bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of Road Traffic Injury Among Adult Motorcyclists in Malé, Maldives
Authors: Waseela Mariyam , Laosee Orapin
Published: June 2014

This study investigates the incidence of nonfatal road traffic injuries (RTIs) in Malé, the capital city of the Maldives, and identifies risk factors associated with RTIs. A cross-sectional descriptive study was conducted among young adult motorcyclists in 3 public areas. A total of 350 self-administered questionnaires were distributed to the motorcycle riders who visited the study areas between December 2012 and January 2013. The incidence of RTIs for the previous 12 months was 39.8% among the 294 respondents who returned a completed questionnaire. About half (49.6%) of those were caused by the riders. The majority of riders were male (96.6%). None of the motorcycle riders wore a helmet. RTIs had a significant association with sex, age, and attitude. Young riders were 1.6 times more likely to be involved in an RTI (adjusted odds ratio [AOR] = 1.67; 95% confidence interval [CI] = 0.94-2.95). Having a negative attitude about road safety was a risk factor of RTIs (AOR = 1.84; 95% CI = 1.11-3.03). Based on the results of the present study, it is important to promote safe riding attitudes in young riders.
Soy and Soy Products Intake, All-Cause Mortality, and Cause-Specific Mortality in Japan
Authors: Yamasaki Kyoko , Kayaba Kazunori , Ishikawa Shizukiyo
Published: June 2014

Soy and soy products are popular ingredients in the Japanese diet. This study aimed to determine whether soy or soy products intake was associated with all-cause mortality in a community-based cohort in Japan. A total of 11 066 participants were obtained from an annual community-based health examination program. A self-administered questionnaire was used to collect information concerning soy and soy products intake and potential confounding factors. Associations between soy and soy products intake and all-cause mortality were assessed using hazard ratios (HRs). After adjusting for all factors, morality was significantly higher in men with infrequent soy intake (HR = 1.53; 95% confidence interval [CI] = 1.13-2.07) and with almost daily intake (HR = 1.55; 95% CI = 1.19-2.03) compared with intake 1 to 2 times per week. Cancer mortality was higher among men who reported rarely eating soy (HR = 1.74; 95% CI = 1.08-2.79). Soy products intake was not statistically significantly associated with all-cause mortality in both sexes.
Pulmonary Endarterectomy
Authors: Banks Dalia A. , Pretorius Gert Victor D. , Kerr Kim M. , Manecke Gerard R.
Published: June 2014

Chronic thromboembolic pulmonary hypertension (CTEPH) results from recurrent or incomplete resolution of pulmonary embolism. CTEPH is much more common than generally appreciated. Although pulmonary embolism (PE) affects a large number of Americans, chronic pulmonary hypertension (PH) remains underdiagnosed. It is imperative that all patients with PH be screened for the presence of CTEPH since this form of PH is potentially curable with pulmonary thromboendarterectomy (PTE) surgery. The success of this procedure depends greatly on the collaboration of a multidisciplinary team approach that includes pulmonary medicine, cardiothoracic surgery, and cardiac anesthesiology. This review, based on the experience of more than 3000 pulmonary endarterectomy surgeries, is divided into 2 parts. Part I focuses on the clinical history and pathophysiology, diagnostic workup, and intraoperative echocardiography. Part II focuses on the surgical approach, anesthetic management, postoperative care, and complications.
US House Price Bubbles and Busts
Authors: Follain James R. , Giertz Seth H.
Published: June 2014

We use data for a large panel of US Metropolitan Statistical Areas (US MSAs) in order to assess the ex ante likelihood of house price bubbles. We employ a vector error correction–based model in order to project house prices under different scenarios. Projected house price (and employment) distributions are generated for each MSA. The model’s predictions are compared to actual outcomes—focusing primarily on the house price bubble and bust of the Great Recession. In applying these results to local governments, we document a substantial rise in property tax rates during the recent crisis. Results from this exercise suggest that interactions between the property tax and house price fluctuations may have exacerbated the bubble and bust. More generally, our analysis underscores the complexity of forecasting bubbles and cautions against attempting to do so using the notion of a national housing market. Even in recent years, housing markets are heavily influenced by local supply and demand conditions.
An Updated and Streamlined Technology Readiness Index
Authors: Parasuraman A. , Colby Charles L.
Published: June 2014

