bluuebunny/crossref_metadata_2025 huggingface dataset:
Office and 24-hour heart rate and target organ damage in hypertensive patients
Authors: García-García Ángel , Gómez-Marcos Manuel A , Recio-Rodríguez José I , Patino-Alonso Maria C , Rodríguez-Sánchez Emiliano , Agudo-Conde Cristina , García-Ortiz Luis ,   the Vaso-risk group
Published: March 2012

Background

We investigated the association between heart rate and its variability with the parameters that assess vascular, renal and cardiac target organ damage.

Methods

A cross-sectional study was performed including a consecutive sample of 360 hypertensive patients without heart rate lowering drugs (aged 56 ± 11 years, 64.2% male). Heart rate (HR) and its standard deviation (HRV) in clinical and 24-hour ambulatory monitoring were evaluated. Renal damage was assessed by glomerular filtration rate and albumin/creatinine ratio; vascular damage by carotid intima-media thickness and ankle/brachial index; and cardiac damage by the Cornell voltage-duration product and left ventricular mass index.

Results

There was a positive correlation between ambulatory, but not clinical, heart rate and its standard deviation with glomerular filtration rate, and a negative correlation with carotid intima-media thickness, and night/day ratio of systolic and diastolic blood pressure. There was no correlation with albumin/creatinine ratio, ankle/brachial index, Cornell voltage-duration product or left ventricular mass index. In the multiple linear regression analysis, after adjusting for age, the association of glomerular filtration rate and intima-media thickness with ambulatory heart rate and its standard deviation was lost. According to the logistic regression analysis, the predictors of any target organ damage were age (OR = 1.034 and 1.033) and night/day systolic blood pressure ratio (OR = 1.425 and 1.512). Neither 24 HR nor 24 HRV reached statistical significance.

Conclusions

High ambulatory heart rate and its variability, but not clinical HR, are associated with decreased carotid intima-media thickness and a higher glomerular filtration rate, although this is lost after adjusting for age.

Trial Registration

ClinicalTrials.gov: NCT01325064
On summary measure analysis of linear trend repeated measures data: performance comparison with two competing methods
Authors: Vossoughi Mehrdad , Ayatollahi SMT , Towhidi Mina , Ketabchi Farzaneh
Published: March 2012

Background

The summary measure approach (SMA) is sometimes the only applicable tool for the analysis of repeated measurements in medical research, especially when the number of measurements is relatively large. This study aimed to describe techniques based on summary measures for the analysis of linear trend repeated measures data and then to compare performances of SMA, linear mixed model (LMM), and unstructured multivariate approach (UMA).

Methods

Practical guidelines based on the least squares regression slope and mean of response over time for each subject were provided to test time, group, and interaction effects. Through Monte Carlo simulation studies, the efficacy of SMA vs. LMM and traditional UMA, under different types of covariance structures, was illustrated. All the methods were also employed to analyze two real data examples.

Results

Based on the simulation and example results, it was found that the SMA completely dominated the traditional UMA and performed convincingly close to the best-fitting LMM in testing all the effects. However, the LMM was not often robust and led to non-sensible results when the covariance structure for errors was misspecified. The results emphasized discarding the UMA which often yielded extremely conservative inferences as to such data.

Conclusions

It was shown that summary measure is a simple, safe and powerful approach in which the loss of efficiency compared to the best-fitting LMM was generally negligible. The SMA is recommended as the first choice to reliably analyze the linear trend data with a moderate to large number of measurements and/or small to moderate sample sizes.
Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance
Authors: Heise Michael , Lautem Anja , Knapstein Johanna , Schattenberg Jörn M , Hoppe-Lotichius Maria , Foltys Daniel , Weiler Nina , Zimmermann Anca , Schad Arno , Gründemann Dirk , Otto Gerd , Galle Peter R , Schuchmann Marcus , Zimmermann Tim
Published: March 2012

Background

Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).

Methods

OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs.

Results

Real time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p ≤ 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression.

In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC.

Conclusion

The downregulation of OCT1 is associated with tumor progression and a worse patient survival.
Cytoplasmic BRMS1 expression in malignant melanoma is associated with increased disease-free survival
Authors: Slipicevic Ana , Holm Ruth , Emilsen Elisabeth , Ree Rosnes Anne Katrine , Welch Danny R , Mælandsmo Gunhild M , Flørenes Vivi Ann
Published: March 2012

Background/aims

Breast cancer metastasis suppressor 1 (BRMS1) blocks metastasis in melanoma xenografts; however, its usefulness as a biomarker in human melanomas has not been widely studied. The goal was to measure BRMS1 expression in benign nevi, primary and metastatic melanomas and evaluate its impact on disease progression and prognosis.

Methods

Paraffin-embedded tissue from 155 primary melanomas, 69 metastases and 15 nevi was examined for BRMS1 expression using immunohistochemistry. siRNA mediated BRMS1 down-regulation was used to study impact on invasion and migration in melanoma cell lines.

