bluuebunny/crossref_metadata_2025 huggingface dataset:
Lactobacillus plantarum ameliorates colonic epithelial barrier dysfunction by modulating the apical junctional complex and PepT1 in IL-10 knockout mice
Authors: Chen Hong-Qi , Yang Jun , Zhang Min , Zhou Yu-Kun , Shen Tong-Yi , Chu Zhao-Xin , Zhang Ming , Hang Xiao-Min , Jiang Yan-Qun , Qin Huan-Long
Published: October 2010

Probiotics are efficacious in the treatment of inflammatory bowel disease. However, the precise mechanisms remain unknown. To determine whether probiotic Lactobacillus plantarum (LP) ameliorates colonic epithelial barrier dysfunction present in interleukin-10 knockout (IL-10−/−) mice, IL-10−/−and wild-type mice received LP or the vehicle for 4 wk. Colitis was assessed by histological scores and clinical manifestation, and gut paracellular permeability was measured by Ussing chamber. Oligopeptide transporter 1 (PepT1)-mediated transepithelial transport was evaluated by measuring the plasma cephalexin concentration. The expression and distribution of apical junctional complex (AJC) proteins and PepT1 were determined by Western blotting and immunofluorescence and their mRNA by reverse transcriptase-PCR. Spontaneous colitis was observed in all IL-10−/−mice in which paracellular permeability was increased, in conjunction with decreased expression and redistribution of zonula occludens-1, occludin, claudin-1, and β-catenin. PepT1 expression was increased, accompanied with an enhanced cephalexin transport. Colonic epithelial barrier dysfunction was further confirmed by increased bacterial translocation and proinflammatory cytokine production. Treatment with LP decreased colonic paracellular permeability with restoration of expression and distribution of AJC proteins and partially prevented PepT1 expression and cephalexin transport in IL-10−/−mice. Moreover, treatment with LP also prevented bacterial translocation and proinflammatory cytokine production in IL-10−/−mice. Results from this study indicated that treatment with LP may ameliorate colonic epithelial barrier dysfunction in IL-10−/−mice, by modulating the AJC- and PepT1-mediated transepithelial transport.
Moderate exercise prevents impaired Ca2+ handling in heart of CO-exposed rat: implication for sensitivity to ischemia-reperfusion
Authors: Farah C. , Meyer G. , André L. , Boissière J. , Gayrard S. , Cazorla O. , Richard S. , Boucher F. , Tanguy S. , Obert P. , Reboul C.
Published: October 2010

Sustained urban carbon monoxide (CO) exposure exacerbates heart vulnerability to ischemia-reperfusion via deleterious effects on the antioxidant status and Ca2+ homeostasis of cardiomyocytes. The aim of this work was to evaluate whether moderate exercise training prevents these effects. Wistar rats were randomly assigned to a control group and to CO groups, living during 4 wk in simulated urban CO pollution (30–100 parts/million, 12 h/day) with (CO-Ex) or sedentary without exercise (CO-Sed). The exercise procedure began 4 wk before CO exposure and was maintained twice a week in standard filtered air during CO exposure. On one set of rats, myocardial ischemia (30 min) and reperfusion (120 min) were performed on isolated perfused rat hearts. On another set of rats, myocardial antioxidant status and Ca2+ handling were evaluated following environmental exposure. As a result, exercise training prevented CO-induced myocardial phenotypical changes. Indeed, exercise induced myocardial antioxidant status recovery in CO-exposed rats, which is accompanied by a normalization of sarco(endo)plasmic reticulum Ca2+-ATPase 2a expression and then of Ca2+ handling. Importantly, in CO-exposed rats, the normalization of cardiomyocyte phenotype with moderate exercise was associated with a restored sensitivity of the myocardium to ischemia-reperfusion. Indeed, CO-Ex rats presented a lower infarct size and a significant decrease of reperfusion arrhythmias compared with their sedentary counterparts. To conclude, moderate exercise, by preventing CO-induced Ca2+ handling and myocardial antioxidant status alterations, reduces heart vulnerability to ischemia-reperfusion.
Regional correlation of emphysematous changes in lung function and structure: a comparison between pulmonary function testing and hyperpolarized MRI metrics
Authors: Emami Kiarash , Chia Elaine , Kadlecek Stephen , MacDuffie-Woodburn John P. , Zhu Jianliang , Pickup Stephen , Blum Allison , Ishii Masaru , Rizi Rahim R.
Published: October 2010

