bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural insights into the membrane-extracted dimeric form of the ATPase TraB from the Escherichia coli pKM101 conjugation system
Authors: Durand Eric , Waksman Gabriel , Receveur-Brechot Veronique
Published: January 2011

Background

Type IV secretion (T4S) systems are involved in secretion of virulence factors such as toxins or transforming molecules, or bacterial conjugation. T4S systems are composed of 12 proteins named VirB1-B11 and VirD4. Among them, three ATPases are involved in the assembly of the T4S system and/or provide energy for substrate transfer, VirB4, VirB11 and VirD4. The X-ray crystal structures of VirB11 and VirD4 have already been solved but VirB4 has proven to be reluctant to any structural investigation so far.

Results

Here, we have used small-angle X-ray scattering to obtain the first structural models for the membrane-extracted, dimeric form of the TraB protein, the VirB4 homolog encoded by the E. coli pKM101 plasmid, and for the monomeric soluble form of the LvhB4 protein, the VirB4 homolog of the T4S system encoded by the Legionella pneumophila lvh operon. We have obtained the low resolution structures of the full-length TraB and of its N- and C-terminal halves. From these SAXS models, we derive the internal organisation of TraB. We also show that the two TraB N- and C-terminal domains are independently involved in the dimerisation of the full-length protein.

Conclusions

These models provide the first structural insights into the architecture of VirB4 proteins. In particular, our results highlight the modular arrangement and functional relevance of the dimeric-membrane-bound form of TraB.
Small dense LDL particles - a predictor of coronary artery disease evaluated by invasive and CT-based techniques: a case-control study
Authors: Toft-Petersen Anne P , Tilsted Hans H , Aarøe Jens , Rasmussen Klaus , Christensen Thorkil , Griffin Bruce A , Aardestrup Inge V , Andreasen Annette , Schmidt Erik B
Published: January 2011

Background

Coronary angiography is the current standard method to evaluate coronary atherosclerosis in patients with suspected angina pectoris, but non-invasive CT scanning of the coronaries are increasingly used for the same purpose.

Low-density lipoprotein (LDL) cholesterol and other lipid and lipoprotein variables are major risk factors for coronary artery disease. Small dense LDL particles may be of particular importance, but clinical studies evaluating their predictive value for coronary atherosclerosis are few.

Methods

We performed a study of 194 consecutive patients with chest pain, a priori considered of low to intermediate risk for significant coronary stenosis (>50% lumen obstruction) who were referred for elective coronary angiography. Plasma lipids and lipoproteins were measured including the subtype pattern of LDL particles, and all patients were examined by coronary CT scanning before coronary angiography.

Results

The proportion of small dense LDL was a strong univariate predictor of significant coronary artery stenosis evaluated by both methods. After adjustment for age, gender, smoking, and waist circumference only results obtained by traditional coronary angiography remained statistically significant.

Conclusion

Small dense LDL particles may add to risk stratification of patients with suspected angina pectoris.
Validity of gait parameters for hip flexor contracture in patients with cerebral palsy
Authors: Choi Sun Jong , Chung Chin Youb , Lee Kyoung Min , Kwon Dae Gyu , Lee Sang Hyeong , Park Moon Soek
Published: January 2011

Background

Psoas contracture is known to cause abnormal hip motion in patients with cerebral palsy. The authors investigated the clinical relevance of hip kinematic and kinetic parameters, and 3D modeled psoas length in terms of discriminant validty, convergent validity, and responsiveness.

Methods

Twenty-four patients with cerebral palsy (mean age 6.9 years) and 28 normal children (mean age 7.6 years) were included. Kinematic and kinetic data were obtained by three dimensional gait analysis, and psoas lengths were determined using a musculoskeletal modeling technique. Validity of the hip parameters were evaluated.

Results

In discriminant validity, maximum psoas length (effect size r = 0.740), maximum pelvic tilt (0.710), maximum hip flexion in late swing (0.728), maximum hip extension in stance (0.743), and hip flexor index (0.792) showed favorable discriminant ability between the normal controls and the patients. In convergent validity, maximum psoas length was not significantly correlated with maximum hip extension in stance in control group whereas it was correlated with maximum hip extension in stance (r = -0.933, p < 0.001) in the patients group. In responsiveness, maximum pelvic tilt (p = 0.008), maximum hip extension in stance (p = 0.001), maximum psoas length (p < 0.001), and hip flexor index (p < 0.001) showed significant improvement post-operatively.