Results

A significantly higher percentage of nevi (87%), compared to primary melanomas (20%) and metastases (48%), expressed BRMS1 in the nucelus (p < 0.0001). Strong nuclear staining intensity was observed in 67% of nevi, and in 9% and 24% of the primary and metastatic melanomas, respectively (p < 0.0001). Comparable cytoplasmic expression was observed (nevi; 87%, primaries; 86%, metastases; 72%). However, a decline in cytoplasmic staining intensity was observed in metastases compared to nevi and primary tumors (26%, 47%, and 58%, respectively, p < 0.0001). Score index (percentage immunopositive celles multiplied with staining intensity) revealed that high cytoplasmic score index (≥ 4) was associated with thinner tumors (p = 0.04), lack of ulceration (p = 0.02) and increased disease-free survival (p = 0.036). When intensity and percentage BRMS1 positive cells were analyzed separately, intensity remained associated with tumor thickness (p = 0.024) and ulceration (p = 0.004) but was inversely associated with expression of proliferation markers (cyclin D3 (p = 0.008), cyclin A (p = 0.007), and p21Waf1/Cip1(p = 0.009)). Cytoplasmic score index was inversely associated with nuclear p-Akt (p = 0.013) and positively associated with cytoplasmic p-ERK1/2 expression (p = 0.033). Nuclear BRMS1 expression in ≥ 10% of primary melanoma cells was associated with thicker tumors (p = 0.016) and decreased relapse-free period (p = 0.043). Nuclear BRMS1 was associated with expression of fatty acid binding protein 7 (FABP7; p = 0.011), a marker of invasion in melanomas. In line with this, repression of BRMS1 expression reduced the ability of melanoma cells to migrate and invadein vitro.

Conclusion

Our data suggest that BRMS1 is localized in cytoplasm and nucleus of melanocytic cells and that cellular localization determines itsin vivoeffect. We hypothesize that cytoplasmic BRMS1 restricts melanoma progression while nuclear BRMS1 possibly promotes melanoma cell invasion.

Please see related article:http://www.biomedcentral.com/1741-7015/10/19
Assessment of utilization of provider-initiated HIV testing and counseling as an intervention for prevention of mother to child transmission of HIV and associated factors among pregnant women in Gondar town, North West Ethiopia
Authors: Malaju Marelign Tilahun , Alene Getu Degu
Published: March 2012

Background

Detection of maternal HIV infection early in pregnancy is critical for prevention of mother to child transmission of HIV/AIDS. Most efforts have focused on VCT as the primary means of encouraging people to become aware of their HIV status. However, its uptake is low in many parts of sub-Saharan Africa including Ethiopia. Provider-initiated HIV testing and counseling provides a critical opportunity to diagnose HIV infection, to begin chronic care, and to prevent mother to child transmission. However, little is known about its acceptance and associated factors among pregnant women in the country and particularly in the present study area.

Methods

Health institution based cross-sectional quantitative study was conducted in Gondar town from July 22-August 18, 2010. A total of 400 pregnant women were involved in the study using stratified sampling technique and multiple logistic regression analysis was employed using SPSS version 16.

Results

A total of 400 pregnant women actively participated in this study and 330 (82.5%) of them accepted provider-initiated HIV testing and counseling to be tested for HIV and 70(17.5%) of them refused. Acceptance of provider-initiated HIV testing and counseling was positively associated with greater number of antenatal care visits [Adj. OR (95%CI)=2.64(1.17, 5.95)], residing in the urban areas[Adj. OR (95%CI)=2.85(1.10, 7.41)], having comprehensive knowledge on HIV [Adj. OR (95%CI)=4.30(1.72, 10.73)], positive partners reaction for HIV positive result [Adj. OR (95%CI)=8.19(3.57, 18.80)] and having knowledge on prevention of mother to child transmission of HIV[Adj. OR (95%CI)=3.27(1.34, 7.94)], but negatively associated with increased maternal age and education level.

Conclusion

Utilization of provider-initiated HIV testing and counseling during antenatal care was relatively high among pregnant women in Gondar town. Couple counseling and HIV testing should be strengthened to promote provider-initiated HIV testing and counseling among male partners and to reduce HIV related violence of women from their partner and access to and consistent use of antenatal care should be improved to increase the uptake of provider-initiated HIV testing and counseling service.
Cardiovascular disease and air pollution in Scotland: no association or insufficient data and study design?
Authors: Willocks Lorna J , Bhaskar Abita , Ramsay Colin N , Lee Duncan , Brewster David H , Fischbacher Colin M , Chalmers James , Morris George , Scott E Marian
Published: March 2012

Background

Coronary heart disease and stroke are leading causes of mortality and ill health in Scotland, and clear associations have been found in previous studies between air pollution and cardiovascular disease. This study aimed to use routinely available data to examine whether there is any evidence of an association between short-term exposure to particulate matter (measured as PM10, particles less than 10 micrograms per cubic metre) and hospital admissions due to cardiovascular disease, in the two largest cities in Scotland during the years 2000 to 2006.

Methods

The study utilised an ecological time series design, and the analysis was based on overdispersed Poisson log-linear models.

Results

No consistent associations were found between PM10 concentrations and cardiovascular hospital admissions in either of the cities studied, as all of the estimated relative risks were close to one, and all but one of the associated 95% confidence intervals contained the null risk of one.

