examined in 409 Japanese patients with chronic HCV infection using the TaqMan PCR genotyping method. The relationship of SNP genotypes and clinical manifestations of patients was analysed. Then, a pair of OAS‐1‐expression plasmids mimicking the clinical‐related SNPs were created and transfected into liver cells carrying the HCV subgenomic replicon or the full‐length genome, JFH1, and HCV replication after transfection was compared.

Results: Patients with genotypes A/A, A/G and G/G of an SNP of OAS‐1 at the exon 3 of its coding sequence were at gradient increased risks of suffering from higher serum alanine aminotransferase (P<0.001) and aspartate aminotransferase (P=0.001), higher degree of liver fibrosis (P=0.010) and higher presence of liver cirrhosis (P=0.001). By multivariate logistic regression analysis, genotype G/G was an independent factor associated with cirrhosis (P=0.013, odds ratio 3.11, 95% confidence interval 1.27–7.63). In liver cells, OAS‐1 with the G allele showed lower ability to inhibit virus replication than OAS‐1 with the A allele (P=0.004).

Conclusions: The SNP of OAS‐1 at the exon 3 of its coding sequence was associated with progression of disease in Japanese patients with HCV infection.
Development and Validation of a Risk Scoring Model to Predict Net Adverse Cardiovascular Outcomes after Primary Percutaneous Coronary Intervention in Patients Pretreated with 600 mg Clopidogrel: Rationale and Design of the RISK‐PCI Study
Authors: MRDOVIC IGOR , SAVIC LIDIJA , PERUNICIC JOVAN , ASANIN MILIKA , LASICA RATKO , MARINKOVIC JELENA , VASILJEVIC ZORANA , OSTOJIC MIODRAG
Published: June 2009

Background: No comprehensive primary PCI (pPCI) risk model to predict net adverse cardiovascular events (NACE) has been reported with the use of clopidogrel 600 mg, which is now considered the standard loading dose. The primary hypothesis of the RISK‐PCI trial is that an accurate risk prediction may be achieved by using clinical, angiographic, and procedural variables available at the time of intervention.

Methods: The present single‐center, longitudinal, cohort study will include 1,750 consecutive patients with ST‐elevation myocardial infarction (STEMI), undergoing pPCI after pretreatment with 300 mg aspirin and 600 mg clopidogrel. The primary end‐points of the trial (NACE) include major adverse cardiovascular events (MACE) and major bleeding. A logistic regression model will be developed to predict 30‐day and 1‐year NACE after pPCI. A risk score derived from study set data will be validated using validation set data.

Results: Until June 1, 2008, 1,166 patients have been enrolled. Thirty‐day follow‐up is available in 1,007 patients.

Conclusions: The RISK‐PCI study is designed to develop an accurate risk scoring system, using variables available at the time of intervention, to predict long‐term adverse outcomes after pPCI.

Trial Registration: Current Controlled Trials Register—ISRCTN83474650—http://www.controlled‐trials.com/ISRCTN83474650).
Culprit‐Only or Multivessel Percutaneous Coronary Stenting in Patients with Non‐ST‐Segment Elevation Acute Coronary Syndromes: One‐Year Follow‐Up
Authors: ZAPATA GERARDO O. , LASAVE LEANDRO I. , KOZAK FERNANDO , DAMONTE ANIBAL , MEIRIÑO ALEJANDRO , ROSSI MAXIMILIANO , CARBÓ SABRINA , POLLICE ANALIA , PAOLASSO ERNESTO , PICABEA EDUARDO
Published: June 2009

Objective: To investigate the major cardiac events at 1‐year follow‐up of multivessel versus culprit‐vessel stenting in patients presenting with non‐ST elevation acute coronary syndrome (NSTE‐ACS) and multivessel disease (MVD).

Introduction: Percutaneous coronary intervention is a standard revascularization strategy for patients with NSTE‐ACS. However, when these patients have MVD it is not clear whether multivessel (MVR) is superior to culprit‐vessel revascularization (CVR).

Methods: We screened 1,100 consecutive patients with NSTE‐ACS from an institutional database. Comparisons of 1‐year outcomes between multivessel and culprit‐vessel revascularized patients were made. The primary outcome was the composite (MACE) of death, myocardial infarction (MI), or any revascularization. Secondary end‐points were the components of the composite end‐point. Regression analysis was performed to detect predictors of MACE.

