bluuebunny/crossref_metadata_2025 huggingface dataset:
TROP2 expression as prognostic marker for gastric carcinoma
Authors: Mühlmann G , Spizzo G , Gostner J , Zitt M , Maier H , Moser P , Gastl G , Zitt M , Müller H M , Margreiter R , Öfner D , Fong D
Published: October 2008

Background:

In gastric cancer the recurrence rate is unacceptably high, even after R0 resection and (neo)adjuvant chemotherapy. Therefore, there is an urgent need for identification of predictive and/or prognostic biomarkers to select high-risk patients who might benefit from additional therapies. Expression of TROP2 has been shown to be associated with tumour aggressiveness and poor prognosis in patients with various epithelial cancers.

Aims:

To investigate TROP2 expression in gastric cancer and its correlation with clinicopathological features and disease outcome.

Methods:

Expression of TROP2 was investigated by immunohistochemistry of tumour specimens from 104 patients who underwent resection for gastric cancer. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model.

Results:

TROP2 was found to be overexpressed in 58 (56%) tumour samples. Significantly higher expression of TROP2 could be detected in intestinal-type carcinomas (p = 0.03). In intestinal-type gastric cancer, TROP2 overexpression was significantly correlated with shorter disease-free survival (DFS) (p = 0.03). Among the total group, TROP2 overexpression was predictive for poor disease-free (p<0.01) and overall (p = 0.03) survival in lymph node positive patients. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent prognostic marker for poor DFS in the subgroup of patients with intestinal-type gastric cancer irrespective of lymph node involvement.

Conclusion:

Results show that TROP2 is an independent prognostic marker for disease recurrence in intestinal type gastric cancer. Due to its wide distribution TROP2 may become an attractive therapeutic target in a subgroup of patients with gastric cancer.
Non-melanocytic mimics of melanoma: Part I: intraepidermal mimics
Authors: Kamil Z S , Tong L C B , Habeeb A Al , Ghazarian D
Published: October 2008

Melanoma comprises a wide range of cytological and architectural features histopathologically and hence can mimic many benign and malignant lesions of epithelial, mesenchymal and hematopoietic cell lines of differentiation.

Therefore, analysis and close clinical, histological, histochemical and immunohistochemical correlation is vital in distinguishing challenging melanoma cases from their mimics. In this review, the different features of the benign, pre-malignant and malignant intraepidermal non-melanocytic tumours and tumour-like lesions that can closely mimic intraepidermal melanoma (melanoma in situ) are emphasised.
Immunohistochemical evaluation of ProEx C in human papillomavirus-induced lesions of the cervix
Authors: Conesa-Zamora P , Doménech-Peris A , Ortiz-Reina S , Orantes-Casado F J , Acosta-Ortega J , García-Solano J , Pérez-Guillermo M
Published: October 2008

Aims:

Considering the sparse information about the clinical utility of the novel immunohistochemical marker ProEx C in histological sections, a decision was taken to study the pattern of ProEx C expression in normal/benign cervical epithelium (N/B), low-grade squamous intraepithelial lesion (LGSIL) and high-grade squamous intraepithelial lesion (HGSIL), as well as the association of ProEx C expression with human papillomavirus (HPV) genotypes.

Methods:

100 cervical samples, including 21 N/B cervices, 16 LGSILs, 61 HGSILs and two cervical invasive carcinomas, were obtained from conisation and hysterectomy. Surgical specimens were arranged in three tissue microarrays and stained for ProEx C. Ninety-three samples were HPV genotyped. Genotyping was performed by DNA amplification and hybridisation with genotype-specific probes on a low-density DNA array.

Results:

ProEx C-positive expression in more than the lower third of the epithelium was observed in 14.3% of N/B, 62.5% of LGSIL and 90.2% of HGSIL. Seventy percent of HPV positivity was found in cases with expression in more than the lower third of the epithelium. Of 31 cases that were positive for HPV16, 16.1% showed ProEx C expression restricted to one or two basal layers, and 83.9% showed ProEx C expression in more than the lower third of the epithelium.

Conclusions:

ProEx C is significantly associated with HPV16 infection and is a useful adjunct in the identification of LGSIL and HGSIL in histological sections when expressed in more than the lower third of the epithelium.
The myofibroblast and its tumours
Authors: Eyden B , Banerjee S S , Shenjere P , Fisher C
Published: October 2008

Tumours and tumour-like lesions of myofibroblasts may present diagnostic difficulty because of their rarity and because of uncertainties in identifying the myofibroblast. The objectives of this review are to provide a definition of the myofibroblast and an account of its biology for facilitating an understanding of the cell and of myofibroblastic lesions; and to describe, in the context of common diagnostic problems, the features of benign and malignant myofibroblastic lesions. The main characteristics of the myofibroblast include a spindled or stellate morphology; immunostaining for α-smooth muscle actin and the extra domain A variant of cellular fibronectin; and an ultrastructure of rough endoplasmic reticulum, peripheral contractile filaments and the cell-to-matrix junction known as the fibronexus. On this basis, lesions traditionally regarded as myofibroblastic are shown to vary in their level of differentiation, and some appear to be smooth muscle rather than myofibroblastic. Immunohistochemistry and electron microscopy, used together, are emphasised as being important for maximum diagnostic confidence in some myofibroblastic lesions.
Hypertrophic cardiomyopathy: current understanding and treatment objectives
Authors: Soor G S , Luk A , Ahn E , Abraham J R , Woo A , Ralph-Edwards A , Butany J
Published: October 2008