Conclusions

This study suggests that in small cities, where air quality is relatively good, then either PM10 concentrations have no effect on cardiovascular ill health, or that the routinely available data and the corresponding study design are not sufficient to detect an association.
High-dose fasudil preserves postconditioning against myocardial infarction under hyperglycemia in rats: role of mitochondrial KATP channels
Authors: Ichinomiya Taiga , Cho Sungsam , Higashijima Ushio , Matsumoto Shuhei , Maekawa Takuji , Sumikawa Koji
Published: March 2012

Background

The current study was carried out to determine whether fasudil hydrochloride (fasudil), a Rho-kinase inhibitor, has myocardial postconditioning (PostC) activity under hyperglycemia as well as normoglycemia, and if so, whether the effects could be mediated by mitochondrial ATP-sensitive potassium (m-KATP) channels.

Methods

Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. After opening the chest, all rats underwent 30-min coronary artery occlusion followed by 2-h reperfusion. The rats received low-dose (0.15 mg/kg) or high-dose (0.5 mg/kg) fasudil or diazoxide, an m-KATP channel opener, at 10 mg/kg, just before reperfusion under normoglycemic or hyperglycemic conditions. In another group, rats received 5-hydroxydecanoic acid (5HD), an m-KATP channel blocker, at 10 mg/kg, before high-dose fasudil. Myocardial infarct size was expressed as a percentage of area at risk (AAR).

Results

Under normoglycemia, low-dose and high-dose fasudil and diazoxide reduced myocardial infarct size (23 ± 8%, 21 ± 9% and 21 ± 10% of AAR, respectively) compared with that in the control (42 ± 7%). Under hyperglycemia, low-dose fasudil (40 ± 11%) and diazoxide (44 ± 14%) could not exert this beneficial effect, but high-dose fasudil reduced myocardial infarct size in the same manner as under normoglycemia (21 ± 13%). 5HD prevented fasudil-induced reduction of myocardial infarct size (42 ± 13%).

Conclusion

Fasudil induces PostC against myocardial infarction via activation of m-KATP channels in the rat. Although hyperglycemia attenuates the PostC, high-dose fasudil can restore cardioprotection.
Genetic polymorphism and natural selection of Duffy binding protein of Plasmodium vivax Myanmar isolates
Authors: Ju Hye-Lim , Kang Jung-Mi , Moon Sung-Ung , Kim Jung-Yeon , Lee Hyeong-Woo , Lin Khin , Sohn Woon-Mok , Lee Jin-Soo , Kim Tong-Soo , Na Byoung-Kuk
Published: March 2012

Background

Plasmodium vivax Duffy binding protein (PvDBP) plays an essential role in erythrocyte invasion and a potential asexual blood stage vaccine candidate antigen against P. vivax. The polymorphic nature of PvDBP, particularly amino terminal cysteine-rich region (PvDBPII), represents a major impediment to the successful design of a protective vaccine against vivax malaria. In this study, the genetic polymorphism and natural selection at PvDBPII among Myanmar P. vivax isolates were analysed.

Methods

Fifty-four P. vivax infected blood samples collected from patients in Myanmar were used. The region flanking PvDBPII was amplified by PCR, cloned into Escherichia coli, and sequenced. The polymorphic characters and natural selection of the region were analysed using the DnaSP and MEGA4 programs.

Results

Thirty-two point mutations (28 non-synonymous and four synonymous mutations) were identified in PvDBPII among the Myanmar P. vivax isolates. Sequence analyses revealed that 12 different PvDBPII haplotypes were identified in Myanmar P. vivax isolates and that the region has evolved under positive natural selection. High selective pressure preferentially acted on regions identified as B- and T-cell epitopes of PvDBPII. Recombination may also be played a role in the resulting genetic diversity of PvDBPII.

Conclusions

PvDBPII of Myanmar P. vivax isolates displays a high level of genetic polymorphism and is under selective pressure. Myanmar P. vivax isolates share distinct types of PvDBPII alleles that are different from those of other geographical areas. These results will be useful for understanding the nature of the P. vivax population in Myanmar and for development of PvDBPII-based vaccine.
Suppression of ribosomal protein synthesis and protein translation factors by Peg-interferon alpha/ribavirin in HCV patients blood mononuclear cells (PBMC)
Authors: Gupta Rahul , Kim Sun , Taylor Milton W
Published: March 2012

Background

We have previously reported the induction of many interferon stimulated genes (ISGs) in PBMC collected from patients infected with HCV at various times after initiation of interferon-ribavirin treatment using DNA microarrays to identify changes in gene expression with time. Almost as many genes are down regulated (suppressed) during interferon-ribavirin treatment as are up regulated.

Methods

DNA microarrays were analyzed by different software, including MAS5 (Affymetrix-Kegg) and GSEA (gene set enrichment analysis) to identify specific pathways both up regulated and down regulated. Data was assessed from a clinical trial, which was a microarray analysis from 68 patients.

Results

Up regulated genes included genes associated with NF-kb, toll like receptor cytokine -cytokine interaction, and complement and adhesion pathways. The most prominent pathway down regulated was that for ribosomal structural proteins, and eukaryotic translational factors. Down regulation of ribosomal protein genes continued through the treatment up to the last measurement, which was at day 28.