Results: A total of 609 patients were considered for this analysis: 204 (33.5%) and 405 (66.5%) had MVR and CVR treatment, respectively. The strategy adopted was based on a clinical decision. The incidence of MACE was lower in MVR (9.45% vs. 16.34%, P = 0.02) with lower revascularization rate (7.46% vs. 13.86%, P = 0.04) than in CVR. There was no difference in death (1.99% vs. 1.98%, P = 0.8) nor death/MI (2.49% vs. 3.22%, P = 0.8) between MVR and CVR, respectively. Multivariate analysis showed CVR as the only independent predictor of improved MACE (OR 0.66, CI95% 1.12–3.47, P = 0.01).

Conclusion: Multivessel stenting in patients with NSTE‐ACS and multivessel disease using a clinical decision of treatment is associated with lower rate of MACE driven by lower repeat revascularization, compared with culprit‐vessel stenting, without difference in rates of death or MI.
Embolic Implications of Combined Risk Factors in Patients with Patent Foramen Ovale (the CARPE Criteria): Consideration for Primary Prevention Closure?
Authors: RIGATELLI GIANLUCA , DELL'AVVOCATA FABIO , GIORDAN MASSIMO , BRAGGION GABRIELE , AGGIO SILVIO , CHINAGLIA MAURO , RONCON LORIS , CARDAIOLI PAOLO , CHEN JACK P.
Published: June 2009

Background: Large patent foramen ovale (PFO), spontaneous right‐to‐left shunt, large atrial septal aneurysm (ASA), coagulation abnormalities, and prominent eustachian valve (EV) have all been independently suggested as risk factors for recurrent stroke. We sought to retrospectively evaluate risk of stroke and impact of transcatheter PFO closure in patients with concurrent large PFO, spontaneous right‐to‐left shunt, large ASA, coagulation abnormalities, and prominent EV.

Methods: Between March 2006 and October 2008, 36 (mean age 44 ± 10.9 years, 28 females) out of 120 consecutive patients referred to our center for transcatheter PFO closure had concomitant diagnosis of (a) large PFO on transcranial Doppler (TCD) and transesophageal echocardiography (TEE), (b) spontaneous right‐to‐left shunt on TCD, (c) large ASA, (d) prominent EV, and (e) coagulation abnormalities. All patients fulfilled the standard current indications for transcatheter closure and underwent preoperative TEE and brain magnetic resonance imaging (MRI), with subsequent intracardiac echocardiographic‐guided transcatheter PFO closure.

Results: Compared to the remaining PFO population in the same period, patients with all five concomitant features had more ischemic brain lesions on MRI, previous history of recurrent stroke, more frequently a history of venous thromboembolism, and more severe migraine with aura. The concomitance of all the features confers the highest risk of recurrent stroke (OR 9.9, 3.0–18 [95% CI], P < 0.001).

Conclusions: Despite its small sample size and nonrandomized retrospective nature, this is the first study to suggest that patients with concurrence of all the investigated characteristics have potentially a higher risk of stroke compared to controls. We thus propose the CARP criteria as a basis for further larger, longitudinal studies to assess the potential benefits of transcatheter closure in this patient subset in the absence of clinical recurrent stroke.
Design and Inference for Cancer Biomarker Study with an Outcome and Auxiliary‐Dependent Subsampling
Authors: Wang Xiaofei , Zhou Haibo
Published: June 2009