The understanding of hypertrophic cardiomyopathy (HCM) has changed dramatically over the last few decades, and it is now understood to be caused by a mutation in one of several cardiac sarcomeric genes. Due to complications such as outflow tract obstruction, diastolic dysfunction, arrhythmias, stroke, infective endocarditis and sudden cardiac death, appropriate and early identification of these patients is imperative. This review attempts to summarise the current state of knowledge on HCM, and provide insight of the appropriate investigations needed in patients with HCM. It also outlines treatment strategies for these patients. Much remains unknown about this complex and intriguing disease, and continued research in identifying the genetic basis of HCM, along with the assessment of therapeutic strategies, will help to optimise patient care.
Akt activates NOS3 and separately restores barrier integrity in H2O2-stressed human cardiac microvascular endothelium
Authors: Dossumbekova Anar , Berdyshev Evgeny V. , Gorshkova Irina , Shao Zuohui , Li Changqing , Long Phillip , Joshi Atul , Natarajan Viswanathan , Vanden Hoek Terry L.
Published: October 2008

The integrity of microvascular endothelium is an important regulator of myocardial contractility. Microvascular barrier integrity could be altered by increased reactive oxygen species (ROS) stress seen within minutes after cardiac arrest resuscitation. Akt and its downstream target nitric oxide (NO) synthase (NOS)3 can protect barrier integrity during ROS stress, but little work has studied these oxidant stress responses in human cardiac microvascular endothelial cells (HCMVEC). We, therefore, studied how ROS affects barrier function and NO generation via Akt and its downstream target NOS3 in HCMVEC. HCMVEC exposed to 500 μM H2O2 had increased Akt phosphorylation within 10 min at both Ser-473 and Thr-308 sites, an effect blocked by the phosphatidylinositol 3-kinase inhibitor LY-294002. H2O2 also induced NO generation that was associated with NOS3 Ser-1177 site phosphorylation and Thr-495 dephosphorylation, with Ser-1177 effects attenuated by LY-294002 and an Akt inhibitor, Akt/PKB signaling inhibitor-2 (API-2). H2O2 induced significant barrier disruption in HCMVEC within minutes, but recovery started within 30 min and normalized over hours. The NOS inhibitor Nω-nitro-l-arginine methyl ester (200 μM) blocked NO generation but had no effect on H2O2-induced barrier permeability or the recovery of barrier integrity. By contrast, the Akt inhibitor API-2 abrogated HCMVEC barrier restoration. These results suggest that oxidant stress in HCMVEC activates NOS3 via Akt. NOS3/NO are not involved in the regulation of H2O2-affected barrier function in HCMVEC. Independent of NOS3 regulation, Akt proves to be critical for the restoration of barrier integrity in HCMVEC.
The antioxidant tempol attenuates pressure overload-induced cardiac hypertrophy and contractile dysfunction in mice fed a high-fructose diet
Authors: Chess David J. , Xu Wenhong , Khairallah Ramzi , O'Shea Karen M. , Kop Willem J. , Azimzadeh Agnes M. , Stanley William C.
Published: October 2008

We have previously shown that high-sugar diets increase mortality and left ventricular (LV) dysfunction during pressure overload. The mechanisms behind these diet-induced alterations are unclear but may involve increased oxidative stress in the myocardium. The present study examined whether high-fructose feeding increased myocardial oxidative damage and exacerbated systolic dysfunction after transverse aortic constriction (TAC) and if this effect could be attenuated by treatment with the antioxidant tempol. Immediately after surgery, TAC and sham mice were assigned to a high-starch diet (58% of total energy intake as cornstarch and 10% fat) or high-fructose diet (61% fructose and 10% fat) with or without the addition of tempol [0.1% (wt/wt) in the chow] and maintained on the treatment for 8 wk. In response to TAC, fructose-fed mice had greater cardiac hypertrophy (55.1% increase in the heart weight-to-tibia length ratio) than starch-fed mice (22.3% increase in the heart weight-to-tibia length ratio). Treatment with tempol significantly attenuated cardiac hypertrophy in fructose-fed TAC mice (18.3% increase in the heart weight-to-tibia ratio). Similarly, fructose-fed TAC mice had a decreased LV area of fractional shortening (from 38 ± 2% in sham to 22 ± 4% in TAC), which was prevented by tempol treatment (33 ± 3%). Markers of lipid peroxidation in fructose-fed TAC hearts were also blunted by tempol. In conclusion, tempol significantly blunted markers of cardiac hypertrophy, LV remodeling, contractile dysfunction, and oxidative stress in fructose-fed TAC mice.
Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1
Authors: Shinmura Ken , Tamaki Kayoko , Bolli Roberto
Published: October 2008