Regional and global relationships of lung function and structure were studied using hyperpolarized3He MRI in a rat elastase-induced model of emphysema ( n = 4) and healthy controls ( n = 5). Fractional ventilation ( r) and apparent diffusion coefficient (ADC) of3He were measured at a submillimeter planar resolution in ventral, middle, and dorsal slices 6 mo after model induction. Pulmonary function testing (PFT) was performed before MRI to yield forced expiratory volume in 50 ms (FEV50), airway resistance (RI), and dynamic compliance (Cdyn). Cutoff threshold values of ventilation and diffusion, r* and ADC*, were computed corresponding to 80% population of pixels falling above or below each threshold value, respectively. For correlation analysis, r* was compared with FEV50/functional residual capacity (FRC), RIand Cdyn, whereas ADC* was compared with FEV50/FRC, total lung capacity (TLC), and Cdyn. Regional correlation of r and ADC was evaluated by dividing each of the three lung slices into four quadrants. Cdynwas significantly larger in elastase rats (0.92 ± 0.16 vs. 0.61 ± 0.12 ml/cmH2O). The difference of RIand FEV50was insignificant between the two groups. The r* of healthy rats was significantly larger than the elastase group (0.42 ± 0.03 vs. 0.28 ± 0.06), whereas ADC* was significantly smaller in healthy animals (0.27 ± 0.04 vs. 0.36 ± 0.01 cm2/s). No systematic difference in these quantities was observed between the three lung slices. A significant 33% increase in ADC* and a significant 31% decline in r* for elastase rats was observed compared with a significant 51% increase in Cdynand a nonsignificant 26% decline in FEV50/FRC. Correlation of imaging and PFT metrics revealed that r and ADC divide the rats into two separate clusters in the sample space.
Combined heat and mental stress alters neurovascular control in humans
Authors: Klein Jenna C. , Crandall Craig G. , Matthew Brothers R. , Carter Jason R.
Published: October 2010

This study examined the effect of combined heat and mental stress on neurovascular control. We hypothesized that muscle sympathetic nerve activity (MSNA) and forearm vascular responses to mental stress would be augmented during heat stress. Thirteen subjects performed 5 min of mental stress during normothermia (Tcore; 37 ± 0°C) and heat stress (38 ± 0°C). Heart rate, mean arterial pressure (MAP), MSNA, forearm vascular conductance (FVC; venous occlusion plethysmography), and forearm skin vascular conductance (SkVCf; via laser-Doppler) were analyzed. Heat stress increased heart rate, MSNA, SkVCf, and FVC at rest but did not change MAP. Mental stress increased MSNA and MAP during both thermal conditions; however, the increase in MAP during heat stress was blunted, whereas the increase in MSNA was accentuated, compared with normothermia (time × condition; P < 0.05 for both). Mental stress decreased SkVCf during heat stress but not during normothermia (time × condition, P < 0.01). Mental stress elicited similar increases in heart rate and FVC during both conditions. In one subject combined heat and mental stress induced presyncope coupled with atypical blood pressure and cutaneous vascular responses. In conclusion, these findings indicate that mental stress elicits a blunted increase of MAP during heat stress, despite greater increases in total MSNA and cutaneous vasoconstriction. The neurovascular responses to combined heat and mental stress may be clinically relevant to individuals frequently exposed to mentally demanding tasks in hyperthermic environmental conditions (i.e., soldiers, firefighters, and athletes).
Adrenergic mechanisms do not contribute to age-related decreases in calf venous compliance
Authors: Sielatycki John A. , Shamimi-Noori Saum , Pfeiffer Michael P. , Monahan Kevin D.
Published: October 2010

Limb venous compliance decreases with advancing age, even in healthy humans. To test the hypothesis that adrenergic mechanisms contribute to age-associated reductions in limb venous compliance, we measured calf venous compliance before and during acute systemic α- and β-adrenergic blockade in eight young (27 ± 1 yr old, mean ± SE) and eight older healthy men (67 ± 2 yr old). Calf venous compliance was determined in supine subjects by inflating a thigh-collecting cuff to 60 mmHg for 8 min and then decreasing it (1 mmHg/s) to 0 mmHg while calf volume was indexed with a strain gauge. The slope (·10−3) of the pressure-compliance relation (compliance= β1 + 2·β2·cuff pressure), which is the first derivative of the quadratic pressure-volume relation [(Δlimb volume) = β0 + β1·(cuff pressure) + β2·(cuff pressure)2] during reductions in cuff pressure, was used to quantify calf venous compliance. Calf venous compliance was ∼30% lower ( P < 0.01) in older compared with young men before adrenergic blockade. In response to adrenergic blockade calf venous compliance did not increase in young (−2.62 ± 0.14 and −2.29 ± 0.18 ml·dl−1·mmHg−1, before and during blockade, respectively) or older men (−1.78 ± 0.27 and −1.68 ± 0.21 ml·dl−1·mmHg−1). Moreover, during adrenergic blockade differences in calf venous compliance between young and older men observed before adrenergic blockade persisted. Collectively, these data strongly suggest that adrenergic mechanisms neither directly restrain calf venous compliance in young or older men nor do they contribute to age-associated reductions in calf venous compliance in healthy men.
TNF Superfamily: A Growing Saga of Kidney Injury Modulators
Authors: Sanchez-Niño Maria D. , Benito-Martin Alberto , Gonçalves Sara , Sanz Ana B. , Ucero Alvaro C. , Izquierdo Maria C. , Ramos Adrian M. , Berzal Sergio , Selgas Rafael , Ruiz-Ortega Marta , Egido Jesus , Ortiz Alberto
Published: October 2010