Conclusions

Maximum pelvic tilt, maximum psoas length, hip flexor index, and maximum hip extension in stance were found to be clinically relevant parameters in evaluating hip flexor contracture.
Antigenic analysis of classical swine fever virus E2 glycoprotein using pig antibodies identifies residues contributing to antigenic variation of the vaccine C-strain and group 2 strains circulating in China
Authors: Chen Ning , Tong Chao , Li Dejiang , Wan Jing , Yuan Xuemei , Li Xiaoliang , Peng Jinrong , Fang Weihuan
Published: January 2011

Background

Glycoprotein E2, the immunodominant protein of classical swine fever virus (CSFV), can induce neutralizing antibodies and confer protective immunity in pigs. Our previous phylogenetic analysis showed that subgroup 2.1 viruses branched away from subgroup 1.1, the vaccine C-strain lineage, and became dominant in China. The E2 glycoproteins of CSFV C-strain and recent subgroup 2.1 field isolates are genetically different. However, it has not been clearly demonstrated how this diversity affects antigenicity of the protein.

Results

Antigenic variation of glycoprotein E2 was observed not only between CSFV vaccine C-strain and subgroup 2.1 strains, but also among strains of the same subgroup 2.1 as determined by ELISA-based binding assay using pig antisera to the C-strain and a representative subgroup 2.1 strain QZ-07 currently circulating in China. Antigenic incompatibility of E2 proteins markedly reduced neutralization efficiency against heterologous strains. Single amino acid substitutions of D705N, L709P, G713E, N723S, and S779A on C-strain recombinant E2 (rE2) proteins significantly increased heterologous binding to anti-QZ-07 serum, suggesting that these residues may be responsible for the antigenic variation between the C-strain and subgroup 2.1 strains. Notably, a G713E substitution caused the most dramatic enhancement of binding of the variant C-strain rE2 protein to anti-QZ-07 serum. Multiple sequence alignment revealed that the glutamic acid residue at this position is conserved within group 2 strains, while the glycine residue is invariant among the vaccine strains, highlighting the role of the residue at this position as a major determinant of antigenic variation of E2. A variant Simpson's index analysis showed that both codons and amino acids of the residues contributing to antigenic variation have undergone similar diversification.

Conclusions

These results demonstrate that CSFV vaccine C-strain and group 2 strains circulating in China differ in the antigenicity of their E2 glycoproteins. Systematic site-directed mutagenesis of the antigenic units has revealed residues that limit cross-reactivity. Our findings may be useful for the development of serological differential assays and improvement of immunogenicity of novel classical swine fever vaccines.
Dietary cholesterol, female gender and n-3 fatty acid deficiency are more important factors in the development of non-alcoholic fatty liver disease than the saturation index of the fat
Authors: Comhair Tine M , Garcia Caraballo Sonia C , Dejong Cornelis HC , Lamers Wouter H , Köhler S Eleonore
Published: January 2011

Background

The central feature of NAFLD is a disturbed fatty-acid metabolism with hepatic lipid accumulation. However, the factors that determine the severity of NAFLD, including the role of nutrition, gender, and plasma lipid levels, remain to be determined.

Methods

High-fat diets (42 en% fat), containing 0.2% cholesterol, were fed to male and female wild-type and hyperlipidemic APOE2ki C57BL/6J mice for three weeks. The fats were, in order of decreasing saturation, fractionated palm fat (fPF; ~95%), cocoa butter (CB; ~60%), olive oil (OO; ~15%), sunflower oil (SO; ~12%), and high-oleic-acid sunflower oil (hoSO; ~7%). Plasma and liver triglycerides (concentration and composition), liver inflammation (Ccl2, Cd68, Tnf-α mRNA), and infiltration of macrophages (Cd68, Cd11b immunohistochemistry) and neutrophils (Mpo) were quantified.

Results

Addition of cholesterol to a low-fat diet decreased plasma HDL and increased (V)LDL levels in APOE2ki mice. Plasma cholesterol levels in female, but not male APOE2ki mice correlated significantly with inflammation. Kupffer cells of inflamed livers were swollen. Wild-type mice refused the highly saturated fPF diet. The high-fat CB, OO, and SO diets induced hyperglycemia and a 2-fold increase in hepatic fat content in male, but not female wild-type mice (in females, hepatic fat content was similar to that in males fed a high-fat diet). All high-fat diets induced macrovesicular setatosis. APOE2ki mice were protected against high-fat diet-induced steatosis and hyperglycemia, except when fed a hoSO diet. This diet caused a 5-fold increase in liver triglyceride and mead-acid content, and an increased expression of lipogenic genes, suggesting a deficiency in poly-unsaturated fatty acids. Irrespective of the composition of the high-fat diet, oleic acid was the main triglyceride component of liver fat in wild-type and APOE2ki mouse livers. Liver inflammation was dependent on genotype (APOE2ki > wild type), gender (female > male), and cholesterol content (high > low) of the diet, but not on dietary fat composition.