Ischemic tolerance decreases with aging, and the cardioprotective effect of ischemic preconditioning (IPC) is impaired in middle-aged animals. We have demonstrated that short-term caloric restriction (CR) improves myocardial ischemic tolerance in young and old animals via the activation of adiponectin-AMP-activated protein kinase (AMPK)-mediated signaling. However, it is unknown whether prolonged CR confers cardioprotection in a similar manner. Furthermore, little is known regarding the myocardial expression of silent information regulator 1 (Sirt1; which reportedly mediates various aspects of the CR response) with prolonged CR. Thus, 6-mo-old male Fischer-344 rats were randomly divided into ad libitum (AL) and CR groups. Six months later, isolated perfused hearts were subjected to 25 min of global ischemia followed by 120 min of reperfusion with or without IPC. CR improved the recovery of left ventricular function and reduced infarct size after ischemia-reperfusion and restored the IPC effect. Serum adiponectin levels increased, but myocardial levels of total and phosphorylated AMPK did not change with prolonged CR. Total levels of Sirt1 did not change with CR; however, in the nuclear fraction, CR significantly increased Sirt1 and decreased acetyl-histone H3. Eleven rats from each group were given N-nitro-l-arginine methyl ester in their drinking water for 4 wk before death. In these hearts, chronic inhibition of nitric oxide synthase prevented the increase in nuclear Sirt1 content by CR and abrogated CR-induced cardioprotection. These results demonstrate that 1) prolonged CR improves myocardial ischemic tolerance and restores the IPC effect in middle-aged rats and 2) CR-induced cardioprotection is associated with a nitric oxide-dependent increase in nuclear Sirt1 content.
Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice
Authors: Ye Yumei , Lin Yu , Manickavasagam Saraswathy , Perez-Polo J. Regino , Tieu Brian C. , Birnbaum Yochai
Published: October 2008

Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-γ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF1α levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS−/− and iNOS−/− mice. Male C57BL/6 wild-type (WT), eNOS−/−, and iNOS−/− mice received 10 mg·kg−1·day−1 Pio (Pio+) or water alone (Pio−) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4 ± 1.4% vs. 39.0 ± 1.1%; P < 0.001), as well as in the eNOS−/− (32.0 ± 1.6% vs. 44.2 ± 1.9%; P < 0.001) and iNOS−/− (18.0 ± 1.2% vs. 45.5 ± 2.3%; P < 0.001) mice. The protective effect of Pio in eNOS−/− mice was smaller than in the WT ( P < 0.001) and iNOS−/− ( P < 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS−/− mice. iNOS was undetectable in all six groups. Pio increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS−/− and iNOS−/−, mice. Pio increased the myocardial 6-keto-PGF1α levels and cPLA2 and COX2 activity in the WT, eNOS−/−, and iNOS−/− mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized.
Effect of stellate ganglionectomy on basal cardiovascular function and responses to β1-adrenoceptor blockade in the rat
Authors: Yoshimoto Misa , Wehrwein Erica A. , Novotny Martin , Swain Greg M. , Kreulen David L. , Osborn John W.
Published: October 2008

Cardiac sympathetic nerve activity is an important short-term controller of cardiac function and arterial pressure. Studies also suggest that long-term increases in cardiac sympathetic nerve activity may contribute to hypertension, coronary artery disease, and cardiac remodeling in heart failure. However, our understanding of the role of cardiac sympathetic nerves in chronic models of cardiovascular disease has been limited by inadequate experimental approaches. The present study was conducted to develop a surgical method to surgically denervate the sympathetic nerves of the rat heart for long-term cardiovascular studies. We characterized the effect of cardiac sympathetic denervation on basal levels of mean arterial pressure (MAP) and heart rate (HR) and the responses to a chronic administration of atenolol, a β1-adrenoceptor antagonist. Rats were instrumented with telemetry transmitters for continuous recording of MAP and HR. After a 4-day baseline period, the rats were subjected to bilateral stellate ganglionectomy (SGX; n = 9) or sham surgery (Sham; n = 8). Seven days following SGX or Sham, the rats were administered atenolol for 5 days, followed by a 7-day recovery period. Following a transient decrease, SGX had no effect on basal MAP but decreased HR compared with baseline and Sham rats. Five days of atenolol treatment decreased MAP similarly in SGX and Sham rats. Atenolol resulted in a marked bradycardia in Sham rats but had a neglible effects on HR in SGX rats. The measurement of the content of cardiac catecholamines in all cardiac chambers at the end of the study verified a successful sympathetic denervation. This study confirms that bilateral SGX is a useful method to study the contribution of cardiac sympathetic nerves on the regulation of cardiac function. Moreover, these results suggest that cardiac sympathetic nerves are relatively unimportant in maintaining the basal level of MAP or the depressor response to atenolol in conscious, unrestrained rats.
Alcohol feeding blocks methacholine-induced airway responsiveness in mice
Authors: Oldenburg P. J. , Wyatt T. A. , Factor P. H. , Sisson J. H.
Published: October 2008