Members of the TNF superfamily participate in kidney disease. Tumor necrosis factor (TNF) and Fas ligand regulate renal cell survival and inflammation, and therapeutic targeting improves the outcome of experimental renal injury. TNF-related apoptosis-inducing ligand (TRAIL and its potential decoy receptor osteoprotegerin are the two most upregulated death-related genes in human diabetic nephropathy. TRAIL activates NF-kappaB in tubular cells and promotes apoptosis in tubular cells and podocytes, especially in a high-glucose environment. By contrast, osteoprotegerin plays a protective role against TRAIL-induced apoptosis. Another family member, TNF-like weak inducer of apoptosis (TWEAK induces inflammation and tubular cell death or proliferation, depending on the microenvironment. While TNF only activates canonical NF-kappaB signaling, TWEAK promotes both canonical and noncanonical NF-kappaB activation in tubular cells, regulating different inflammatory responses. TWEAK promotes the secretion of MCP-1 and RANTES through NF-kappaB RelA-containing complexes and upregulates CCl21 and CCL19 expression through NF-kappaB inducing kinase (NIK-) dependent RelB/NF-kappaB2 complexes. In vivo TWEAK promotes postnephrectomy compensatory renal cell proliferation in a noninflammatory milieu. However, in the inflammatory milieu of acute kidney injury, TWEAK promotes tubular cell death and inflammation. Therapeutic targeting of TNF superfamily cytokines, including multipronged approaches targeting several cytokines should be further explored.
Integral HOMFLY‐PT and sl(n)‐Link Homology
Authors: Krasner Daniel
Published: October 2010

Using the diagrammatic calculus for Soergel bimodules, developed by Elias and
Khovanov, as well as Rasmussen′s spectral sequence, we construct an integral version of HOMFLY‐PT and sl(n)‐link homology.
Acquired TNFRSF14 Mutations in Follicular Lymphoma Are Associated with Worse Prognosis
Authors: Cheung K-John J. , Johnson Nathalie A. , Affleck Joslynn G. , Severson Tesa , Steidl Christian , Ben-Neriah Susana , Schein Jacqueline , Morin Ryan D. , Moore Richard , Shah Sohrab P. , Qian Hong , Paul Jessica E. , Telenius Adele , Relander Thomas , Lam Wan , Savage Kerry , Connors Joseph M. , Brown Carolyn , Marra Marco A. , Gascoyne Randy D. , Horsman Douglas E.
Published: October 2010

Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism–detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35–9.878, P = 0.011) and 3.19 (95% confidence interval, 1.06–9.57, P = 0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes. Cancer Res; 70(22); 9166–74. ©2010 AACR.
Nox2 NADPH Oxidase Promotes Pathologic Cardiac Remodeling Associated with Doxorubicin Chemotherapy
Authors: Zhao Youyou , McLaughlin Declan , Robinson Emma , Harvey Adam P. , Hookham Michelle B. , Shah Ajay M. , McDermott Barbara J. , Grieve David J.
Published: October 2010

Doxorubicin is a highly effective cancer treatment whose use is severely limited by dose-dependent cardiotoxicity. It is well established that doxorubicin increases reactive oxygen species (ROS) production. In this study, we investigated contributions to doxorubicin cardiotoxicity from Nox2 NADPH oxidase, an important ROS source in cardiac cells, which is known to modulate several key processes underlying the myocardial response to injury. Nox2-deficient mice (Nox2−/−) and wild-type (WT) controls were injected with doxorubicin (12 mg/kg) or vehicle and studied 8 weeks later. Echocardiography indicated that doxorubicin-induced contractile dysfunction was attenuated in Nox2−/− versus WT mice (fractional shortening: 29.5 ± 1.4 versus 25.7 ± 1.0%; P < 0.05). Similarly, in vivo pressure-volume analysis revealed that systolic and diastolic function was preserved in doxorubicin-treated Nox2−/− versus WT mice (ejection fraction: 52.6 ± 2.5 versus 28.5 ± 2.3%, LVdP/dtmin: −8,379 ± 416 versus −5,198 ± 527 mmHg s−1; end-diastolic pressure-volume relation: 0.051 ± 0.009 versus 0.114 ± 0.012; P < 0.001). Furthermore, in response to doxorubicin, Nox2−/− mice exhibited less myocardial atrophy, cardiomyocyte apoptosis, and interstitial fibrosis, together with reduced increases in profibrotic gene expression (procollagen IIIαI, transforming growth factor-β3, and connective tissue growth factor) and matrix metalloproteinase-9 activity, versus WT controls. These alterations were associated with beneficial changes in NADPH oxidase activity, oxidative/nitrosative stress, and inflammatory cell infiltration. We found that adverse effects of doxorubicin were attenuated by acute or chronic treatment with the AT1 receptor antagonist losartan, which is commonly used to reduce blood pressure. Our findings suggest that ROS specifically derived from Nox2 NADPH oxidase make a substantial contribution to several key processes underlying development of cardiac contractile dysfunction and remodeling associated with doxorubicin chemotherapy. Cancer Res; 70(22); 9287–97. ©2010 AACR.
Clinical Features of 2009 Pandemic Infuenza A (H1N1) Virus Infection in Chronic Hemodialysis Patients
Authors: Li Han , Wang Shi-xiang
Published: October 2010