SummaryIn cancer research, it is important to evaluate the performance of a biomarker (e.g., molecular, genetic, or imaging) that correlates patients' prognosis or predicts patients' response to treatment in a large prospective study. Due to overall budget constraint and high cost associated with bioassays, investigators often have to select a subset from all registered patients for biomarker assessment. To detect a potentially moderate association between the biomarker and the outcome, investigators need to decide how to select the subset of a fixed size such that the study efficiency can be enhanced. We show that, instead of drawing a simple random sample from the study cohort, greater efficiency can be achieved by allowing the selection probability to depend on the outcome and an auxiliary variable; we refer to such a sampling scheme as outcome and auxiliary‐dependent subsampling (OADS). This article is motivated by the need to analyze data from a lung cancer biomarker study that adopts the OADS design to assess epidermal growth factor receptor (EGFR) mutations as a predictive biomarker for whether a subject responds to a greater extent to EGFR inhibitor drugs. We propose an estimated maximum‐likelihood method that accommodates the OADS design and utilizes all observed information, especially those contained in the likelihood score of EGFR mutations (an auxiliary variable of EGFR mutations) that is available to all patients. We derive the asymptotic properties of the proposed estimator and evaluate its finite sample properties via simulation. We illustrate the proposed method with a data example.
Covariate Adjustment and Ranking Methods to Identify Regions with High and Low Mortality Rates
Authors: Li Huilin , Graubard Barry I. , Gail Mitchell H.
Published: June 2009

Summary Identifying regions with the highest and lowest mortality rates and producing the corresponding color‐coded maps help epidemiologists identify promising areas for analytic etiological studies. Based on a two‐stage Poisson–Gamma model with covariates, we use information on known risk factors, such as smoking prevalence, to adjust mortality rates and reveal residual variation in relative risks that may reflect previously masked etiological associations. In addition to covariate adjustment, we study rankings based on standardized mortality ratios (SMRs), empirical Bayes (EB) estimates, and a posterior percentile ranking (PPR) method and indicate circumstances that warrant the more complex procedures in order to obtain a high probability of correctly classifying the regions with the upper 100γ% and lower 100γ% of relative risks for γ= 0.05, 0.1, and 0.2. We also give analytic approximations to the probabilities of correctly classifying regions in the upper 100γ% of relative risks for these three ranking methods. Using data on mortality from heart disease, we found that adjustment for smoking prevalence has an important impact on which regions are classified as high and low risk. With such a common disease, all three ranking methods performed comparably. However, for diseases with smaller event counts, such as cancers, and wide variation in event counts among regions, EB and PPR methods outperform ranking based on SMRs.
A simple method to create buttonhole cannulation tracks in a busy hemodialysis unit
Authors: MARTICORENA Rosa M. , HUNTER Joyce , COOK Ramona , KASHANI Mina , DELACRUZ Julia , PETERSHOFER Elizabeth , MACLEOD Steve , DACOURIS Niki , McFARLANE Philip A. , DONNELLY Sandra M. , GOLDSTEIN Marc B.
Published: June 2009

The preference for fistulae as the hemodialysis access of choice has led to a significant number of accesses that are less than ideal for cannulation. Buttonhole cannulation is ideal for such accesses, but the technique for creation provides major challenges. In 12 patients, buttonhole tunnel tracks were created by leaving the polyurethane catheter of a Clampcath® hemodialysis needle indwelling for 10 days after the initial cannulation. After each dialysis the catheter was flushed, and dressed with an antibacterial ointment and gauze. Dialysis was carried out via the catheter during that time. After day 10, the catheter was removed, the tunnel track covered with an antibacterial dressing and the tunnel track was cannulated with a dull buttonhole needle at the next dialysis. Successful buttonhole accesses were created in 11 patients after 10 days, the 12th patient required a single sharp needle cannulation before using dull needles. During the first 2 weeks of dull needle cannulation both pain experienced on cannulation and the difficulty cannulating the access were significantly less than in the classical buttonhole technique (P<0.01). Complications during the follow‐up period (6 months–1.5 years) included difficulty cannulating with a dull needle (22) and antibacterial agent induced contact dermatitis (4). There was no episode of sepsis or tunnel track infection. Initial cannulation of the fistula using a Clampcath® hemodialysis needle, leaving the polyurethane catheter indwelling for 10 days, is a simple, safe, and effective technique for the creation of buttonhole tunnel tracks.
Microcavity Formation in Alumina Using Ti Templates II: Mechanism and Kinetics
Authors: Hanson Ronald E. , Kisi Erich H. , Goodshaw Heather J. , Forrester Jennifer S.
Published: June 2009