Historical accounts of alcohol administration to patients with breathing problems suggest that alcohol may have bronchodilating properties. We hypothesized that acute alcohol exposure will alter airway responsiveness (AR) in mice. To test this hypothesis, C57BL/6 mice were fed either 20% alcohol in drinking water (fed) or received a single intraperitoneal (ip) injection of alcohol (3 g/kg). Control groups received regular drinking water or ip saline. AR was assessed by means of ventilation or barometric plethysmography and reported as either total lung resistance or enhanced pause for each group of mice. To confirm alcohol exposure, elevated blood alcohol levels were documented. Alcohol feeding significantly blocked methacholine-triggered AR compared with water-fed controls. Comparable blunting of AR was also accomplished through a single ip injection of alcohol when compared with saline-injected controls. The alcohol response was slowly reversible in both routes of administration after withdrawal of alcohol: AR attenuation by alcohol persisted 12–20 h (ip) or up to 2 wk (fed) after blood alcohol cleared consistent with a sustained bronchodilator effect. These data demonstrate that brief alcohol exposure blunts AR in this murine model of alcohol exposure suggesting a role for alcohol in the modulation of bronchial motor tone.
Tracheobronchial air-liquid interface cell culture: a model for innate mucosal defense of the upper airways?
Authors: Kesimer Mehmet , Kirkham Sara , Pickles Raymond J. , Henderson Ashley G. , Alexis Neil E. , DeMaria Genevieve , Knight David , Thornton David J. , Sheehan John K.
Published: October 2008

Human tracheobronchial epithelial cells grown in air-liquid interface culture have emerged as a powerful tool for the study of airway biology. In this study, we have investigated whether this culture system produces “mucus” with a protein composition similar to that of in vivo, induced airway secretions. Previous compositional studies of mucous secretions have greatly underrepresented the contribution of mucins, which are major structural components of normal mucus. To overcome this limitation, we have used a mass spectrometry-based approach centered on prior separation of the mucins from the majority of the other proteins. Using this approach, we have compared the protein composition of apical secretions (AS) from well-differentiated primary human tracheobronchial cells grown at air-liquid interface and human tracheobronchial normal induced sputum (IS). A total of 186 proteins were identified, 134 from AS and 136 from IS; 84 proteins were common to both secretions, with host defense proteins being predominant. The epithelial mucins MUC1, MUC4, and MUC16 and the gel-forming mucins MUC5B and MUC5AC were identified in both secretions. Refractometry showed that the gel-forming mucins were the major contributors by mass to both secretions. When the composition of the IS was corrected for proteins that were most likely derived from saliva, serum, and migratory cells, there was considerable similarity between the two secretions, in particular, in the category of host defense proteins, which includes the mucins. This shows that the primary cell culture system is an important model for study of aspects of innate defense of the upper airways related specifically to mucus consisting solely of airway cell products.
Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis
Authors: Iyer Smita S. , Ramirez Allan M. , Ritzenthaler Jeffrey D. , Torres-Gonzalez Edilson , Roser-Page Susanne , Mora Ana L. , Brigham Kenneth L. , Jones Dean P. , Roman Jesse , Rojas Mauricio
Published: October 2008

Several lines of evidence indicate that depletion of glutathione (GSH), a critical thiol antioxidant, is associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, GSH synthesis depends on the amino acid cysteine (Cys), and relatively little is known about the regulation of Cys in fibrosis. Cys and its disulfide, cystine (CySS), constitute the most abundant low-molecular weight thiol/disulfide redox couple in the plasma, and the Cys/CySS redox state (EhCys/CySS) is oxidized in association with age and smoking, known risk factors for IPF. Furthermore, oxidized EhCys/CySS in the culture media of lung fibroblasts stimulates proliferation and expression of transitional matrix components. The present study was undertaken to determine whether bleomycin-induced lung fibrosis is associated with a decrease in Cys and/or an oxidation of the Cys/CySS redox state and to determine whether these changes were associated with changes in EhGSH/glutathione disulfide (GSSG). We observed distinct effects on plasma GSH and Cys redox systems during the progression of bleomycin-induced lung injury. Plasma EhGSH/GSSG was selectively oxidized during the proinflammatory phase, whereas oxidation of EhCys/CySS occurred at the fibrotic phase. In the epithelial lining fluid, oxidation of EhCys/CySS was due to decreased food intake. Thus the data show that decreased precursor availability and enhanced oxidation of Cys each contribute to the oxidation of extracellular Cys/CySS redox state in bleomycin-induced lung fibrosis.
Evidence for cell fusion is absent in vascular lesions associated with pulmonary arterial hypertension
Authors: Majka S. M. , Skokan M. , Wheeler L. , Harral J. , Gladson S. , Burnham E. , Loyd J. E. , Stenmark K. R. , Varella-Garcia M. , West J.
Published: October 2008

Pulmonary arterial hypertension (PAH) is a fatal disease associated with severe remodeling of the large and small pulmonary arteries. Increased accumulation of inflammatory cells and apoptosis-resistant cells are contributing factors. Proliferative apoptosis-resistant cells expressing CD133 are increased in the circulation of PAH patients. Circulating cells can contribute to tissue repair via cell fusion and heterokaryon formation. We therefore hypothesized that in the presence of increased leukocytes and CD133-positive (CD133pos) cells in PAH lung tissue, cell fusion and resulting genomic instability could account for abnormal cell proliferation and the genesis of vascular lesions. We performed analyses of CD45/CD133 localization, cell fusion, and proliferation during late-stage PAH in human lung tissue from control subjects and subjects with idiopathic (IPAH) and familial (FPAH) PAH. Localization, proliferation, and quantitation of cell populations in individual patients were performed by immunolocalization. The occurrence of cellular fusion in vascular lesions was analyzed in lung tissue by fluorescence in situ hybridization. We found the accumulation of CD45pos leukocytic cells in the tissue parenchyma and perivascular regions in PAH patients and less frequently observed myeloid cells (CD45/CD11b). CD133pos cells were detected in occlusive lesions and perivascular areas in those with PAH and were more numerous in those with IPAH lesions than in FPAH lesions. Cells coexpressing CD133 and smooth muscle α-actin were occasionally observed in occlusive lesions and perivascular areas. Proliferating cells were more prominent in IPAH lesions and colocalized with CD45 or CD133. We found no evidence of increased ploidy to suggest cell fusion. Taken together, these data suggest that abnormal lesion formation in PAH occurs in the absence of cell fusion.
Carotid Atherosclerotic Plaques Stabilize After Stroke
Authors: Peeters W. , Hellings W.E. , de Kleijn D.P.V. , de Vries J.P.P.M. , Moll F.L. , Vink A. , Pasterkamp G.
Published: October 2008