Background/Aims: Infection is one of the most common complications and is considered the second leading cause of death in dialysis patients with end-stage renal disease. After the first cases of 2009 pandemic influenza A (H1N1) virus in China became public, persons with suspected infection and those who were in contact with persons with suspected infection were tested. Whether the presentation and clinical course of H1N1 influenza is similar in the dialysis population to the general population is currently unknown. Hemodialysis patients in whom an infection was confirmed were hospitalized and quarantined, and patients on chronic hemodialysis were closely observed for the purpose of investigating the nature and duration of the disease. Methods: From May 2009 to February 2010, we observed 15 hemodialysis patients infected with the 2009 pandemic influenza A (H1N1) virus who were quarantined in Beijing Chao-Yang Hospital, Capital Medical University. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) testing was used to confirm infection, the clinical features of the disease were closely monitored. Results: The mean age of the 15 patients was 47.6 years, and 9 of the 15 patients were male. The diagnoses were all made in the hospital. All of the 15 patients had fluid overload. The median incubation period of the virus in hemodialysis patients was 4 days (range: 1–7 days). The most common symptoms were dyspnea (in all of the 15 patients) and productive cough (in all of the 15 patients). One of the 15 patients had low-grade fever, and the other 14 patients were afebrile. Lymphopenia, which was common in 12 of the patients, typically occurred on day 2 (range: days 1–3) and resolved by day 9 (range: days 7–11). Hypoxemia was observed in all of the patients. Six of the 15 patients developed respiratory failure requiring mechanical ventilation on days 7–9 because they were complicated by Escherichia coli nosocomial pneumonia. All the patients were placed in respiratory isolation and were treated with oseltamivir. The median length of time during which patients had positive real-time RT-PCR test results was 12 days (range: 7–19 days), which was longer than that in general population. Conclusions: The presentation and clinical course of H1N1 influenza A in the hemodialysis patients was atypical and relatively serious, which differed from the general population in China. Furthermore, these patients may have an extended period of viral shedding.
Recurrent Transient Loss of Consciousness Induced by Acute Massive Gastrointestinal Hemorrhage during Hemodialysis: A Case Report
Authors: Li Han , Wang Shi-xiang
Published: October 2010

A 67-year-old man with chronic hemodialysis (HD), who had end-stage renal disease secondary to diabetic nephropathy and had been on HD for 9 years with ultrapure dialysis solution, is presented with recurrent transient loss of consciousness during HD.
Functional and Radiological Evaluations of Unstable Displaced Proximal Humeral Fractures Treated with Closed Reduction and Percutaneous Pinning Fixation
Authors: Yu Zhe , Zheng Lianhe , Wang Yucai , Zhang Yong , Zhang Xudong , Ma Bao’an
Published: October 2010

Objective: The purpose of this study is to evaluate the functional and radiological outcomes of patients with unstable displaced proximal humeral fractures treated with closed reduction and percutaneous pinning (CRPP) fixation. Methods: We retrospectively reviewed 87 cases of displaced (2-, 3- or 4-part fractures according to Neer classification) proximal humeral fractures treated with CRPP fixation in our center from September 2003 to September 2008. Sixty-four patients were followed up for a period ranging from 12 to 48 months (averaging 16.2 months) and evaluated for the functional and radiological outcomes by a series of standard questionnaire and measurement. Results: The fractures in all 64 patients were healed with an average time of 15.4 weeks (ranging from 12 to 43 weeks), and the mean interval between the operation and full functional exercise was 17.3 weeks (ranging from 14 to 38 weeks). At the final follow-up visit, no patients showed shoulder instability; the mean range of abduction motion was 157.1° (ranging from 70 to 180°). For all patients, no statistically significant difference in the functional outcomes was observed between their 6-month and final follow-up visits, nor in the radiological findings between their immediately postoperative and fi- nal follow-up examinations. Conclusion: CRPP fixation is a feasible treatment option for unstable displaced proximal humeral fractures, especially for 2- and 3-part fractures in elderly patients. Although technically demanding, it offers reliable stability without extensive soft tissue dissection, allowing the early painless range of motion. This technique could also promote bone healing, prevent ischemic osteonecrosis of the head of humerus and lead to few complications.
A dose-finding study with TAK-442, an oral factor Xa inhibitor, in patients undergoing elective total knee replacement surgery
Authors: Cao Charlie , Eriksson Bengt I. , Fisher William , Kupfer Stuart , Raskob Gary , Spaeder Jeffrey , Turpie Alexander G. G. , Weitz Jeffrey I.
Published: October 2010

This multicentre dose-finding study compared TAK-442, an oral factor Xa inhibitor, with enoxaparin for thromboprophylaxis after knee arthroplasty. In this parallel group study, patients were randomised to oral TAK-442 (40 or 80 mg once-daily [QD] or 10, 20, 40, or 80 mg twice-daily [BID] started 6–8 hours postoperatively), which was blinded as to dose, or to open-label subcutaneous enoxaparin (30 mg BID starting 12–24 hours postoperatively) for 10 days. Treatments were continued until bilateral venography was performed (maximum of 14 days). The primary efficacy endpoint was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism or all-cause mortality, while the primary safety endpoint was major bleeding. Of 1,038 patients randomised who received at least one dose of study drug, 949 completed the study and 730 (76.9%) were evaluable for the primary efficacy analysis. Recruitment into the 10 and 20 mg BID dose groups was stopped early because the incidences of the primary efficacy endpoint were significantly higher than that with enoxaparin. The primary efficacy endpoint occurred in 22.0% of patients given enoxaparin and in 39.0%, 38.4%, 23.5%, 21.4%, 26.8%, and 14.3% of those receiving TAK-442 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, and 80 mg BID, respectively. The incidences of major and clinically relevant non-major bleeding with TAK-442 were not dose-dependent or different from that with enoxaparin. All TAK-442 doses except 10 and 20 mg BID displayed similar efficacy and safety profiles to enoxaparin.
The dengue virus envelope protein induced PAI-1 gene expression via MEK/ERK pathways
Authors: Lin Yi-Ying , Chen Lien-Cheng , Wang Yi-Fen , Yeh Trai-Ming , Su Shu-Jem , Cheng Wei-Cheng , Chen Chang-Yu , Lin Kuan-Hua , Chou Miao-Chen , Shyu Huey-Wen
Published: October 2010