Conclusions

Dietary cholesterol plays a determining, independent role in inflammation, especially in female mice. The fatty-acid saturation of the diet hardly affected hepatic steatosis or inflammation.
A living cell quartz crystal microbalance biosensor for continuous monitoring of cytotoxic responses of macrophages to single-walled carbon nanotubes
Authors: Wang Gang , Dewilde Abiche H , Zhang Jianping , Pal Anoop , Vashist Malavika , Bello Dhimiter , Marx Kenneth A , Braunhut Susan J , Therrien Joel M
Published: January 2011

Background

Numerous engineered nanomaterials (ENMs) exist and new ENMs are being developed. A challenge to nanotoxicology and environmental health and safety is evaluating toxicity of ENMs before they become widely utilized. Cellular assays remain the predominant test platform yet these methods are limited by using discrete time endpoints and reliance on organic dyes, vulnerable to interference from ENMs. Label-free, continuous, rapid response systems with biologically meaningful endpoints are needed. We have developed a device to detect and monitor in real time responses of living cells to ENMs. The device, a living cell quartz crystal microbalance biosensor (QCMB), uses macrophages adherent to a quartz crystal. The communal response of macrophages to treatments is monitored continuously as changes in crystal oscillation frequency (Δf). We report the ability of this QCMB to distinguish benign from toxic exposures and reveal unique kinetic information about cellular responses to varying doses of single-walled carbon nanotubes (SWCNTs).

Results

We analyzed macrophage responses to additions of Zymosan A, polystyrene beads (PBs) (benign substances) or SWCNT (3-150 μg/ml) in the QCMB over 18 hrs. In parallel, toxicity was monitored over 24/48 hrs using conventional viability assays and histological stains to detect apoptosis. In the QCMB, a stable unchanging oscillation frequency occurred when cells alone, Zymosan A alone, PBs alone or SWCNTs without cells at the highest dose alone were used. With living cells in the QCMB, when Zymosan A, PBs or SWCNTs were added, a significant decrease in frequency occurred from 1-6 hrs. For SWCNTs, this Δf was dose-dependent. From 6-18 hrs, benign substances or low dose SWCNT (3-30 μg/ml) treatments showed a reversal of the decrease of oscillation frequency, returning to or exceeding pre-treatment levels. Cell recovery was confirmed in conventional assays. The lag time to see the Δf reversal in QCMB plots was linearly SWCNT-dose dependent. Lastly, the frequency never reversed at high dose SWCNT (100-150 μg/ml), and apoptosis/necrosis was documented in conventional 24 and 48 hr-assays.

Conclusion

These data suggest that the new QCMB detects and provides unique information about peak, sub-lethal and toxic exposures of living cells to ENMs before they are detected using conventional cell assays.
Dutch randomized trial comparing standard catheter-directed thrombolysis versus Ultrasound-accElerated Thrombolysis for thromboembolic infrainguinal disease (DUET): design and rationale
Authors: Schrijver A Marjolein , Reijnen Michel MPJ , van Oostayen Jacques A , Nolthenius Rudolf PJ Tutein , van der Valk Pieter HM , Hoksbergen Arjan WJ , Lely Rutger J , Fioole Bram , Vroegindeweij Dammis , van Leersum Marc , de Vries Jean-Paul PM
Published: January 2011

Background

The use of thrombolytic therapy in the treatment of thrombosed infrainguinal native arteries and bypass grafts has increased over the years. Main limitation of this treatment modality, however, is the occurrence of bleeding complications. Low intensity ultrasound (US) has been shown to accelerate enzymatic thrombolysis, thereby reducing therapy time. So far, no randomized trials have investigated the application of US-accelerated thrombolysis in the treatment of thrombosed infra-inguinal native arteries or bypass grafts. The DUET study (Dutch randomized trial comparing standard catheter-directed thrombolysis versus Ultrasound-accElerated Thrombolysis for thrombo-embolic infrainguinal disease) is designed to assess whether US-accelerated thrombolysis will reduce therapy time significantly compared with standard catheter-directed thrombolysis.

Methods/design

Sixty adult patients with recently (between 1 and 7 weeks) thrombosed infrainguinal native arteries or bypass grafts with acute limb ischemia class I or IIa, according to the Rutherford classification for acute ischemia, will be randomly allocated to either standard thrombolysis (group A) or US-accelerated thrombolysis (group B). Patients will be recruited from 5 teaching hospitals in the Netherlands during a 2-year period. The primary endpoint is the duration of catheter-directed thrombolysis needed for uninterrupted flow in the thrombosed infrainguinal native artery or bypass graft, with outflow through at least 1 crural artery.

Discussion

The DUET study is a randomized controlled trial that will provide evidence of whether US-accelerated thrombolysis will significantly reduce therapy time in patients with recently thrombosed infrainguinal native arteries or bypass grafts, without an increase in complications.

Trial registration

Current Controlled Trials ISRCTN72676102
Sparsification of RNA structure prediction including pseudoknots
Authors: Möhl Mathias , Salari Raheleh , Will Sebastian , Backofen Rolf , Sahinalp S Cenk
Published: January 2011

Background

Although many RNA molecules contain pseudoknots, computational prediction of pseudoknotted RNA structure is still in its infancy due to high running time and space consumption implied by the dynamic programming formulations of the problem.