Objective—

Rupture of unstable atherosclerotic plaques is the pathological substrate for acute ischemic events. Underlying cellular and molecular characteristics of plaque rupture have been studied extensively. However, the natural course of symptomatic plaque remodeling after ischemic events is relatively unexplored.

Methods and Results—

Atherosclerotic carotid plaques were obtained from 804 symptomatic (stroke=204 and TIA=426) and asymptomatic (n=174) patients undergoing carotid endarterectomy. The presence of macrophages, smooth muscle cells (SMC), collagen, calcification, and lipid-core size were assessed histologically. At protein level, inflammatory mediators (interleukin [IL]-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, interferon-gamma [INF-γ], tumor necrosis factor-alpha [TNF-α], matrix degrading proteinases (MMPs), and an apoptosis marker (caspase-3) were determined. We associated plaque characteristics with time elapsed between the latest event and surgery. Early after stroke and TIA, plaques revealed an unstable phenotype. After stroke, the content of macrophages decreased significantly with time (
P
=0.02), whereas SMC content tended to increase. At protein level, IL-6, IL-8 expression levels and caspase activity strongly decreased after stroke or TIA.

Conclusions—

Symptomatic carotid lesions remodel into more stable plaques over time after stroke. Changes in IL-6 and IL-8 and caspase preceded the decrease of macrophages. These temporal phenotypic plaque alterations should be taken into account for biomarker and therapeutic target validation studies using human atherosclerotic plaques.
Two Separate Worlds
Authors: Zanolini Morrison Gina
Published: October 2008

In this study, 21 African American, Asian American, and Latino students were interviewed in order to ascertain the nature of their experience as students of color on a small, predominantly White university campus in the northeastern United States. The data revealed awareness as the overarching theme in the phenomenon, in that awareness (or lack of it) produced “two separate worlds”: one for the White majority and another for students of color. The data also revealed a divergence in the phenomenon in that a small group of the youngest participants with the lightest skin color felt very much a part of the same world as their White counterparts. Cultural identity development theory is discussed as a possible explanation for the divergence in that it is linked to awareness and inherently incorporates relevant sociopolitical issues such as race, color, prejudice, and discrimination.
From Concentration to Dispersion
Authors: Jin Huang  , Baorong Guo  , Bricout John C.
Published: October 2008

In China, there has seen a significant increase in the disability employment rate over the past 20 years, largely due to socioeconomic growth factors and disability employment policy development. Extant research has failed to account for the systemic policy and socioeconomic changes that have radically changed the employment landscape for persons with disabilities in China over the past three decades. An examination of disability employment in China reveals a shift of the policy approach from concentration to dispersion. The concentration approach, compatible with a central planned economy, has given its way to its market-based parallel, the dispersion approach. Characteristics of the three main forms of disability employment—welfare enterprises, the quota schemes, and self-employment—are discussed in depth. Finally, modifications to the current disability employment policies are suggested.
Developing Online Community Accessibility Guidelines for Persons With Disabilities and Older Adults
Authors: Jaeger Paul T. , Bo Xie
Published: October 2008

As online communities have become an important means of social interaction and community participation, ensuring their universal accessibility is essential for social inclusion. Although accessibility standards have been developed to make information-oriented Web sites more inclusive to users with disabilities and older adults, similar efforts have not been devoted to accessibility standards tailored specifically for online communities that are primarily communication oriented. Existing guidelines for Web site accessibility can be used as the starting point in designing accessible online communities for persons with disabilities and older adults, and public policy needs to play a significant role in ensuring the accessibility of the Web 2.0 environment. To ensure full accessibility of the online environment, however, it is necessary to move beyond guidelines that focus on one-way transfer of information and to develop guidelines for multidirectional communication. This article explores the social, policy, and developmental issues of the accessibility of online communities.
The Kuder Skills Assessment—College and Adult Version
Authors: Rottinghaus Patrick J.
Published: October 2008

This article introduces the Kuder Skills Assessment—College and Adult version (KSA-CA; Rottinghaus, 2006), a new measure incorporating advances in the measurement of self-efficacy across 16 basic occupational domains (e.g., finance, information technology) and the six Kuder Clusters. Similar to the original development sample, all scales of the KSA-CA were highly internally consistent, and demonstrated expected gender differences and relations with each other in a sample of 241 business students from a large Midwestern university. Of the 198 participants who had selected a specific business major, four specialty areas were identified: accounting, management, finance, and marketing. Mean KSA-CA scores were examined between the development and business samples and among the specialty groups. The business sample scored higher than the development sample across nine domains, including all with business-related content. Several relevant scales distinguished subgroups of business majors supporting the validity of the specialized KSA-CA scales.
Examining the Application of Holland's Theory to Vocational Interests and Choices of Chinese College Students
Authors: Mei Tang
Published: October 2008