Dengue virus (DV) infections cause mild dengue fever or severe life-threatening dengue haemorrhagic fever (DHF)/ dengue shock syndrome (DSS). DV-infected patients have high plasma concentrations of plasminogen activator inhibitor type I (PAI-1). However, the mechanism to cause haemorrhage in DV infections remains poorly understood. In this study, investigation was carried out on the purified recombinant domain III of the envelope glycoprotein of DV serotypes 2 (EIII) and the signalling pathways of EIII leading to PAI-1 gene expression were measured by RT-PCR, Western blot, and immunofluorescence stain. Reporter gene constructs containing serially 5’-deleted sequences of the proximal human PAI-1 promoter region were constructed and then transfected to Huh7 cells, a human hepatoma cell line, prior to EIII treatment. EIII increased the PAI-1 mRNA and protein levels in a dose-dependent manner in Huh7 cells. Results showed that U0126, an inhibitor of extracellular signal-regulated kinase (ERK) kinase (MEK), almost completely suppressed EIII-induced PAI-1 expression. The results suggest that the MEK/ERK signalling pathways mediate the EIII-dependent induction of PAI-1 gene expression via the proximal promoter region.
The unsialylated subpopulation of recombinant activated factor VII binds to the asialo-glycoprotein receptor (ASGPR) on primary rat hepatocytes
Authors: Nielsen Hanne M. , Christensen Erik I. , Appa Rupa S. , Seested Torben
Published: October 2010

Recombinant activated factor VII (rFVIIa; NovoSeven®) is a heterogeneously glycosylated serine protease used for treatment of haemophiliacs with inhibitors. The drug substance contains a subpopulation consisting of ~20% of rFVIIa molecules which are unsialylated and consists of carbohydrate moieties with terminally exposed galactose and N-acetyl-D-galactosamine (GalNAc). Recently, data from an in situ per-fused liver model showed that a subpopulation of rFVIIa, appearing to be unsialylated rFVIIa, was cleared by the liver, thus suggesting a carbohydrate-moiety mediated mechanism. The parenchymal cells of the liver, hepatocytes, are known to abundantly express functional carbohydrate-specific receptors and in this study we therefore used primary rat hepatocytes to study binding and intracellular fate of rFVIIa at a cellular level. Immunofluorescence microscopy showed that rFVIIa was distributed into distinct intracellular vesicles and electron microscopic autoradiography revealed that radioiodinated rFVIIa distributed only into cytoplasmic free vesicles resembling endosomes and lysosomes. These findings suggest that endocytosis of rFVIIa in hepatocytes could be partly mediated via initial membrane binding to a receptor. Quantitative binding studies showed that the presence of excess unlabelled asialo-orosomucoid, asialo-rFVIIa and GalNAc significantly decreased binding of 125I-rFVIIa. An antibody which specifically binds to the carbohydrate recognition domain of the asialoglycoprotein receptor (ASGPR) significantly decreased binding of asialo-rFVIIa by ~36% and rFVIIa by ~19%. Together our data showed that a receptor-mediated mechanism involving the ASGPR is able to bind a subpopulation of unsialylated rFVIIa, while a hepatic mechanism for binding and clearing sialylated rFVIIa is still unknown.
Cysteine residues in CUB-1 domain are critical for ADAMTS13 secretion and stability
Authors: Zhou Zhou , Yeh Hui-Chun , Jing Hua , Wang Christina , Tao Zhenyin , Choi Huiwan , Aboulfatova Khatira , Li Renhao , Dong Jing-fei
Published: October 2010

Upon stimulation, endothelial cells release von Willebrand factor (VWF) enriched in ultra-large (UL) forms that are rapidly cleaved by ADAMTS13. The zinc metalloprotease fits in the consensus for members of the ADAMTS family, but also contains two unique C-terminal CUB domains. There are five and two cysteine residues in the CUB-1 and CUB-2 domains, respectively, instead of four as deducted from the consensus. In this study, we investigated the role of cysteine residues in the CUB-1 domain in ADAMTS13 synthesis and activity. CUB-1 and cysteine mutations were expressed in mammalian cell lines and examined for synthesis, secretion, stability, and VWF-cleaving activity. When expressed as an isolated domain, CUB-1, but not CUB-2, covalently aggregated. Converting any of the four cysteines that fit in the CUB consensus (C1192, C1213, C1236 and C1254) reduced the secretion of the mutants to the conditioned medium, but not to extracellular matrix. The mutations also resulted in a moderate increase in proteolytic degradation and decrease in cleaving VWF under static, but not flowing conditions. In contrast, replacing C1275, which was found to be in the thiol form, with a serine residue prevented covalent aggregation of CUB-1, but had no effect on secretion and VWF-cleaving activity. C1275S was also markedly resistant to proteolytic degradation. The data illustrate the importance of consensus cysteines in the secretion and proteolytic activity of ADAMTS13. They also identify an ADAMTS-13 mutant that is resistant to proteolytic degradation, while maintaining a normal VWF-cleaving activity.
The Mechanical Stress–Activated Serum-, Glucocorticoid-Regulated Kinase 1 Contributes to Neointima Formation in Vein Grafts
Authors: Cheng Jizhong , Wang Ying , Ma Yewei , Chan Bonita Tak-yee , Yang Min , Liang Anlin , Zhang Liping , Li Huihua , Du Jie
Published: October 2010

Rationale:

Mechanical stress plays an important role in proliferation of venous smooth muscle cells (SMCs) in neointima, a process of formation that contributes to failure of vein grafts. However, it is unknown what intracellular growth signal leads to proliferation of venous SMCs.