The Technology Readiness Index (TRI), a 36-item scale to measure people’s propensity to embrace and use cutting-edge technologies, was published in the Journal of Service Research over a decade ago. Researchers have since used it in a variety of contexts in over two dozen countries. Meanwhile, several revolutionary technologies (mobile commerce, social media, and cloud computing) that were in their infancy just a decade ago are now pervasive and significantly impacting people’s lives. Based on insights from extensive experience with the TRI and given the significant changes in the technology landscape, the authors undertook a two-phase research project to update and streamline the TRI. After providing a brief overview of technology readiness and the original TRI, this article (a) describes the multiple research stages and analyses that produced TRI 2.0, a 16-item scale; (b) compares TRI 2.0 with the original TRI in terms of content, structure, and psychometric properties; and (c) demonstrates TRI 2.0’s reliability, validity, and usefulness as a customer segmentation tool. The article concludes with potential applications of TRI 2.0 and directions for future research.
Supervision conversations about social justice and social work practice
Authors: Hair Heather J
Published: June 2014

In today’s environment dominated by managerialism and fiscal restraint, actualizing the principle of social justice has become a daunting task for social workers. Supervision has been identified as a promising site for enacting social justice, but evidence is lacking that supervision conversations support socially just practice. A concurrent mixed model nested research design was used to explore the needs of social workers for supervision conversations about social justice and practice. A mixed method web-survey on supervision was completed by 636 social workers from a broad spectrum of social work practice settings and geographical locations in Ontario, Canada. Quantitative data and written responses from open-ended questions are presented as an integrated narrative.

Findings

The results demonstrate that social worker participants shared a need for supervisors to promote and provide space for conversations about multiple aspects of social justice and practice. This need for a social justice focus had not been currently or recently experienced by a significant number of participants who worked in a variety of settings.

Applications

In response to the findings and their inferences, implications for supervision knowledge, practice and policy development are provided that could help social workers better actualize social justice in their day-to-day practice.
Parents as Teachers Health Literacy Demonstration Project
Authors: Carroll Lauren N. , Smith Sandra A. , Thomson Nicole R.
Published: June 2014

The Parents as Teachers (PAT) Health Literacy Demonstration project assessed the impact of integrating data-driven reflective practices into the PAT home visitation model to promote maternal health literacy. PAT is a federally approved Maternal, Infant, Early Childhood Home Visiting program with the goal of promoting school readiness and healthy child development. This 2-year demonstration project used an open-cohort longitudinal design to promote parents’ interactive and reflective skills, enhance health education, and provide direct assistance to personalize and act on information by integrating an empowerment paradigm into PAT’s parent education model. Eight parent educators used the Life Skills Progression instrument to tailor the intervention to each of 103 parent–child dyads. Repeated-measures analysis of variance, paired t tests, and logistic regression combined with qualitative data demonstrated that mothers achieved overall significant improvements in health literacy, and that home visitors are important catalysts for these improvements. These findings support the use of an empowerment model of health education, skill building, and direct information support to enable parents to better manage personal and child health and health care.
Melatonin and Melatonin Agonist for Delirium in the Elderly Patients
Authors: Chakraborti Dwaipayan , Tampi Deena J. , Tampi Rajesh R.
Published: June 2014