Results

In this paper, we introduce sparsification to significantly speedup the dynamic programming approaches for pseudoknotted RNA structure prediction, which also lower the space requirements. Although sparsification has been applied to a number of RNA-related structure prediction problems in the past few years, we provide the first application of sparsification to pseudoknotted RNA structure prediction specifically and to handling gapped fragments more generally - which has a much more complex recursive structure than other problems to which sparsification has been applied. We analyse how to sparsify four pseudoknot structure prediction algorithms, among those the most general method available (the Rivas-Eddy algorithm) and the fastest one (Reeder-Giegerich algorithm). In all algorithms the number of "candidate" substructures to be considered is reduced.

Conclusions

Our experimental results on the sparsified Reeder-Giegerich algorithm suggest a linear speedup over the unsparsified implementation.
Age Related Incidence and Early Outcomes of Hip Fractures: A Prospective Cohort Study of 1177 patients
Authors: Pillai Anand , Eranki Vivek , Shenoy Ravikiran , Hadidi Mahar
Published: January 2011

Introduction

Associated with the increase in the aging population, there is an increase in the incidence of hip fractures worldwide. Outcome following such fractures is affected by age of the patient. This study aims to assess the incidence and early outcome of hip fractures, comparing between different age groups.

Methods

Data of hip fractures collected over a period of five years was analysed. Patients were divided into three groups, group A (patients under the age of 64), group B (patients between 65 and 84 years of age), and group C (patients over the age of 85).

Results

Of the 1177 patients included in the study, there were 90 patients in group A, 702 patients in group B and 385 patients in group C. There was a female preponderance across all age groups, and this increased as age advanced (p < 0.0001). A significantly larger number of older patients lived alone and needed aids to walk before the injury (p < 0.0001). There was no significant difference in the type of fracture across the three groups (p = 0.13). A higher proportion of the elderly with intracapsular fractures were treated by replacement arthroplasty. Older patients who had internal fixation of intracapsular fractures had a better walking ability at 4 months. The overall deterioration in mobility was greater in older patients (p < 0.0001). Mortality was higher in older patients.

Conclusions

Hip fractures are more common among females irrespective of age group. Older patients have a higher mortality and a greater deterioration of walking ability after such injuries. Internal fixation of intracapsular fractures have demonstrated satisfactory early outcome in the immediate period. This could be attributed to retention of native bone, better propioception and shorter operation time.
Anti-proliferative effects of raw and steamed extracts of Panax notoginseng and its ginsenoside constituents on human liver cancer cells
Authors: Toh Ding-Fung , Patel Dhavalkumar Narendrabhai , Chan Eric Chun-Yong , Teo Alvin , Neo Soek-Ying , Koh Hwee-Ling
Published: January 2011

Background

Panax notoginseng is a potential source of anticancer compounds. This study aims to investigate the effects of steaming on the chemical profile of P. notoginseng and the anti-proliferative effects of P. notoginseng on liver cancer cells.

Methods

Samples of powdered raw P. notoginseng roots were steamed for various durations. Extracts of the raw and steamed samples were subjected to ultra-high pressure liquid chromatography/mass spectrometry (UHPLC-MS) analysis for chemical profiling. The anti-proliferative effects on three human liver cancer cells, namely SNU449, SNU182 and HepG2, were evaluated using colorimetric WST-1 assay.

Results

Steaming changed chromatographic and pharmacological profiles of P. notoginseng, causing differences in activities such as inhibition of cancer growth. Steamed P. notoginseng exhibited greater anti-proliferative effects against liver cancer cells (SNU449, SNU182 and HepG2) than its raw form; steaming up to 24 hours increased bioactivities. Steaming increased the concentrations of ginsenoside Rh2, Rk1, Rk3 and 20S-Rg3 and enhanced growth inhibition of liver cancer cells.

Conclusion

Steaming changes the chemical profile as well as anti-cancer biological activities of P. notoginseng. Steamed P. notoginseng contains potential compounds for the treatment of liver cancer.
Saponin accumulation in the seedling root of Panax notoginseng
Authors: Wang Dong , Zhu Hongtao , Chen Keke , Xu Min , Zhang Yingjun , Yang Chongren
Published: January 2011

Background

Panax notoginsengis an important Chinese medicinal plant. Dammarene-type triterpenoid saponins are main pharmacologically effective compounds inP. notoginseng. This study aims to investigate the formation and accumulation of saponins inP. notoginsengroots during germination and juvenile stage.

Methods

P. notoginsengseeds were collected and stored in wet sand. After germination, the seedlings were transplanted into a soil nursery bed and cultivated for one year. During this period, samples were collected every month and the concentrations of ginsengnosides Rg1, Re, Rb1, Rd and notoginsengnoside R1were determined by HPLC.