Objective:

The objective of this study is to identify mechanisms of mechanical stretch on neointima formation.

Methods and Results:

By a microarray analysis, we found that mechanical cyclic stretch (15% elongation) stimulated the transcription of SGK-1 (serum-, glucocorticoid-regulated kinase-1). Mechanical stretch–induced SGK-1 mRNA expression was blocked by actinomycin D. The mechanism for the SGK-1 expression involved MEK1 but not p38 or JNK signaling pathway. SGK-1 activation in response to stretch is blocked by insulin-like growth factor (IGF)-1 receptor inhibitor and mammalian target of rapamycin complex (mTORC)2 inhibitor (Ku-0063794) but not mTORC1 inhibitor (rapamycin). Mechanical stretch–induced bromodeoxyuridine incorporation was reduced by 83.5% in venous SMCs isolated from SGK-1 knockout mice. In contrast, inhibition of Akt, another downstream signal of PI3K resulted in only partial inhibition of mechanical stretch–induced proliferation of venous SMCs. Mechanical stretch also induced phosphorylation and nuclear exportation of p27

kip1

, whereas knockout of SGK-1 attenuated this effect of mechanical stretch on p27

kip1

. In vivo, we found that placement of a vein graft into artery increased SGK-1 expression. Knockout of SGK-1 effectively prevented neointima formation in vein graft. There is significant lower level of p27

kip1

located in the nucleus of neointima cells in SGK-1 knockout mice compared with that of wild-type vein graft. In addition, we also found that wire injury of artery or growth factors in vitro increased expression of SGK-1.

Conclusions:

These results suggest that SGK-1 is an injury-responsive kinase that could mediate mechanical stretch–induced proliferation of vascular cells in vein graft, leading to neointima formation.
Relating Passive 37-GHz Scattering to Radar Profiles in Strong Convection
Authors: Cecil Daniel J.
Published: October 2010

Tropical Rainfall Measuring Mission (TRMM) Microwave Imager and precipitation radar measurements are examined for strong convective systems. Storms having similar values of minimum 37-GHz polarization-corrected temperature (PCT) are grouped together, and their vertical profiles of maximum radar reflectivity are composited. Lower 37-GHz PCT corresponds to stronger radar profiles (high reflectivity through a deep layer), but characteristic profiles for a given 37-GHz PCT are different for deep tropical ocean, deep tropical land, subtropical ocean, and subtropical land regions. Tropical oceanic storms have a sharper decrease of reflectivity just above the freezing level than storms from other regions with the same brightness temperature. Storms from subtropical land regions have the slowest decrease of reflectivity with height and the greatest mixed-phase-layer ice water content (IWC). Linear fits of 37-GHz PCT versus IWC for each region are used to scale the brightness temperatures. Counts of storms with these scaled brightness temperatures below certain thresholds suggest that not as many of the strongest storms occur in central Africa as in subtropical parts of South America, the United States, and central Asia.
Spectral Analysis of Multidimensional Stochastic Geophysical Models with an Application to Decadal ENSO Variability
Authors: Kleeman Richard
Published: October 2010

Simple linear models with additive stochastic forcing have been rather successful in explaining the observed spectrum of important climate variables. Motivated by this, the authors analyze the spectral character of such a general stochastic system of finite dimension. The spectral matrix is derived in the case that the spectrum is a linear combination of dynamical variables and their stochastic forcings. It is found that the most convenient basis for analysis is provided by the normal modes. In general the spectrum consists of two pieces. The first “diagonal” piece is a symmetric Lorentzian curve centered on the normal mode frequencies with breadth and strength determined by the normal mode dissipation. The second cross-spectrum piece derives usually from the coherency of the stochastic forcing of two different normal modes. The cross-spectrum is smaller in magnitude than the corresponding two diagonal pieces. This relative magnitude is controlled by the Wiener coherency, which is equal to the magnitude of the correlation of the stochastic forcings of different normal modes. This new analysis framework is studied in detail for the ENSO case for which a two-dimensional stochastically forced oscillator has been previously suggested as a minimal model. It is found that the observed spectrum is rather easily reproduced given appropriate dissipation. Further, it is found that the cross-spectrum results in a phase-dependent enhancement or suppression of frequencies smaller than the dominant ENSO frequency. This therefore provides a new mechanism for decadal ENSO variability. Since the cross-spectrum is phase dependent, the decadal variability generated has a distinctive spatial character. The significance of the cross-spectrum depends on the Wiener coherency, which in turn depends on the statistics of the stochastic forcing.
Accommodation Study for an Anemometer on a Martian Lander
Authors: Lenoir Benjamin , Banfield Donald , Caughey David A.
Published: October 2010