In part I of this work, it was found that titanium (Ti) wire encapsulated within mechanically milled alumina powder and sintered at 1350°C forms potentially useful microcavities due to the consolidation of Kirkendall porosity. Here a series of samples sintered at 1350°C in the range 0–24 h has shown the remarkable way in which these cavities form. The cavity has already started in samples quenched from the top of the heating ramp (0 min at 1350°C). It is surrounded by a diffusion zone ∼300 μm in diameter, which does not change size throughout the firing process although the contents change markedly. The diffusion zone microstructure is initially complex with phase sequence TiO2/Al2O3/TiO2+Al2O3/Al2TiO5. Microstructure evolution may be summarized as outward growth of the cavity accompanied by inward growth of the Al2TiO5 resulting in a ∼190‐μm‐diameter cavity surrounded by a 50‐μm‐thick layer of Al2TiO5. The formation of the cavity and surrounding microstructure is discussed although some features, such as the nucleation of Al2TiO5 in the part of the diffusion zone furthest from the Ti source and the ring of Al2O3, which persists in between Ti‐rich parts of the diffusion zone are still poorly understood.
Dating Aggression and Risk Behaviors Among Teenage Girls Seeking Gynecologic Care
Authors: Whiteside Lauren K. , Walton Maureen A. , Stanley Rachel , Resko Stella M. , Chermack Steve T. , Zimmerman Marc A. , Cunningham Rebecca M.
Published: June 2009

Objectives:  The objective was to describe rates of dating aggression and related high‐risk behavior among teens presenting to the emergency department (ED) seeking gynecologic care, compared to those seeking care for other reasons.

Methods:  Female patients ages 14–18 years presenting to the ED during the afternoon/evening shift of a large urban teaching hospital over a 19‐month period were approached to participate and completed a self‐administered computerized survey regarding sexual risk behaviors, past‐year alcohol use, dating aggression, and peer aggression. Logistic regression analysis was used to identify factors associated with the evaluation of gynecologic complaint as noted by completion of a pelvic exam.

Results:  A total of 949 teens were enrolled (87% response rate), with 148 receiving gynecologic evaluation. Among girls undergoing a gynecologic evaluation, 49% reported past‐year dating aggression, compared to 34% of those who did not undergo gynecologic evaluation (odds ratio [OR] = 1.81, 95% confidence interval [CI] = 1.30 to 2.62). Logistic regression analysis predicting gynecologic evaluation found statistically significant variables to be older age (OR = 1.95, 95% CI = 1.24 to 3.06), African American race (OR = 1.58, 95% CI = 1.04 to 2.40), parental public assistance (OR = 1.64, 95% CI = 1.10 to 2.45), alcohol use (OR = 2.31, 95% CI = 1.57 to 3.38), and dating aggression (OR = 1.51, 95% CI = 1.03 to 2.21).

Conclusions:  Of the teens undergoing gynecologic evaluation in this urban ED, 49% reported dating aggression. These teens also reported higher rates of other sexual risk behaviors compared to their peers. Care providers in urban EDs treating all female teens and particularly those seeking gynecologic care should be aware of this high rate of dating aggression and screen for aggression in dating relationships in this high‐risk group.
Functional Rescue of β1‐Adrenoceptor Dimerization and Trafficking by Pharmacological Chaperones
Authors: Kobayashi Hiroyuki , Ogawa Koji , Yao Rong , Lichtarge Olivier , Bouvier Michel
Published: June 2009

Site‐directed mutagenesis guided by evolutionary trace analysis revealed that substitution of V179 and W183 within a cluster of evolutionarily important residues on the surface of the fourth transmembrane domain of the β1‐adrenergic receptor (β1AR) significantly reduced the propensity of the receptor to self‐assemble into homodimers as assessed by bioluminescence resonance energy transfer in living cells. These results suggest that mutation of V179 and W183 result in conformational changes that reduce homodimerization either directly by interfering with the dimerization interface or indirectly by causing local misfolding that result in reduced self‐assembly. However, the mutations did not cause a general misfolding of the β1AR as they did not prevent heterodimerization with the β2AR. The homodimerization‐compromised mutants were significantly retained in the endoplasmic reticulum (ER) and could not be properly matured and trafficked to the cell surface. Lipophilic β‐adrenergic ligands acted as pharmacological chaperones by restoring both dimerization and plasma membrane trafficking of the ER‐retained dimerization‐compromised β1AR mutants. These results clearly indicate that homodimerization occurs early in the biosynthetic process in the ER and that pharmacological chaperones can promote both dimerization and cell surface targeting, most likely by stabilizing receptor conformations compatible with the two processes.
Death by Committee: Organellar Trafficking and Communication in Apoptosis
Authors: Aslan Joseph E. , Thomas Gary
Published: June 2009