This study investigates the applicability of Holland's career development theory in cross-cultural settings by examining vocational interests of Chinese college students and the relationship between those interests and their career choices. One hundred sixty five Chinese college students complete a Chinese version of the Self-Directed Search and a questionnaire requesting their demographic information, career choices, reasons for making a particular choice, and suggested areas needed for vocational guidance. The Multidimensional Scaling results supported the RIASEC order of Holland's typology for male students and equivalent distance among six types for female students. The majority of participants had a medium level of congruence between interests and choices as measured by the C-Index. Personal interests, social needs, and job market are identified as the top reasons for making a career choice. Practical outcome-oriented career implementation skills are more desired than self-exploration for vocational guidance.
Glanzmann's Thrombasthenia: An Overview
Authors: Kannan Meganathan , Saxena Renu
Published: October 2008

Glanzmann's thrombasthenia (GT) is an autosomal recessive inherited bleeding disorder due to a defect in platelet function. The hallmark of this disease is severely reduced/absent platelet aggregation in response to multiple physiological agonists. Bleeding signs in GT include epistaxis, bruising, gingival hemorrhage, gastrointestinal hemorrhage, hematuria, menorrhagia, and hemarthrosis. Homozygous or compound heterozygous mutations in the genes of GPIIb and GPIIIa lead to GT. A patient with GT, with no possible causative mutations in GPIIb and GPIIIa genes, may harbor defects in a regulatory element affecting the transcription of these 2 genes. GT occurs in high frequency in certain ethnic populations with an increased incidence of consanguinity such as in Indians, Iranians, Iraqi Jews, Palestinian and Jordanian Arabs, and French Gypsies. Carrier detection in GT is important to control the disorder in family members. Carrier detection can be done both by protein analysis and direct gene analysis.
Potential Role of Thrombelastography in the Monitoring of Acquired Factor VIII Inhibitor Hemophilia A: Report on a 78-year-old Woman With Life-threatening Bleedings
Authors: Spiezia Luca , Meneghetti Leonardo , Dalla Valle Fabio , Tognin Giulio , Radu Claudia , Saggiorato Graziella , Fadin Mariangela , Zanon Ezio , Simioni Paolo
Published: October 2008

A 78-year-old woman was admitted to our hospital because of syncope associated with hematomas in both legs. Acquired hemophilia A (AHA) with a low antifactor VIII antibodies activity was diagnosed. Whole blood (WB) thrombelastographic profile depicted a hypocoagulable state. During hospitalization, the patient experienced life-threatening bleedings in the neck and in the right thigh. FVIII concentrates and rFVIIa was safe and effective in controlling acute hemorrhagic symptoms. Immunosuppressive therapy was used successfully to eradicate the inhibitor. At discharge, FVIII inhibitor was absent and thrombelastogram showed a normal profile. Our report confirms that AHA is a heterogeneous condition in terms of risk of bleeding. Even though the criteria for the diagnosis of AHA is quite well defined, a laboratory test useful to predict the bleeding risk and monitor the response to treatment is lacking. ROTEM profile appears to be correlated with the response to treatment and with the eradication of the inhibitor.
The Effects of “Bug-in-Ear” Supervision on Special Education Teachers' Delivery of Learn Units
Authors: Goodman Janet I. , Brady Michael P. , Duffy Mary Lou , Scott Jack , Pollard Nancy E.
Published: October 2008

Supervision and coaching strategies that provide immediate feedback can help improve instruction for novice teachers. In this study, feedback was provided to teachers using “bug-in-ear” technology to coach them to deliver effective instructional interactions: “learn units.” Three novice teachers in K—8 classrooms with students with disabilities including emotional disorders, autism, attention-deficit/hyperactivity disorder, and developmental delays participated in the study. Results from the multiple-baseline design showed that the rate and accuracy of effective teaching behaviors increased when in-class feedback was delivered via the electronic “bugs.” For two of the three teachers, these increases maintained when the instructional feedback was faded. This study extends previous research and suggests an effective coaching supervision strategy for novice teachers.
Generalized Effects of Video Modeling on Establishing Instructional Stimulus Control in Children With Autism
Authors: Nikopoulos Christos K. , Canavan Caroline , Nikopoulou-Smyrni Panagiota
Published: October 2008

Video modeling has been suggested as a powerful treatment tool that has concentrated on increasing a variety of skills in children with autism. However, it has rarely been examined as a behavioral procedure for eliminating kinds of behaviors (e.g., noncompliance), a target that is often included in children’s support plans. The present study provides preliminary effects of video modeling on establishing instructional stimulus control over a simple behavior (cleaning up a toy) that required the termination of an ongoing activity. Three children with autism participated, and experimental control was accomplished using a multiple-baseline-across-subjects design. The results showed that this procedure can be effective for children with lower baseline levels of disruptive behaviors and more developed imitation skills. Successful responding generalized across stimuli and subjects and was maintained at a 1-month follow-up assessment. Specific guidelines for building video modeling into real teaching situations are also discussed.
The Impact of Training on the Accuracy of Teacher-Completed Direct Behavior Ratings (DBRs)
Authors: LeBel Teresa J. , Kilgus Stephen P. , Briesch Amy M. , Chafouleas Sandra
Published: October 2008