Measuring the wind velocity and its turbulent fluctuations near the surface of Mars is an important component of the future exploration of Mars, not only to minimize risk in landing, but also to understand some of the most important fundamental processes that dominate Mars’ behavior today. Previous missions have included instrumentation to measure 2D mean winds, but a more sophisticated instrument has been designed that allows for fast, precise 3D measurements of the wind and its turbulent properties. These richer observations raise the question of how best to place such an instrument on a future Martian lander to minimize the flow distortions imposed by the lander, and how to correct for the perturbations that cannot be avoided. To carry out this research, computational fluid dynamic simulations in three dimensions were performed using Fluent, a commercially available software. The first step was to model the conditions at the surface of Mars and, more particularly, the quantities describing the flow in the boundary layer. Using these models, simulations were conducted with two simple shapes for the lander and with eight turbulence conditions representing neutral stability flows in the Martian boundary layer. The results are believed to be generally robust for neutral stability cases because the simulations exhibited little variability as a function of the turbulence conditions. This allowed criteria to be established that would optimize the placement of an anemometer in close proximity to a Martian lander under these conditions. The optimal position that has been derived is an elevation of 55° with a minimum distance from the lander of 0.8 times the characteristic size of the lander.
Risky Altruism as a Predictor of Criminal Victimization
Authors: Homant Robert J.
Published: October 2010

This research tested the hypothesis that risky altruism is a significant predictor of criminal victimization. Two hundred sixty-eight respondents filled out a questionnaire measuring their experiences as crime victims, several personality variables, and their degree of altruism. Using factor analysis, a general altruism scale was subdivided into risky and safe altruism. Risky altruism correlated .31 with victimization, compared to .09 for safe altruism. This basic finding was true for both personal and property crime, and the pattern held for four different subgroups: a student sample and citizens from high-, moderate-, and low-crime areas. Separate measures of recent victimization and victimization directly related to helping someone (altruistic victimization) also showed significant relationships with risky altruism. Risky and safe altruism had different patterns of relationships with personality variables, with risky altruism being less related to prosocial personality, agreeableness, and conscientiousness, and more related to extraversion and sensation seeking.
A Method for Measuring Organizational Functioning in Juvenile Justice Facilities Using Resident Ratings
Authors: Mulvey Edward P. , Schubert Carol A. , Odgers Candice A.
Published: October 2010

Institutional care is an enduring component of the continuum of care in the juvenile justice system, yet youth perceptions of the placement experience are often overlooked as a source of information about this practice. Little attention is paid to how institutional placements are received by youth as opposed to how they are conceived by the justice system. This article offers an empirically based framework for assessing organizational climate in facilities housing serious young offenders based on youth self-reports. The authors provide evidence that juvenile offenders can provide reliable and internally consistent ratings regarding several dimensions of an institution’s environment, using straightforward and relatively easily administered instruments. This work lays the foundation for the development of methods for ongoing monitoring of juvenile justice facilities and the testing of whether aspects of the environments of these facilities affect the subsequent community adjustment of their residents.
Fourteen-Week Toxicity Study of Green Tea Extract in Rats and Mice
Authors: Chan Po C. , Ramot Yuval , Malarkey David E. , Blackshear Pamela , Kissling Grace E. , Travlos Greg , Nyska Abraham
Published: October 2010

The toxicity of green tea extract (GTE) was evaluated in 14-week gavage studies in male and female F344/NTac rats and B6C3F1 mice at doses up to 1,000 mg/kg. In the rats, no treatment-related mortality was noted. In the mice, treatment-related mortality occurred in male and female mice in the 1,000 mg/kg dose groups. The cause of early deaths was likely related to liver necrosis. Treatment-related histopathological changes were seen in both species in the liver, nose, mesenteric lymph nodes, and thymus. In addition, in mice, changes were seen in the Peyer’s patches, spleen, and mandibular lymph nodes. The no adverse effect level (NOAEL) for the liver in both species was 500 mg/kg. In the nose of rats, the NOAEL in males was 62.5 mg/kg, and in females no NOAEL was found. No NOAEL was found in the nose of female or male mice. The changes in the liver and nose were considered primary toxic effects of GTE, while the changes in other organs were considered to be secondary effects. The nose and liver are organs with high metabolic enzyme activity. The increased susceptibility of the nose and liver suggests a role for GTE metabolites in toxicity induction.
Renal Dysplasia in Beagle Dogs
Authors: Bruder Marc C. , Shoieb Ahmed M. , Shirai Norimitsu , Boucher Germaine G. , Brodie Thomas A.
Published: October 2010

Anomalies of renal development comprise abnormalities in the amount of renal tissue (agenesis and hypoplasia); anomalies of renal position, form, and orientation; and renal dysplasia. There are previous reports of canine renal dysplasia in different breeds but none in the Beagle breed. This is the first report of renal dysplasia in this breed of dog. Morphologic descriptions of the range of microscopic features observed in four cases of renal dysplasia from preclinical studies in laboratory Beagle dogs are presented (including persistent primitive mesenchyme, persistence of metanephric ducts, asynchronous differentiation of nephrons, and atypical tubular epithelium), along with a basis for the classification of the lesion.
Cerebromalacia with Epilepsy and Cortical Blindness in a Laboratory Japanese Macaque (Macaca fuscata)
Authors: Yoshizawa Katsuhiko , Nakao Kazuko , Habiro Mayu , Hayashi Kazuko , Kuwata Maki , Uehara Norihisa , Yuri Takashi , Nakamura Kae , Tsubura Airo
Published: October 2010