Conclusions

This suppression of the protein synthetic apparatus might explain the long-term side effects of interferon-ribavirin, and explain a non-specific effect of interferon-ribavirin on viral protein synthesis. There was no evidence for unique transcription factors or micro RNA involvement.
Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy
Authors: Lee Young-Ho , Choi Kyung Vin , Moon Jin Hwa , Jun Hyun-Joo , Kang Hye-Ryeong , Oh Se-In , Kim Hyung Sun , Um Jang Soo , Kim Mi Jung , Choi Yun Young , Lee Young-Jun , Kim Hee-Jin , Lee Jong-Hwa , Son Su Min , Choi Soo-Jin , Oh Wonil , Yang Yoon-Sun
Published: March 2012

Backgrounds

We conducted a pilot study of the infusion of intravenous autologous cord blood (CB) in children with cerebral palsy (CP) to assess the safety and feasibility of the procedure as well as its potential efficacy in countering neurological impairment.

Methods

Patients diagnosed with CP were enrolled in this study if their parents had elected to bank their CB at birth. Cryopreserved CB units were thawed and infused intravenously over 10~20 minutes. We assessed potential efficacy over 6 months by brain magnetic resonance imaging (MRI)-diffusion tensor imaging (DTI), brain perfusion single-photon emission computed tomography (SPECT), and various evaluation tools for motor and cognitive functions.

Results

Twenty patients received autologous CB infusion and were evaluated. The types of CP were as follows: 11 quadriplegics, 6 hemiplegics, and 3 diplegics. Infusion was generally well-tolerated, although 5 patients experienced temporary nausea, hemoglobinuria, or urticaria during intravenous infusion. Diverse neurological domains improved in 5 patients (25%) as assessed with developmental evaluation tools as well as by fractional anisotropy values in brain MRI-DTI. The neurologic improvement occurred significantly in patients with diplegia or hemiplegia rather than quadriplegia.

Conclusions

Autologous CB infusion is safe and feasible, and has yielded potential benefits in children with CP.
Throughput-optimal scheduling for cooperative relaying in wireless access networks
Authors: Pham Ngoc-Thai , Huynh Thong , Hwang Won-Joo
Published: March 2012

This article considers the cooperation between base station and relay stations to increase system throughput in time-slotted relaying wireless networks, such as dynamic time division multiple access systems. We focus on optimal throughput scheduling policies for the cooperative relaying at the network layer level. It is shown that the resulting policy for this cooperative protocol obtains the optimal throughput region. Random packet queueing at the relay stations may cause a packet-reordering effect, which may be an obstacle for real-time applications. We alter the design for throughput-optimal scheduling to remove this effect and guarantee a near optimal throughput region.
Imbalance of heterologous protein folding and disulfide bond formation rates yields runaway oxidative stress
Authors: Tyo Keith EJ , Liu Zihe , Petranovic Dina , Nielsen Jens
Published: March 2012

Background

The protein secretory pathway must process a wide assortment of native proteins for eukaryotic cells to function. As well, recombinant protein secretion is used extensively to produce many biologics and industrial enzymes. Therefore, secretory pathway dysfunction can be highly detrimental to the cell and can drastically inhibit product titers in biochemical production. Because the secretory pathway is a highly-integrated, multi-organelle system, dysfunction can happen at many levels and dissecting the root cause can be challenging. In this study, we apply a systems biology approach to analyze secretory pathway dysfunctions resulting from heterologous production of a small protein (insulin precursor) or a larger protein (α-amylase).

Results

HAC1-dependent and independent dysfunctions and cellular responses were apparent across multiple datasets. In particular, processes involving (a) degradation of protein/recycling amino acids, (b) overall transcription/translation repression, and (c) oxidative stress were broadly associated with secretory stress.

Conclusions

Apparent runaway oxidative stress due to radical production observed here and elsewhere can be explained by a futile cycle of disulfide formation and breaking that consumes reduced glutathione and produces reactive oxygen species. The futile cycle is dominating when protein folding rates are low relative to disulfide bond formation rates. While not strictly conclusive with the present data, this insight does provide a molecular interpretation to an, until now, largely empirical understanding of optimizing heterologous protein secretion. This molecular insight has direct implications on engineering a broad range of recombinant proteins for secretion and provides potential hypotheses for the root causes of several secretory-associated diseases.
Characterization and determination of holin protein of Streptococcus suis bacteriophage SMP in heterologous host
Authors: Shi Yibo , Yan Yaxian , Ji Wenhui , Du Bin , Meng Xiangpeng , Wang Hengan , Sun Jianhe
Published: March 2012

Background

Holins are a group of phage-encoded membrane proteins that control access of phage-encoded endolysins to the peptidoglycan, and thereby trigger the lysis process at a precise time point as the 'lysis clock'. SMP is an isolated and characterized Streptococcus suis lytic phage. The aims of this study were to determine the holin gene, HolSMP, in the genome of SMP, and characterized the function of holin, HolSMP, in phage infection.