The purpose of this study was to investigate the effects of three levels of training (direct, indirect, and none) on teachers’ ability to accurately rate video of student behavior. Direct and indirect training groups received instructional sessions on direct behavior ratings (DBRs), with the direct training group receiving opportunities for practice and feedback. Each training group viewed a video of a typical classroom environment and then rated the proportion of time the student displayed disruptive behavior and academic engagement. Accuracy was examined through comparison of the teachers’ ratings with direct observation data. Teacher acceptability of using DBRs was also assessed. Overall, the results suggested that the most intensive level of training (i.e., direct) did not improve the accuracy with which teachers rated behaviors using DBRs. Limitations and future implications are discussed.
Vascular smooth muscle–derived tissue factor is critical for arterial thrombosis after ferric chloride–induced injury
Authors: Wang Li , Miller Christine , Swarthout Robert F. , Rao Mohan , Mackman Nigel , Taubman Mark B.
Published: October 2008

Tissue factor (TF) initiates coagulation, regulates hemostasis, and plays a critical role in mediating arterial thrombosis. TF is up-regulated in vascular smooth muscle cells (VSMCs) in atherosclerosis and arterial injury. To examine the biologic role of VSMC-derived TF, we crossed TFflox/flox mice with SM22αCre+/− mice. TF mRNA and activity were decreased in the aortic media of TF-deficient mice by 96% and 94.8%, respectively. There were no differences in TF activity measured in plasma or concentrated microparticles. TF-deficient mice were generated with the expected frequency, showed no evidence of bleeding or increased mortality, and had similar activated partial thromboplastin and tail vein bleeding times. Thrombus-mediated flow reduction in response to ferric chloride injury of the carotid arteries was significantly attenuated in VSMC-specific TF-deficient. Stable occlusion was seen in 11 of 12 wild-type mice, but in only 6 of 16 VSMC-specific TF-deficient mice (P = .001). These data suggest that VSMC-derived TF is critical in a macrovascular model of arterial thrombosis. This mouse model should be valuable in determining the contribution of VSMC-derived TF in other TF-mediated phenomena, such as restenosis.
Systemic blood coagulation activation in acute coronary syndromes
Authors: Undas Anetta , Szułdrzyński Konstanty , Brummel-Ziedins Kathleen E. , Tracz Wiesława , Zmudka Krzysztof , Mann Kenneth G.
Published: October 2008

We evaluated systemic alterations to the blood coagulation system that occur during a coronary thrombotic event. Peripheral blood coagulation in patients with acute coronary thrombosis was compared with that in people with stable coronary artery disease (CAD). Blood coagulation and platelet activation at the microvascular injury site were assessed using immunochemistry in 28 non-anticoagulated patients with acute myocardial infarction (AMI) versus 28 stable CAD patients matched for age, sex, risk factors, and medications. AMI was associated with increased maximum rates of thrombin-antithrombin complex generation (by 93.8%; P < .001), thrombin B-chain formation (by 57.1%; P < .001), prothrombin consumption (by 27.9%; P = .012), fibrinogen consumption (by 27.0%; P = .02), factor (f) Va light chain generation (by 44.2%; P = .003), and accelerated fVa inactivation (by 76.1%; P < .001), and with enhanced release of platelet-derived soluble CD40 ligand (by 44.4%; P < .001). FVa heavy chain availability was similar in both groups because of enhanced formation and activated protein C (APC)–mediated destruction. The velocity of coagulant reactions in AMI patients showed positive correlations with interleukin-6. Heparin treatment led to dampening of coagulant reactions with profiles similar to those for stable CAD. AMI-induced systemic activation of blood coagulation markedly modifies the pattern of coagulant reactions at the site of injury in peripheral vessels compared with that in stable CAD patients.
The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein
Authors: Bruce Lesley J. , Guizouarn Hélène , Burton Nicholas M. , Gabillat Nicole , Poole Joyce , Flatt Joanna F. , Brady R. Leo , Borgese Franck , Delaunay Jean , Stewart Gordon W.
Published: October 2008

Overhydrated hereditary stomatocytosis (OHSt) is a rare dominantly inherited hemolytic anemia characterized by a profuse membrane leak to monovalent cations. Here, we show that OHSt red cell membranes contain slightly reduced amounts of Rh-associated glycoprotein (RhAG), a putative gas channel protein. DNA analysis revealed that the OHSt patients have 1 of 2 heterozygous mutations (t182g, t194c) in RHAG that lead to substitutions of 2 highly conserved amino acids (Ile61Arg, Phe65Ser). Unexpectedly, expression of wild-type RhAG in Xenopus laevis oocytes induced a monovalent cation leak; expression of the mutant RhAG proteins induced a leak about 6 times greater than that in wild type. RhAG belongs to the ammonium transporter family of proteins that form pore-like structures. We have modeled RhAG on the homologous Nitrosomonas europaea Rh50 protein and shown that these mutations are likely to lead to an opening of the pore. Although the function of RhAG remains controversial, this first report of functional RhAG mutations supports a role for RhAG as a cation pore.
Incomplete T-cell receptor–β peptides target the mitochondrion and induce apoptosis
Authors: Shani Nir , Rubin-Lifshitz Hila , Peretz-Cohen Yifat , Shkolnik Ketty , Shinder Vera , Cohen-Sfady Michal , Shav-Tal Yaron , Barda-Saad Mira , Zipori Dov
Published: October 2008