The objective of this review is to summarize the available data on the use of melatonin and melatonin agonist for the prevention and management of delirium in the elderly patients from randomized controlled trials (RCTs). A systematic search of 5 major databases PubMed, MEDLINE, PsychINFO, Embase, and Cochrane Library was conducted. This search yielded a total of 2 RCTs for melatonin. One study compared melatonin to midazolam, clonidine, and control groups for the prevention and management of delirium in individuals who were pre- and posthip post-hip arthroplasty. The other study compared melatonin to placebo for the prevention of delirium in older adults admitted to an inpatient internal medicine service. Data from these 2 studies indicate that melatonin may have some benefit in the prevention and management of delirium in older adults. However, there is no evidence that melatonin reduces the severity of delirium or has any effect on behaviors or functions in these individuals. Melatonin was well tolerated in these 2 studies. The search for a melatonin agonist for delirium in the elderly patients yielded 1 study of ramelteon. In this study, ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo. Ramelteon was well tolerated in this study.
JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo
Authors: Gallipoli Paolo , Cook Amy , Rhodes Susan , Hopcroft Lisa , Wheadon Helen , Whetton Anthony D. , Jørgensen Heather G. , Bhatia Ravi , Holyoake Tessa L.
Published: June 2014

Key Points

The JAK2/STAT5 pathway is a relevant therapeutic target in CML SPCs. Targeting the JAK2/STAT5 pathway by nilotinib and RUX in combination leads to enhanced eradication of primitive CML stem cells.
MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis
Authors: Rondelli Damiano , Goldberg Judith D. , Isola Luis , Price Leah S. , Shore Tsiporah B. , Boyer Michael , Bacigalupo Andrea , Rambaldi Alessandro , Scarano Marco , Klisovic Rebecca B. , Gupta Vikas , Andreasson Bjorn , Mascarenhas John , Wetzler Meir , Vannucchi Alessandro M. , Prchal Josef T. , Najfeld Vesna , Orazi Attilio , Weinberg Rona S. , Miller Crystal , Barosi Giovanni , Silverman Lewis R. , Prosperini Giuseppe , Marchioli Roberto , Hoffman Ronald
Published: June 2014

Key Points

A high survival rate was seen in primary or secondary MF patients transplanted from matched related donors using the FluMel regimen. FluMel plus ATG in HSCT from unrelated donors for MF patients is associated with an increased risk of graft failure.
Fuzzy technique for microcalcifications clustering in digital mammograms
Authors: Vivona Letizia , Cascio Donato , Fauci Francesco , Raso Giuseppe
Published: June 2014

Background

Mammography has established itself as the most efficient technique for the identification of the pathological breast lesions. Among the various types of lesions, microcalcifications are the most difficult to identify since they are quite small (0.1-1.0 mm) and often poorly contrasted against an images background. Within this context, the Computer Aided Detection (CAD) systems could turn out to be very useful in breast cancer control.

Methods

In this paper we present a potentially powerful microcalcifications cluster enhancement method applicable to digital mammograms. The segmentation phase employs a form filter, obtained from LoG filter, to overcome the dependence from target dimensions and to optimize the recognition efficiency. A clustering method, based on a Fuzzy C-means (FCM), has been developed. The described method, Fuzzy C-means with Features (FCM-WF), was tested on simulated clusters of microcalcifications, implying that the location of the cluster within the breast and the exact number of microcalcifications are known.

The proposed method has been also tested on a set of images from the mini-Mammographic database provided by Mammographic Image Analysis Society (MIAS) publicly available.

Results

The comparison between FCM-WF and standard FCM algorithms, applied on both databases, shows that the former produces better microcalcifications associations for clustering than the latter: with respect to the private and the public database we had a performance improvement of 10% and 5% with regard to the Merit Figure and a 22% and a 10% of reduction of false positives potentially identified in the images, both to the benefit of the FCM-WF. The method was also evaluated in terms of Sensitivity (93% and 82%), Accuracy (95% and 94%), FP/image (4% for both database) and Precision (62% and 65%).