Results

HolSMP was predicted to encode a small membrane protein with three hydrophobic transmembrane helices. During SMP infections, HolSMP was transcribed as a late gene and HolSMP accumulated harmlessly in the cell membrane before host cell lysis. Expression of HolSMP in Escherichia coli induced an increase in cytoplasmic membrane permeability, an inhibition of host cell growth and significant cell lysis in the presence of LySMP, the endolysin of phage SMP. HolSMP was prematurely triggered by the addition of energy poison to the medium. HolSMP complemented the defective λ S allele in a non-suppressing Escherichia coli strain to produce phage plaques.

Conclusions

Our results suggest that HolSMP is the holin protein of phage SMP and a two-step lysis system exists in SMP.
Kupffer cells ameliorate hepatic insulin resistance induced by high-fat diet rich in monounsaturated fatty acids: the evidence for the involvement of alternatively activated macrophages
Authors: Papackova Zuzana , Palenickova Eliska , Dankova Helena , Zdychova Jana , Skop Vojtech , Kazdova Ludmila , Cahova Monika
Published: March 2012

Background

Resident macrophages (Kupffer cells, KCs) in the liver can undergo both pro- or anti-inflammatory activation pathway and exert either beneficiary or detrimental effects on liver metabolism. Until now, their role in the metabolically dysfunctional state of steatosis remains enigmatic. Aim of our study was to characterize the role of KCs in relation to the onset of hepatic insulin resistance induced by a high-fat (HF) diet rich in monounsaturated fatty acids.

Methods

Male Wistar rats were fed either standard (SD) or high-fat (HF) diet for 4 weeks. Half of the animals were subjected to the acute GdCl3 treatment 24 and 72 hrs prior to the end of the experiment in order to induce the reduction of KCs population. We determined the effect of HF diet on activation status of liver macrophages and on the changes in hepatic insulin sensitivity and triacylglycerol metabolism imposed by acute KCs depletion by GdCl3.

Results

We found that a HF diet rich in MUFA itself triggers an alternative but not the classical activation program in KCs. In a steatotic, but not in normal liver, a reduction of the KCs population was associated with a decrease of alternative activation and with a shift towards the expression of pro-inflammatory activation markers, with the increased autophagy, elevated lysosomal lipolysis, increased formation of DAG, PKCε activation and marked exacerbation of HF diet-induced hepatic insulin resistance.

Conclusions

We propose that in the presence of a high MUFA content the population of alternatively activated resident liver macrophages may mediate beneficial effects on liver insulin sensitivity and alleviate the metabolic disturbances imposed by HF diet feeding and steatosis. Our data indicate that macrophage polarization towards an alternative state might be a useful strategy for treating type 2 diabetes.
IMRT for locally advanced anal cancer: clinical experience of the Montpellier Cancer Center
Authors: Vieillot Sabine , Fenoglietto Pascal , Lemanski Claire , Moscardo Carmen Llacer , Gourgou Sophie , Dubois Jean-Bernard , Aillères Norbert , Azria David
Published: March 2012

Purpose

To assess outcomes of patients with carcinoma of the anal canal (CAC) treated with intensity-modulated radiation therapy (IMRT).

Method and materials

From August 2007 to January 2011, seventy-two patients suffering from CAC were treated with IMRT. Concurrent chemotherapy was added in case of locally advanced tumors. Radiation course consisted in delivering an initial plan to the PTV1 defined as the primary tumor and the risk area including pelvic and inguinal nodes. Forty-five Gy in daily 1.8 Gy-daily fractions were delivered five days a week. A second plan of 14.4-20 Gy to the primary tumor (PTV2) was administered in 1.8-2 Gy-daily fractions, 5 days a week. We present here the results of dosimetry, toxicities, and clinical outcome of the first 39 patients with a median follow-up of 24 months.

Results

Thirty-one women and eight men were included in the present analysis. Tumors were classified as stages I, II, III and IV in 2, 7, 27 and 2 patients, respectively. Median age was 59 years (range, 38-85). Radiotherapy alone (RT) or combined with chemotherapy (RCT) were delivered in 6 (15%) and 33 (85%) patients, respectively.

Six patients (15%) required a treatment break ≥ 3 days, and median time for treatment break was 8 days (range, 3-14 days). Acute grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were seen in 10 and 5% of patients, respectively. Grade 4 toxicity was only hematologic and occurred in 12% patients receiving RCT. With a median follow-up of 24 months, no patient experienced any late grade 4 toxicity. The 2-year overall survival rate was 89%, the 2-year local relapse free survival was 77% and the 2-year colostomy-free survival rate was 85%.

Conclusion

IMRT is well tolerated with acceptable treatment interruption allowing dose escalation.
Neuregulin repellent signaling via ErbB4 restricts GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations
Authors: Li Hao , Chou Shen-Ju , Hamasaki Tadashi , Perez-Garcia Carlos G , O'Leary Dennis DM
Published: March 2012

Background

Cortical GABAergic interneurons (INs) are generated in the medial ganglionic eminence (MGE) and migrate tangentially into cortex. Because most, if not all, migrating MGE-derived INs express the neuregulin (NRG) receptor, ErbB4, we investigated influences of Nrg1 isoforms and Nrg3 on IN migration through ventral telencephalon (vTel) and within cortex.