Results

There was little saponin in theP. notoginsengseed. The chemical composition of seed was different from that of root. After germination, Rb1, Rg1, Re, Rd and R1appeared successively in the seedling root. And in the five-month-old root, all these five main saponins came into existence. The accumulation of saponins inP. notoginsengroot was affected by seasons.

Conclusion

The accumulation of saponins showed a time-dependent increase after germination ofP. notoginseng.
Evaluation of the efficacy of radiation-modifying compounds using γH2AX as a molecular marker of DNA double-strand breaks
Authors: Mah Li-Jeen , Orlowski Christian , Ververis Katherine , Vasireddy Raja S , El-Osta Assam , Karagiannis Tom C
Published: January 2011

Radiation therapy is a widely used therapeutic approach for cancer. To improve the efficacy of radiotherapy there is an intense interest in combining this modality with two broad classes of compounds, radiosensitizers and radioprotectors. These either enhance tumour-killing efficacy or mitigate damage to surrounding non-malignant tissue, respectively. Radiation exposure often results in the formation of DNA double-strand breaks, which are marked by the induction of H2AX phosphorylation to generate γH2AX. In addition to its essential role in DDR signalling and coordination of double-strand break repair, the ability to visualize and quantitate γH2AX foci using immunofluorescence microscopy techniques enables it to be exploited as an indicator of therapeutic efficacy in a range of cell types and tissues. This review will explore the emerging applicability of γH2AX as a marker for monitoring the effectiveness of radiation-modifying compounds.
Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine?
Authors: Kumar Mia , Zhao Xuelian , Wang Xin Wei
Published: January 2011

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.
Long-term outcome in medical patients aged 80 or over following admission to an intensive care unit
Authors: Roch Antoine , Wiramus Sandrine , Pauly Vanessa , Forel Jean-Marie , Guervilly Christophe , Gainnier Marc , Papazian Laurent
Published: January 2011

Introduction

The aim of this study was to evaluate factors influencing short- and long-term survival in medical patients aged 80 and over following admission to an intensive care unit.

Methods

All patients aged 80 years or over and admitted between 2001 and 2006 were included in this study. Survival was evaluated between the time of admission and June 2009; factors associated with mortality were determined. Health-related quality of life was evaluated using Short Form (SF)-36 in long-term survivors.

Results

For the 299 patients included (mean age, 84 ± 4 y), hospital mortality was 55%. Factors independently associated with hospital mortality were a higher SAPS II score at ICU admission; the existence of a fatal disease as reflected by the McCabe score and a cardiac diagnosis at admission. In the 133 hospital survivors, median survival time was 710 days (95% CI, 499-921). Two-year mortality rates were 79% of the initial cohort and 53% of hospital survivors. The standardized ratio of mortality at 2 years after hospital discharge was 2.56 (95% CI, 2.08-3.12) when compared with age- and gender-adjusted mortality of the general population. Factors independently associated with mortality at 2 years after hospital discharge were SAPS II score at ICU admission and the McCabe score. Conversely, functional status prior to admission as assessed by Knaus or Karnofsky scores was not associated with long-term mortality. In long-term survivors, SF-36 physical function scores were poor but scores for pain, emotional well-being and social function were not much affected.

Conclusions

The severity of acute disease at admission influences mortality at the hospital and following discharge in patients aged 80 or over. Although up to 50% of patients discharged from the hospital were still alive at 2 years, mortality was increased when compared with the general population. Physical function of long-term hospital survivors was greatly altered.
Measurement of ventilation and cardiac related impedance changes with electrical impedance tomography
Authors: Grant Caroline A , Pham Trang , Hough Judith , Riedel Thomas , Stocker Christian , Schibler Andreas
Published: January 2011

Introduction

Electrical impedance tomography (EIT) has been shown to be able to distinguish both ventilation and perfusion. With adequate filtering the regional distributions of both ventilation and perfusion and their relationships could be analysed. Several methods of separation have been suggested previously, including breath holding, electrocardiograph (ECG) gating and frequency filtering. Many of these methods require interventions inappropriate in a clinical setting. This study therefore aims to extend a previously reported frequency filtering technique to a spontaneously breathing cohort and assess the regional distributions of ventilation and perfusion and their relationship.

Methods

Ten healthy adults were measured during a breath hold and while spontaneously breathing in supine, prone, left and right lateral positions. EIT data were analysed with and without filtering at the respiratory and heart rate. Profiles of ventilation, perfusion and ventilation/perfusion related impedance change were generated and regions of ventilation and pulmonary perfusion were identified and compared.

Results

Analysis of the filtration technique demonstrated its ability to separate the ventilation and cardiac related impedance signals without negative impact. It was, therefore, deemed suitable for use in this spontaneously breathing cohort.

Regional distributions of ventilation, perfusion and the combined ΔZV/ΔZQ were calculated along the gravity axis and anatomically in each position. Along the gravity axis, gravity dependence was seen only in the lateral positions in ventilation distribution, with the dependent lung being better ventilated regardless of position. This gravity dependence was not seen in perfusion.