Conclusions

Thanks to the private database and to the informations contained in it regarding every single microcalcification, we tested the developed clustering method with great accuracy. In particular we verified that 70% of the injected clusters of the private database remained unaffected if the reconstruction is performed with the FCM-WF. Testing the method on the MIAS databases allowed also to verify the segmentation properties of the algorithm, showing that 80% of pathological clusters remained unaffected.
Insulin alleviates the inflammatory response and oxidative stress injury in cerebral tissues in septic rats
Authors: Chen Qiyi , Yu Wenkui , Shi Jiangliang , Shen Juanhong , Gao Tao , Zhang Juanjuan , Xi Fengchan , Li Jieshou , Li Ning
Published: June 2014

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction that occurs secondary to infection in the body without overt central nervous system (CNS) infection. SAE is frequently encountered in critically ill patients in intensive care units and can be detected in up to 50–70% of septic patients. Previous studies have demonstrated that inflammatory cytokine release and oxidative stress injury are major pathophysiological mechanisms of SAE in critically ill patients. However, there are no effective strategies for the treatment of SAE. Insulin has important immunomodulatory effects and protective effects against oxidative stress injury in the peripheral organs of septic patients. However, very few studies of the possible effects of insulin in cerebral tissues of septic patients have been reported. Therefore, in this study, we aimed to explore whether insulin therapy can inhibit cytokine production (IL-1, IL-6, and TNF-a) and oxidative stress injury of the brain tissue in septic rats. We observed that the protein concentrations of IL-1, IL-6, and TNF-а, in addition to MDA and H2O2 were notably increased, inversely SOD, and GSH were sigificantly decreased in cortex, hippocampus, and hypothalamus of septic rats. Furthermore, the levels of S100 and NSE significantly increased. After 6 hours of insulin therapy, we found that the cytokine concentrations notably decreased and oxidative stress injuries in the cortex, hypothalamus, and hippocampus were alleviated in septic rats. In addition, the S100 and NSE levels significantly decreased. We concluded that insulin can inhibit the production of inflammatory cytokines and the oxidative stress response, thereby improving brain tissue damage.
Preventive effect of a high fluoride toothpaste and arginine-carbonate toothpaste on dentinal tubules exposure followed by acid challenge: a dentine permeability evaluation
Authors: Pinto Shelon Cristina Souza , Bandéca Matheus Coelho , Pinheiro Michele Carolina , Cavassim Rodrigo , Tonetto Mateus Rodrigues , Borges Alvaro Henrique , Sampaio José Eduardo Cezar
Published: June 2014

Background

Considering the current high use of high fluoride toothpastes, the aim of the study was to quantify alterations in the root dentine permeability submitted to treatment with a high fluoride toothpaste and 8% arginine, calcium carbonate, sodium monofluorophosphate toothpaste as a preventive treatment for dentinal tubules exposure followed by acid challenge.

Methods

Thirty-third molars were sectioned below the cementoenamel. The root segments were connected to a hydraulic pressure apparatus to measure dentine permeability after the following sequential steps (n = 10 per group): I) Baseline; II) treatment with phosphoric acid for 30 s (maximum permeability); III) Toothbrushing (1 min) according to the experimental groups (G1- control; G2- 5000 ppm fluoride toothpaste; G3- 8% arginine-calcium carbonate toothpaste); IV) acid challenge for 5 min (orange juice). The data were converted into percentage, considering stage II as 100%.

Results

The results have shown a statistically significant decreasing on dentine permeability after treatment with toothpaste (Friedman test and Dunn’s post hoc test). Comparison among groups demonstrated a high increasing on dentine permeability when acid challenge was performed after toothbrushing with distilled water (control group) (Kruskal-Wallis and Dunn’s post hoc test).