Results

During IN migration, NRG expression domains and distributions of ErbB4-expressing, MGE-derived INs are complementary with minimal overlap, both in vTel and cortex. In wild-type mice, within fields of NRG expression, these INs are focused at positions of low or absent NRG expression. However, in ErbB4-/- HER4heart mutant mice in which INs lack ErbB4, these complementary patterns are degraded with considerable overlap evident between IN distribution and NRG expression domains. These findings suggest that NRGs are repellents for migrating ErbB4-expressing INs, a function supported by in vitro and in vivo experiments. First, in collagen co-cultures, MGE-derived cells preferentially migrate away from a source of secreted NRGs. Second, cells migrating from wild-type MGE explants on living forebrain slices from wild-type embryonic mice tend to avoid endogenous NRG expression domains, whereas this avoidance behavior is not exhibited by ErbB4-deficient cells migrating from MGE explants and instead they have a radial pattern with a more uniform distribution. Third, ectopic NRG expression in the IN migration pathway produced by in utero electroporation blocks IN migration and results in cortex distal to the blockade being largely devoid of INs. Finally, fewer INs reach cortex in ErbB4 mutants, indicating that NRG-ErbB4 signaling is required for directing IN migration from the MGE to cortex.

Conclusions

Our results show that NRGs act as repellents for migrating ErbB4-expressing, MGE-derived GABAergic INs and that the patterned expression of NRGs funnels INs as they migrate from the MGE to their cortical destinations.
Development of marker-free transgenic Jatrophaplants with increased levels of seed oleic acid
Authors: Qu Jing , Mao Hui-Zhu , Chen Wen , Gao Shi-Qiang , Bai Ya-Nan , Sun Yan-Wei , Geng Yun-Feng , Ye Jian
Published: March 2012

Background

Jatropha curcas is recognized as a new energy crop due to the presence of the high amount of oil in its seeds that can be converted into biodiesel. The quality and performance of the biodiesel depends on the chemical composition of the fatty acids present in the oil. The fatty acids profile of the oil has a direct impact on ignition quality, heat of combustion and oxidative stability. An ideal biodiesel composition should have more monounsaturated fatty acids and less polyunsaturated acids. Jatropha seed oil contains 30% to 50% polyunsaturated fatty acids (mainly linoleic acid) which negatively impacts the oxidative stability and causes high rate of nitrogen oxides emission.

Results

The enzyme 1-acyl-2-oleoyl-sn-glycero-3-phosphocholine delta 12-desaturase (FAD2) is the key enzyme responsible for the production of linoleic acid in plants. We identified three putative delta
12
fatty acid desaturase genes in Jatropha (JcFAD2s) through genome-wide analysis and downregulated the expression of one of these genes, JcFAD2-1, in a seed-specific manner by RNA interference technology. The resulting JcFAD2-1 RNA interference transgenic plants showed a dramatic increase of oleic acid (> 78%) and a corresponding reduction in polyunsaturated fatty acids (< 3%) in its seed oil. The control Jatropha had around 37% oleic acid and 41% polyunsaturated fatty acids. This indicates that FAD2-1 is the major enzyme responsible for converting oleic acid to linoleic acid in Jatropha. Due to the changes in the fatty acids profile, the oil of the JcFAD2-1 RNA interference seed was estimated to yield a cetane number as high as 60.2, which is similar to the required cetane number for conventional premium diesel fuels (60) in Europe. The presence of high seed oleic acid did not have a negative impact on other Jatropha agronomic traits based on our preliminary data of the original plants under greenhouse conditions. Further, we developed a marker-free system to generate the transgenic Jatropha that will help reduce public concerns for environmental issues surrounding genetically modified plants.

Conclusion

In this study we produced seed-specific JcFAD2-1 RNA interference transgenic Jatropha without a selectable marker. We successfully increased the proportion of oleic acid versus linoleic in Jatropha through genetic engineering, enhancing the quality of its oil.
Highly pathogenic avian influenza viruses inhibit effective immune responses of human blood-derived macrophages
Authors: Friesenhagen Judith , Boergeling Yvonne , Hrincius Eike , Ludwig Stephan , Roth Johannes , Viemann Dorothee
Published: March 2012

Human blood-derived macrophages are non-permissive for influenza virus propagation, and fail to elicit inflammatory and antiviral responses upon infection with high pathogenic avian influenza viruses.

Systemic infections with HPAIVs, such as H5N1, are characterized by cytokine burst and sepsis. We investigated the role of human monocyte-derived macrophages in these events after infection with different influenza virus strains. Macrophages were infected with low pathogenic H1N1 (PR8) or high pathogenic H7N7 (FPV) and H5N1 (KAN-1) subtypes. Macrophages were found to be nonpermissive for influenza virus propagation. Surprisingly, transcriptome analysis revealed an insufficient innate immune response of macrophages only to HPAIV infections. Induction of inflammatory cytokines, as well as type I IFNs, was significantly attenuated in H5N1- and H7N7-infected cells, contradicting a primary role of macrophages for the cytokine burst. Furthermore, inflammasome activation was impaired significantly in HPAIV-infected macrophages. Interestingly, this finding correlated with a complete suppression of viral protein M2 expression after HPAIV infection, which is known to be involved in influenza viral inflammasome activation. In summary, our data provide first evidences for a strategy of how HPAIVs avoid initial inflammatory responses of macrophages facilitating virus spreading and progression to the systemic stage of disease.
Extrapyramidal motor side-effects of first- and
second-generation antipsychotic drugs
Authors: Peluso Michael J. , Lewis Shôn W. , Barnes Thomas R. E. , Jones Peter B.
Published: March 2012

Background

Second-generation antipsychotics have been thought to cause fewer
extrapyramidal side-effects (EPS) than first-generation antipsychotics,
but recent pragmatic trials have indicated equivalence.