Apoptosis proceeds through a set of evolutionarily conserved processes that co‐ordinate the elimination of damaged or unneeded cells. This program of cell death is carried out by organelle‐directed regulators, including the Bcl‐2 proteins, and ultimately executed by proteases of the caspase family. Although the biochemical mechanisms of apoptosis are increasingly understood, the underlying cell biology orchestrating programmed cell death remains enigmatic. In this review, we summarize the current understanding of Bcl‐2 protein regulation and caspase activation while examining cell biological mechanisms and consequences of apoptotic induction. Organellar contributions to apoptotic induction include death receptor endocytosis, mitochondrial and lysosomal permeabilization, endoplasmic reticulum calcium release and fragmentation of the Golgi apparatus. These early apoptotic events are accompanied by stabilization of the microtubule cytoskeleton and translocation of organelles to the microtubule organizing center. Together, these phenomena establish a model of apoptotic induction whereby a cytoskeletal‐dependent coalescence and ’scrambling’ of organelles in the paranuclear region co‐ordinates apoptotic communication, caspase activation and cell death.
Quantification of Nuclear Protein Transport using Induced Heterodimerization
Authors: Busch Albert , Kiel Tilman , Hübner Stefan
Published: June 2009

Trafficking of proteins between the cytoplasm and nucleus occurs exclusively across the nuclear pore complex of eucaryotic cells. Fundamental aspects of this process affect temporal and spatial parameters, the latter carried out by specific import [nuclear localization sequence (NLS)] and export [nuclear export sequence (NES)] sequences. In this study, we focused on the adaptation of a protein heterodimerization assay to kinetically measure Crm1‐mediated nuclear export in living cells using the rapalog AP21967, a heterodimerizing agent and NLS‐ and NES‐containing fusion proteins equipped with distinct AP21967‐specific binding motifs. In HeLa cells, we observed rapid nuclear export of the NLS‐containing fusion protein in the presence of AP21967, with the extent of this process being a function of the number of AP21967‐binding motifs. AP21967‐induced nuclear export was specifically inhibited by the Crm1‐binding molecule leptomycin B. Half maximal export was achieved after ∼ 10 min. We further applied protein heterodimerization in HeLa cells to study induced NLS‐mediated nuclear import. Only in the presence of heterodimerizer AP21967 nuclear import of a cytoplasmically localizing fusion protein was observed. Induced protein heterodimerization is thus a valuable tool to quantitatively study nucleocytoplasmic protein trafficking in cultured cells, in a non‐invasive, time‐saving manner.
Membrane Contact Sites between Apicoplast and ER in Toxoplasma gondii Revealed by Electron Tomography
Authors: Tomova Cveta , Humbel Bruno M. , Geerts Willie J. C. , Entzeroth Rolf , Holthuis Joost C. M. , Verkleij Arie J.
Published: June 2009

Toxoplasma gondii is an obligate intracellular parasite from the phylum Apicomplexa. A hallmark of these protozoans is the presence of a unique apical complex of organelles that includes the apicoplast, a plastid acquired by secondary endosymbiosis. The apicoplast is indispensible for parasite viability. It harbours a fatty acid biosynthesis type II (FAS II) pathway and plays a key role in the parasite lipid metabolism. Possibly, the apicoplast provides components for the establishment and the maturation of the parasitophorous vacuole, ensuring the successful infection of the host cell. This implies the presence of a transport mechanism for fast and accurate allocation of lipids between the apicoplast and other membrane‐bound compartments in the parasite cell. Using a combination of high‐pressure freezing, freeze‐substitution and electron tomography, we analysed the ultrastructural organization of the apicoplast of T. gondii in relation with the endoplasmic reticulum (ER). This allowed us to clearly show the presence of four continuous membranes surrounding the apicoplast. We present, for the first time, the existence of membrane contact sites between the apicoplast outermost membrane and the ER. We describe the morphological characteristics of these structures and discuss their potential significance for the subcellular distribution of lipids in the parasite.