When looking anatomically, differences were only apparent in the lateral positions. The lateral position ventilation distributions showed a difference in the left lung, with the right lung maintaining a similar distribution in both lateral positions. This is likely caused by more pronounced anatomical changes in the left lung when changing positions.

Conclusions

The modified filtration technique was demonstrated to be effective in separating the ventilation and perfusion signals in spontaneously breathing subjects. Gravity dependence was seen only in ventilation distribution in the left lung in lateral positions, suggesting gravity based shifts in anatomical structures. Gravity dependence was not seen in any perfusion distributions.
Preoperative Chemoradiotherapy Using Concurrent Capecitabine and Irinotecan in Magnetic Resonance Imaging–Defined Locally Advanced Rectal Cancer: Impact on Long-Term Clinical Outcomes
Authors: Gollins Simon , Sun Myint Arthur , Haylock Brian , Wise Marcus , Saunders Mark , Neupane Rekha , Essapen Sharadah , Samuel Les , Dougal Mark , Lloyd Arwel , Morris Jackie , Topham Clare , Susnerwala Shabbir
Published: January 2011

Purpose

To assess long-term clinical outcomes of preoperative chemoradiotherapy of magnetic resonance imaging (MRI)–defined locally advanced rectal adenocarcinoma using concurrent irinotecan and capecitabine.

Patients and Methods

One hundred ten patients without distant metastases entered this phase II trial North West/North Wales Clinical Oncology Group (NWCOG) -2 after MRI demonstration of tumor threatening (≤ 2 mm) or involving mesorectal fascia. Pelvic radiotherapy was given to 45 Gy in 25 fractions over 5 weeks with concurrent oral capecitabine at 650 mg/m2 twice per day continuously days 1 through 35 and intravenous irinotecan at 60 mg/m2 once weekly weeks 1 to 4. One hundred seven patients subsequently underwent surgical resection.

Results

Comparing prechemoradiotherapy MRI scans with histology of the resected specimen, 72 patients (67%) had their initial MRI T stage downstaged and 64 patients (80%) had their N stage downstaged. Twenty-four patients (22%) demonstrated a pathologic complete response (ypCR) and 98 patients (92%) demonstrated a negative circumferential resection margin (> 1 mm). Three-year local recurrence-free survival was 96.9%, metastasis-free survival (MFS) was 71.1%, disease-free survival was (DFS) 63.5%, and overall survival (OS) was 88.2%. By univariate analysis, lower histologic stage was significantly associated with superior MFS, DFS, and OS, whether expressed as ypT0-2 versus ypT3-4, ypN0 versus ypN1-2, or ypCR/microfoci (near-ypCR) versus other patients. By multivariate analysis both ypN stage (P = .048) and ypCR/microfoci/others (P = .013) remained significant predictors of DFS but only ypCR/microfoci/others for OS (P = .005) with no difference in outcome between ypCR compared to microfoci.

Conclusion

This regimen demonstrates high response rates and promising long-term survival. Downstaging to ypCR/microfoci may be a useful short-term surrogate for long-term survival but needs validation in large phase III trials powered for survival outcomes.
Future Directions in the Treatment of Neuroendocrine Tumors: Consensus Report of the National Cancer Institute Neuroendocrine Tumor Clinical Trials Planning Meeting
Authors: Kulke Matthew H. , Siu Lillian L. , Tepper Joel E. , Fisher George , Jaffe Deborah , Haller Daniel G. , Ellis Lee M. , Benedetti Jacqueline K. , Bergsland Emily K. , Hobday Timothy J. , Van Cutsem Eric , Pingpank James , Oberg Kjell , Cohen Steven J. , Posner Mitchell C. , Yao James C.
Published: January 2011

Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses.
Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas
Authors: Kopp Janel L. , Dubois Claire L. , Schaffer Ashleigh E. , Hao Ergeng , Shih Hung Ping , Seymour Philip A. , Ma Jenny , Sander Maike
Published: January 2011