The default pathway of cell-surface T-cell receptor (TCR) complex formation, and the subsequent transport to the membrane, is thought to entail endoplasmic reticulum (ER) localization followed by proteasome degradation of the unassembled chains. We show herein an alternative pathway: short, incomplete peptide versions of TCRβ naturally occur in the thymus. Such peptides, which have minimally lost the leader sequence or have been massively truncated, leaving only the very C terminus intact, are sorted preferentially to the mitochondrion. As a consequence of the mitochondrial localization, apoptotic cell death is induced. Structure function analysis showed that both the specific localization and induction of apoptosis depend on the transmembrane domain (TMD) and associated residues at the COOH-terminus of TCR. Truncated forms of TCR, such as the short peptides that we detected in the thymus, may be products of protein degradation within thymocytes. Alternatively, they may occur through the translation of truncated mRNAs resulting from unfruitful rearrangement or from germline transcription. It is proposed that mitochondria serve as a subcellular sequestration site for incomplete TCR molecules.
IL-17 contributes to CD4-mediated graft-versus-host disease
Authors: Kappel Lucy W. , Goldberg Gabrielle L. , King Christopher G. , Suh David Y. , Smith Odette M. , Ligh Cassandra , Holland Amanda M. , Grubin Jeremy , Mark Nicholas M. , Liu Chen , Iwakura Yoichiro , Heller Glenn , van den Brink Marcel R. M.
Published: October 2008

CD4+ interleukin-17 (IL-17)+ T cells (Th17 cells) have been implicated in allograft rejection of solid organs and several autoimmune diseases. However, the functional role of Th17 cells in the development of acute graft-versus-host disease (GVHD) has not been well-characterized. We detected significant numbers of alloreactive CD4+ donor T cells expressing IL-17, IL-17F, or IL-22 in the lymphoid organs of recipients of an allogeneic bone marrow transplant. We found no differences in GVHD mortality or graft-versus-tumor (GVT) activity between wild type (WT) and IL-17−/− T-cell recipients. However, upon transfer of murine IL-17−/− CD4+ T cells in an allogeneic BMT model, GVHD development was significantly delayed behind recipients of WT CD4+ T cells, yet overall GVHD mortality was unaffected. Moreover, recipients of IL-17−/− CD4+ T cells had significantly fewer Th1 cells during the early stages of GVHD. Furthermore, we observed a decrease in the number of IFN-γ–secreting macrophages and granulocytes and decreased production of proinflammatory cytokines (interferon [IFN]-γ, IL-4, and IL-6) in recipients of IL-17−/− CD4+ T cells. We conclude that IL-17 is dispensable for GVHD and GVT activity by whole T cells, but contributes to the early development of CD4-mediated GVHD by promoting production of proinflammatory cytokines.
Copy number variations (CNVs) identified in Korean individuals
Authors: Kang Tae-Wook , Jeon Yeo-Jin , Jang Eunsu , Kim Hee-Jin , Kim Jeong-Hwan , Park Jong-Lyul , Lee Siwoo , Kim Yong Sung , Kim Jong Yeol , Kim Seon-Young
Published: October 2008

Background

Copy number variations (CNVs) are deletions, insertions, duplications, and more complex variations ranging from 1 kb to sub-microscopic sizes. Recent advances in array technologies have enabled researchers to identify a number of CNVs from normal individuals. However, the identification of new CNVs has not yet reached saturation, and more CNVs from diverse populations remain to be discovered.

Results

We identified 65 copy number variation regions (CNVRs) in 116 normal Korean individuals by analyzing Affymetrix 250 K Nsp whole-genome SNP data. Ten of these CNVRs were novel and not present in the Database of Genomic Variants (DGV). To increase the specificity of CNV detection, three algorithms, CNAG, dChip and GEMCA, were applied to the data set, and only those regions recognized at least by two algorithms were identified as CNVs. Most CNVRs identified in the Korean population were rare (<1%), occurring just once among the 116 individuals. When CNVs from the Korean population were compared with CNVs from the three HapMap ethnic groups, African, European, and Asian; our Korean population showed the highest degree of overlap with the Asian population, as expected. However, the overlap was less than 40%, implying that more CNVs remain to be discovered from the Asian population as well as from other populations. Genes in the novel CNVRs from the Korean population were enriched for genes involved in regulation and development processes.

Conclusion

CNVs are recently-recognized structural variations among individuals, and more CNVs need to be identified from diverse populations. Until now, CNVs from Asian populations have been studied less than those from European or American populations. In this regard, our study of CNVs from the Korean population will contribute to the full cataloguing of structural variation among diverse human populations.
Role of cytochrome P450 in drug interactions
Authors: Bibi Zakia
Published: October 2008

Drug-drug interactions have become an important issue in health care. It is now realized that many drug-drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra-hepatic tissues. Many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP) enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple-drug therapies. In future, it may help to identify individuals at greatest risk of drug interactions and adverse events.