Aims

To determine whether second-generation antipsychotics had better outcomes
in terms of EPS than first-generation drugs.

Method

We conducted an intention-to-treat, secondary analysis of data from an
earlier randomised controlled trial (n = 227). A
clinically significant difference was defined as double or half the
symptoms in groups prescribed first- v.
second-generation antipsychotics, represented by odds ratios greater than
2.0 (indicating advantage for first-generation drugs) or less than 0.5
(indicating advantage for the newer drugs). We also examined EPS in terms
of symptoms emergent at 12 weeks and 52 weeks, and symptoms that had
resolved at these time points.

Results

At baseline those randomised to the first-generation antipsychotic group
(n = 118) had similar EPS to the second-generation
group (n = 109). Indications of resolved Parkinsonism
(OR = 0.5) and akathisia (OR = 0.4) and increased tardive dyskinesia (OR
= 2.2) in the second-generation drug group at 12 weeks were not
statistically significant and the effects were not present by 52 weeks.
Patients in the second-generation group were dramatically (30-fold) less
likely to be prescribed adjunctive anticholinergic medication, despite
equivalence in terms of EPS.

Conclusions

The expected improvement in EPS profiles for participants randomised to
second-generation drugs was not found; the prognosis over 1 year of those
in the first-generation arm was no worse in these terms. The place of
careful prescription of first-generation drugs in contemporary practice
remains to be defined, potentially improving clinical effectiveness and
avoiding life-shortening metabolic disturbances in some patients
currently treated with the narrow range of second-generation
antipsychotics used in routine practice. This has educational
implications because a generation of psychiatrists now has little or no
experience with first-generation antipsychotic prescription.
Research Resource: Whole-Genome Estrogen Receptor α Binding in Mouse Uterine Tissue Revealed by ChIP-Seq
Authors: Hewitt Sylvia C. , Li Leping , Grimm Sara A. , Chen Yu , Liu Liwen , Li Yin , Bushel Pierre R. , Fargo David , Korach Kenneth S.
Published: March 2012

To advance understanding of mechanisms leading to biological and transcriptional endpoints related to estrogen action in the mouse uterus, we have mapped ERα and RNA polymerase II (PolII) binding sites using chromatin immunoprecipitation followed by sequencing of enriched chromatin fragments. In the absence of hormone, 5184 ERα-binding sites were apparent in the vehicle-treated ovariectomized uterine chromatin, whereas 17,240 were seen 1 h after estradiol (E2) treatment, indicating that some sites are occupied by unliganded ERα, and that ERα binding is increased by E2. Approximately 15% of the uterine ERα-binding sites were adjacent to (<10 kb) annotated transcription start sites, and many sites are found within genes or are found more than 100 kb distal from mapped genes; however, the density (sites per base pair) of ERα-binding sites is significantly greater adjacent to promoters. An increase in quantity of sites but no significant positional differences were seen between vehicle and E2-treated samples in the overall locations of ERα-binding sites either distal from, adjacent to, or within genes. Analysis of the PolII data revealed the presence of poised promoter-proximal PolII on some highly up-regulated genes. Additionally, corecruitment of PolII and ERα to some distal enhancer regions was observed. A de novo motif analysis of sequences in the ERα-bound chromatin confirmed that estrogen response elements were significantly enriched. Interestingly, in areas of ERα binding without predicted estrogen response element motifs, homeodomain transcription factor-binding motifs were significantly enriched. The integration of the ERα- and PolII-binding sites from our uterine sequencing of enriched chromatin fragments data with transcriptional responses revealed in our uterine microarrays has the potential to greatly enhance our understanding of mechanisms governing estrogen response in uterine and other estrogen target tissues.
Axial patterning interactions in the sea urchin embryo: suppression of nodal by Wnt1 signaling
Authors: Wei Zheng , Range Ryan , Angerer Robert , Angerer Lynne
Published: March 2012