One major unresolved question in the field of pancreas biology is whether ductal cells have the ability to generate insulin-producing β-cells. Conclusive examination of this question has been limited by the lack of appropriate tools to efficiently and specifically label ductal cells in vivo. We generated Sox9CreERT2 mice, which, during adulthood, allow for labeling of an average of 70% of pancreatic ductal cells, including terminal duct/centroacinar cells. Fate-mapping studies of the Sox9+ domain revealed endocrine and acinar cell neogenesis from Sox9+ cells throughout embryogenesis. Very small numbers of non-β endocrine cells continue to arise from Sox9+ cells in early postnatal life, but no endocrine or acinar cell neogenesis from Sox9+ cells occurs during adulthood. In the adult pancreas, pancreatic injury by partial duct ligation (PDL) has been suggested to induce β-cell regeneration from a transient Ngn3+ endocrine progenitor cell population. Here, we identify ductal cells as a cell of origin for PDL-induced Ngn3+ cells, but fail to observe β-cell neogenesis from duct-derived cells. Therefore, although PDL leads to activation of Ngn3 expression in ducts, PDL does not induce appropriate cues to allow for completion of the entire β-cell neogenesis program. In conclusion, although endocrine cells arise from the Sox9+ ductal domain throughout embryogenesis and the early postnatal period, Sox9+ ductal cells of the adult pancreas no longer give rise to endocrine cells under both normal conditions and in response to PDL.
Feedback regulation ofDrosophilaBMP signaling by the novel extracellular protein Larval Translucida
Authors: Szuperák Milán , Salah Sally , Meyer Emily J. , Nagarajan Usha , Ikmi Aissam , Gibson Matthew C.
Published: January 2011

The cellular response to the Drosophila BMP 2/4-like ligand Decapentaplegic (DPP) serves as one of the best-studied models for understanding the long-range control of tissue growth and pattern formation during animal development. Nevertheless, fundamental questions remain unanswered regarding extracellular regulation of the ligand itself, as well as the nature of the downstream transcriptional response to BMP pathway activation. Here, we report the identification of larval translucida (ltl), a novel target of BMP activity in Drosophila. Both gain- and loss-of-function analyses implicate LTL, a leucine-rich repeat protein, in the regulation of wing growth and vein patterning. At the molecular level, we demonstrate that LTL is a secreted protein that antagonizes BMP-dependent MAD phosphorylation, indicating that it regulates DPP/BMP signaling at or above the level of ligand-receptor interactions. Furthermore, based on genetic interactions with the DPP-binding protein Crossveinless 2 and biochemical interactions with the glypican Dally-like, we propose that LTL acts in the extracellular space where it completes a novel auto-regulatory loop that modulates BMP activity.
Noonan syndrome gain-of-function mutations inNRAScause zebrafish gastrulation defects
Authors: Runtuwene Vincent , van Eekelen Mark , Overvoorde John , Rehmann Holger , Yntema Helger G. , Nillesen Willy M. , van Haeringen Arie , van der Burgt Ineke , Burgering Boudewijn , Hertog Jeroen den
Published: January 2011

Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras–mitogen-activated-protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome.
Transition State in a Prevented Proton Transfer Observed in Real Time
Authors: Iwakura Izumi , Yabushita Atsushi , Kobayashi Takayoshi
Published: January 2011

Direct observation of the molecular structural change during chemical reactions including transition states is desirable to fully clarify the mechanism of chemical reactions. Time-dependent frequency variations in molecular vibration modes reflect structural change in transition states. Ultrafast changes in molecular structure during bond breaking and bond reformation can be clearly visualized using ultrafast spectroscopy. This study elucidated molecular structural information in states along the chemical reaction including transition state in the proton transfer of indigodisulfonate salt. The photoexcited proton transfer was found to follow a stepwise pathway. The monoalcohol intermediate generated by the proton transfer was found to return immediately to the original indigo without proton-transfer configuration. This back reaction of this is the reason for the ultra-photostability of indigo over extremely long exposure to light. This shows that real-time vibrational spectroscopy by a few femtosecond pulse laser enables the observation of dynamic behavior of molecular vibrations during chemical reactions, leading to the clarification of reaction mechanisms or the development of new chemical reactions.
Structures and Luminescence Properties of Cyclometalated Dinuclear Platinum(II) Complexes Bridged by Pyridinethiolate Ions
Authors: Aoki Rie , Kobayashi Atsushi , Chang Ho-Chol , Kato Masako
Published: January 2011

A series of cyclometalated dinuclear platinum(II) complexes bridged by pyridine-2-thiolate (pyt) ions, [Pt2(L)2(pyt)2] (HL = 2-(p-tolyl)pyridine (Hptpy), 2-(2-thienyl)pyridine (Hthpy), or benzo[h]quinoline (Hbzqn)), as well as their two-electron-oxidized dinuclear platinum(III) complexes, [Pt2Cl2(L)2(pyt)2], have been synthesized and characterized. The structures and luminescence properties have been investigated by comparing them with those of the corresponding 2-phenylpyridinato (ppy) complex. All divalent complexes have similar dinuclear frameworks, with short Pt···Pt distances (ca. 2.85 Å), and exhibit similar intense luminescence from the triplet metal–metal-to-ligand charge-transfer (3MMLCT) state in glassy solutions. However, they provide different luminescence features reflecting their dynamic behaviors in fluid solutions and their intermolecular interactions in the solid state. [Pt2(bzqn)2(pyt)2] containing fused aromatic rings exhibits the most sensitive features to the environment, i.e., it shows the most red-shifted luminescence spectrum in the solid state due to the intermolecular π–π interaction. However, in fluid solution, it provides very weak luminescence based on a rapid nonradiative deactivation mainly caused by the fluctuation of the intramolecular π–π repulsion between the ligands. [Pt2(ptpy)2(pyt)2], on the other hand, is the most stable luminophore, which always exhibits intense luminescence with an almost constant emission maximum independent of its temperature and state.
Measurements of Plasma Methoxytyramine, Normetanephrine, and Metanephrine as Discriminators of Different Hereditary Forms of Pheochromocytoma
Authors: Eisenhofer Graeme , Lenders Jacques WM , Timmers Henri , Mannelli Massimo , Grebe Stefan K , Hofbauer Lorenz C , Bornstein Stefan R , Tiebel Oliver , Adams Karen , Bratslavsky Gennady , Linehan W Marston , Pacak Karel
Published: January 2011