The authors performed a pathological examination of a 5-year-old female laboratory Japanese monkey who developed cortical blindness and epileptic seizures. Generalized, tonic-clonic seizures started to occur during behavioral training to get the animal to enter a carrying cage for future psychological experiments. Blindness was suspected because of a lack of approaching behavior toward foods such as fruits. Although the monkey was extensively treated with anticonvulsants, the clinical signs did not improve. An increased serum creatine phosphokinase (CPK) level and bilateral occipital brain atrophy were detected. Histopathologically, a severe degree of cerebromalacia was detected bilaterally in the occipital lobe, and necrosis and gliosis were seen mainly in the temporal lobe. Focal inflammation was found in the meninges. No other changes were observed in other nervous tissues or organs, and no signs of a parasitic or viral infection were found in the systemic organs. Spontaneously occurring lesions in the central nervous system have been rarely reported in laboratory monkeys. In the present case, the cause of cerebromalacia could not be confirmed, but the relationship between symptoms such as abnormal vision and the presence of brain lesions was distinct. The authors believe that this case is a valuable historical control case for the laboratory Japanese macaque.
Choice of Morphometric Methods and Consequences in the Regulatory Environment
Authors: Boyce John T. , Boyce Rogely Waite , Gundersen Hans Jorgen
Published: October 2010

In certain cases, quantitative tissue structural data derived from tissue sections may be required to make critical decisions in the drug development or risk assessment process. Most frequently, these questions center on test article–related effects on cell number. In this opinion article, the limitations of estimating cell number by standard cell or nuclear profile counts from sections/blocks collected for routine histopathology are discussed from both a scientific and regulatory perspective and contrasted with the robust, sensitive, statistically based methods of design-based stereology. Specific existing industry practices are reviewed. Recent advances in stereological theory, software, hardware, and automated immunohistochemical staining now make it feasible to implement unbiased stereological methods to assess test article–related effects on cell number in a regulatory toxicology setting. These design-based stereological methods for counting cells are recommended when the quantification of small changes in cell number is critical to the risk assessment or decision-making process. These methods provide levels of sensitivity and statistical guarantees of accuracy that no other currently available tissue section–based methodology can provide.
Pathological Study of Acute Pulmonary Toxicity Induced by Intratracheally Instilled Asian Sand Dust (Kosa)
Authors: Naota Misaki , Mukaiyama Toru , Shimada Akinori , Yoshida Atushi , Okajima Mina , Morita Takehito , Inoue Kenichiro , Takano Hirohisa
Published: October 2010

The objective of this study was to investigate acute lung toxicity caused by Asian sand dust. Simulated Asian sand dust collected from the Tennger desert in China (CJ-2 particles) and Asian sand dust collected from the atmosphere in Japan (Tottori particles) were used. Saline suspensions of 50, 200, 800, and 3,000 µg Asian sand dust were intratracheally instilled to ICR mice. Localized accumulation of the dust particles was observed in the bronchioles and the alveoli of the lung tissues; acute inflammatory changes characterized by infiltration of macrophages and neutrophils were observed around the particles. Degenerated alveolar walls and bronchial epithelial cells, as well as a weakened positive immunolabeling for laminin, were observed to be associated with particle attachment. Positive immunolabelings for interleukin-6, tumor necrosis factor–α inducible nitric oxide synthase, and dimeric copper- and zinc-containing superoxide dismutase were observed mainly in the inflammatory cells in the lesions; these findings were not observed in the controls or in areas lacking lesions. These results suggest that Asian sand dust particles caused damage to the lung tissue through a direct physical effect. In addition, secondary released cytokines and oxidative stress generated in the lesion may be involved in the development of the acute lung toxicity.
Assimilation, contrast and voter projections of parties in left-right space
Authors: Drummond Andrew J.
Published: October 2010

When voters place parties in their system along the left-right dimension, they often pull their preferred party closer towards them (assimilation) and push the opposition further away (contrast). This article asks a simple question: are such assimilation and contrast effects similarly powerful across different types of electoral system? I hypothesize that systems employing single-member districts will tend to strengthen assimilation and contrast because they mechanically reduce the number of parties, while shifting the focus of electoral competition away from the party and towards the candidate. Using data from 18 advanced democracies compiled by the Comparative Study of Electoral Systems and hierarchical modelling I find that contrast effects are indeed stronger in majoritarian systems, while assimilation effects appear similarly strong regardless of the institutional setting. These findings suggest that institutional design holds lasting consequences for how we perceive politics and, perhaps also, for our ability to effectuate democracy.
Role-based access in a unified electronic patient record
Authors: Skilton Alysia , Alex Gray W. , Allam Omnia , Morrey Dave
Published: October 2010

As modern healthcare shifts towards a patient-centric model, there is an increasing emphasis on teamwork. Legacy healthcare information systems are ill equipped to meet new requirements arising from this change. Many projects have been undertaken to address various aspects of the challenge of supporting patient-centric work. In the UK, development and adoption of a unified electronic patient record (EPR) that serves practitioners across the country is a high priority. This article considers what additional support healthcare teams will require beyond the cross-discipline unified EPR. A system that considers practitioners as part of a patient’s care team and which tracks teams and professional roles is proposed and evaluated as a means to provide each practitioner with a view of the EPR appropriate to his/her professional role and to provide improved support for collaboration among team members.