Wnt and Nodal signaling pathways are required for initial patterning of cell fates along anterior-posterior (AP) and dorsal-ventral (DV) axes, respectively, of sea urchin embryos during cleavage and early blastula stages. These mechanisms are connected because expression of nodal depends on early Wnt/β-catenin signaling. Here, we show that an important subsequent function of Wnt signaling is to control the shape of the nodal expression domain and maintain correct specification of different cell types along the axes of the embryo. In the absence of Wnt1, the posterior-ventral region of the embryo is severely altered during early gastrulation. Strikingly, at this time, nodal and its downstream target genes gsc and bra are expressed ectopically, extending posteriorly to the blastopore. They override the initial specification of posterior-ventral ectoderm and endoderm fates, eliminating the ventral contribution to the gut and displacing the ciliary band dorsally towards, and occasionally beyond, the blastopore. Consequently, in Wnt1 morphants, the blastopore is located at the border of the re-specified posterior-ventral oral ectoderm and by larval stages it is in the same plane near the stomodeum on the ventral side. In normal embryos, a Nodal-dependent process downregulates wnt1 expression in dorsal posterior cells during early gastrulation, focusing Wnt1 signaling to the posterior-ventral region where it suppresses nodal expression. These subsequent interactions between Wnt and Nodal signaling are thus mutually antagonistic, each limiting the range of the other’s activity, in order to maintain and stabilize the body plan initially established by those same signaling pathways in the early embryo.
Relationship between DNA-Transfection Efficiency and Chemical Structures of Aromatic Cationic Lipids
Authors: Mochizuki Shinichi , Kamikawa Yumi , Nishina Koichi , Fujii Shota , Hamada Emi , Kusuki Shota , Matsuo Takuma , Sakurai Kazuo
Published: March 2012

Gene therapy by introducing a foreign DNA into a cell with defective gene has been expected to treat various incurable diseases such as cancers, inherited diseases, and cardiovascular disease. Cationic lipids have been used as a carrier of therapeutic DNAs because they can form a complex with DNA and such a complex can be incorporated into cells and transport the bound DNA to cytosol. This complex is called lipoplex and categorized as a nonviral vector. We synthesized various kinds of cationic lipids with aromatic ring attached different hydrophilic groups, alkyl chain length and position of alkyl chains and evaluated their transfection efficiency. The lipids with primary amine and ethylenediamine-attached C12 at meta–meta position showed the highest transfection efficiencies, which reaches the same level as commercially available transfection reagent. The order of transfection efficiency in terms of alkyl chain length is follows: C12 C9 ≈ C18. The lipids with a primary amine showed better transfection efficiency than that with a quaternary ammonium salt. These results show that these cationic lipids with amine group attached aromatic structure can be used for novel transfection reagents.
Suppressive effects of PG201, an antiarthritic botanical formulation, on lipopolysaccharide-induced inflammatory mediators in Raw264.7 cells
Authors: Choi Jinyong , Kim Seon-Hee , Kim Sunyoung
Published: March 2012

PG201, an ethanol extract from a mixture of 12 herbs, has strong antiarthritic activity. To understand the molecular mechanisms underlying its anti-inflammatory effects, PG201-mediated suppression of inflammatory mediators was studied in Raw264.7, a mouse macrophage cell line. PG201 decreased the expression of interleukin (IL)-1 β, IL-6 and CC chemokine ligand-2, but not tumor necrosis factor- α, at the protein and mRNA levels in lipopolysaccharide-stimulated Raw264.7 cells. Results from a gel retardation assay indicated that PG201 substantially reduced the DNA-binding activity of the activator protein-1 and cyclic adenosine monophosphate-responsive element-binding protein transcription factors, but not nuclear factor- κB. Western blot and Northern blot analyses showed that PG201 reduced inducible nitric oxide synthase and cytosolic phospholipase A2(cPLA2) protein expression, but did not affect mRNA expression, ultimately resulting in decreased nitric oxide and prostaglandin E2. The protein expression of cPLA2was decreased by PG201 in the presence of cycloheximide, an inhibitor of translation, suggesting that PG201 may facilitate the degradation of cPLA2. Taken together, these results suggest that PG201 selectively affects the expression of proteins that play key roles in the inflammatory response at transcriptional and post-translational levels.
Effect of catch-up growth by various dietary patterns and resveratrol intervention on bone status
Authors: Chen Lu-Lu , Wang Su-Xing , Dai Yu , Buckoreelall Payal , Zhang Ping , Zhang Hao-Hao , Kong Wen
Published: March 2012

Catch-up growth (CUG) after food restriction can increase the risks for insulin resistance-related diseases, and to our knowledge, no previous studies have addressed how bone is influenced by CUG when refeeding diet content differs. The objective of this study was to investigate the bone status resulting from CUG induced by varying refeeding dietary patterns, and to assess the potential influencing factors and the effect of resveratrol on bone status during CUG. Experimental rats were randomly divided into five groups: normal chow (NC) group; CUG group (CUG, containing two subgroups, respectively, refeeding with normal chow or high-fat diet); high-fat diet (HF) group; and resveratrol intervention groups (CUGE and HFE). Bone parameters were detected by dual-energy X-ray absorptiometry. Serum concentrations of tumor necrosis factor (TNF)- α, body weight and food intake were also recorded. Our results showed that food restriction induced a significant decrease in bone parameters. Eight-week CUG by normal chow had a greater degree of improvement in bone mineral density than high-fat diet, and even returned to normal level similar to NC. Bone parameters were elevated in varying degrees in the HF group compared with the NC group. In the resveratrol intervention groups, bone parameters significantly increased. Furthermore, bone parameters were inversely related with serum TNF- α concentrations, but showed positive correlation with body weight. In conclusion, the study shows that CUG can partially reverse the deleterious effects of caloric restriction on bone health, especially in the refeeding with normal chow group. Moreover, resveratrol has a protective effect on bone status during the period of CUG. Serum TNF- α levels and body weight also seem to play an important role in regulating bone parameters.