BACKGROUND

Pheochromocytomas are rare catecholamine-producing tumors derived in more than 30% of cases from mutations in 9 tumor-susceptibility genes identified to date, including von Hippel-Lindau tumor suppressor (VHL); succinate dehydrogenase complex, subunit B, iron sulfur (Ip) (SDHB); and succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD). Testing of multiple genes is often undertaken at considerable expense before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine, and methoxytyramine, the O-methylated metabolites of catecholamines, might help to distinguish different hereditary forms of the tumor.

METHODS

Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome, and 59 with mutations of SDHB or SDHD.

RESULTS

In contrast to patients with VHL, SDHB, and SDHD mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDHB and SDHD mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL, SDHB, and SDHD gene mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDHB and SDHD mutations from those with VHL mutations in an additional 78% of cases.

CONCLUSIONS

The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily used tool to guide cost-effective genotyping of underlying disease-causing mutations.
Myeloperoxidase Improves Risk Stratification in Patients with Ischemia and Normal Cardiac Troponin I Concentrations
Authors: Apple Fred S , Smith Stephen W , Pearce Lesly A , Schulz Karen M , Ler Ranka , Murakami MaryAnn M
Published: January 2011

BACKGROUND

We assessed the ability of myeloperoxidase (MPO) to identify the risk for major adverse cardiac events (MACE) in patients who present with ischemic symptoms suggestive of acute coronary syndrome and have a normal cardiac troponin I (cTnI) value.

METHODS

We used Siemens (n = 400) and Abbott (n = 350) assays to measure MPO and cTnI in plasma samples from 400 patients. Event rates (myocardial infarction, cardiac death, percutaneous coronary intervention, coronary artery bypass grafting) were estimated by the Kaplan–Meier method and compared with the log-rank statistic.

RESULTS

At the 30-day follow-up, the adjusted hazard ratios for MACE were 3.9 (P < 0.001) for increased cTnI and 2.7 (P = 0.006) for increased MPO for the Siemens assays and were 5.5 (P < 0.001) for increased cTnI and 2.9 (P = 0.001) for increased MPO for the Abbott assays. Similar findings were observed with 6 months of follow-up. Patients who initially had a normal cTnI value and an increased Siemens MPO value demonstrated a higher rate of MACE at 30 days than those in whom both values were normal (16.1% vs 3.6%, P = 0.002) and 6 months (18.1% vs 5.0%, P = 0.002). Similarly, patients who had an increased Abbott MPO result demonstrated a higher MACE rate at 30 days (12.3% vs 3.9%, P = 0.03) and at 6 months (16.2% vs 5.1%, P = 0.01) than those with normal values.

CONCLUSIONS

A combination of MPO and cTnI allowed the identification of a greater proportion of patients at risk for MACE than the use of cTnI alone. Increased MPO values remained predictive of future cardiac events even when the cTnI value was normal.
Überlegungen zum Adressaten von Eusebs Historia ecclesiastica
Authors: Verdoner Marie
Published: January 2011

In this essay, a prevailing confusion concerning the readership of Eusebius' Historia ecclesiastica is sought to be remedied by virtue of a literary reading of the Historia ecclesiastica as a unified whole. The approach taken does neither intend to find out who actually read the work nor who the intended readers were. Instead of that, the question of the implied readership is raised. It is contended that the Historia ecclesiastica is characterized by an immediate understanding between the reader and the narrator, and that the reader must possess a certain amount of knowledge of Christianity in order to profit from the work. Furthermore, it is shown that the implied reader must able to follow rather technical discussions concerning the genealogy of Christ or the delimitation of the New Testament canon. It follows that the reader should not be regarded as uneducated. While the predominant emic-perspective of the Historia ecclesiastica suggests that the implied readers should be understood as Christians, the apologetic introduction to the work might imply that adversaries of the Christian faith should also be counted among the implied readers. As regards to this problem, the stance of the essay is to regard the adversaries as a secondary audience. Furthermore, it is rejected that the implied readership should also consist of pagans and Jews sympathetic towards Christianity, as these groups are not offered any foothold in the work.