Conclusion

The toothpaste treatment may provide sufficient resistance on dentine surface, preventing dentinal tubules exposure after acid challenge.
Distribution of estrogenic steroids in municipal wastewater treatment plants in Tehran, Iran
Authors: Mohagheghian Azita , Nabizadeh Ramin , Mesdghinia Alireza , Rastkari Noushin , Mahvi Amir Hossein , Alimohammadi Mahmood , Yunesian Masoud , Ahmadkhaniha Reza , Nazmara Shahrokh
Published: June 2014

Background

Estrogenic steroids such as estrone (E1), 17β–estradiol (E2), estriol (E3), and 17α–ethinylestradiol (EE2) are among the most potent endocrine disrupting compounds (EDCs). Compared with North America, Europe and Japan there is no reliable information on the concentration of steroid hormones in wastewater treatment plants (WWTPs) influents and effluents in Iran. The aim of the present study was to determine the amounts of E1, E2, E3, and EE2 influents and effluents of 7 municipal WWTPs across Tehran, the capital city of Iran, in two seasons, summer and autumn, through solid-phase extraction (SPE) gas chromatography–mass spectrometry (GC–MS).

Results

The results showed that the concentrations of E1, E2, and EE2 in influents ranged from 6.54–18.76 ng/L, 1.02–8 ng/L and 4.18–11.76 ng/L, respectively. Also, the concentrations of E1, E2, and EE2 in effluents ranged from 1.04–4.99 ng/L, 0.5–2.20 ng/L and 0.5–2.58 ng/L, respectively. The levels of E3 were below the detection limit (0.5 ng/L). The percentage removal rate of E1, E2 and EE2 ranged between 61.76–87.25%, 50.98–82.63%, and 66.3–90.25%, respectively. Results indicated no significant correlation between hormone concentrations and seasons.

Conclusions

The study showed that WWTP number 7 had significant differences in influent hormone concentrations compared with others. Results only showed a significant relationship between hormones and TSS removal rate, but there was no significant relationship between hormones and COD removal rate. The removal rate of hormone in WWTP number 4 and 7 were significantly different from the others. There was no significant correlation between hormone concentrations and seasons.
Epigenetic engineering and the art of epigenetic manipulation
Authors: Magnani Luca
Published: June 2014

A report on the Epigenetic Engineering Meeting hosted by the Barts Institute of Cancer, held in London, UK, May 7, 2014
Changes of occlusal plane inclination after orthodontic treatment in different dentoskeletal frames
Authors: Li Jin-le , Kau Chung How , Wang Min
Published: June 2014

Background

The inclination of the occlusal plane (OP) is related to facial types and experiences physiological growth-related changes. The aims of this research were to determine if there were any differences in the inclination of OP in subjects with three types of skeletal malocclusion and to investigate the characteristics and differences of functional occlusal plane (FOP) compared to bisected occlusal plane (BOP).

Methods

A sample of 90 Caucasians patients was skeletal-classified into three (n = 30), and pre- and post-treatment cephalograms were digitized. Six linear and 8 angular cephalometric measurements were selected. The changes of OP inclination within each group and the differences among the three groups pre- and post-treatment were compared with paired t test and ANOVA test, respectively. The comparison and correlation between BOP and FOP were analyzed with paired t test and coefficient of correlation, respectively.

Results

The BOP angle increased in all of the three groups but only had statistically significant differences in skeletal class II patients in a mean of 1.51° (p < 0.05). The FOP-SN angle showed stability (p > 0.05) in all three groups. The inclination of FOP was closely related to that of BOP (p < 0.001) but revealed discrepancies in each group.

Conclusions

BOP and FOP were statistically significantly steeper in class II subjects compared to the other two groups both before and after treatment. The BOP angle statistically significantly increased by 1.51° in skeletal class II patients. BOP was a more reproducible reference plane compared to FOP during cephalometric tracing process, while FOP showed stability in orthodontically treated patients with all three skeletal patterns.
Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages
Authors: Geng Yanqiu , Zhang Li , Fu Bo , Zhang Jianrong , Hong Quan , Hu Jie , Li Diangeng , Luo Congjuan , Cui Shaoyuan , Zhu Fei , Chen Xiangmei
Published: June 2014

Introduction

The mortality of rhabdomyolysis-induced acute kidney injury (AKI) is still high, as there is no effective therapy. It has been shown that bone marrow-derived mesenchymal stem cells (MSCs) can induce M2 macrophages, which mediate MSC protection in other experimental inflammation-related organ injury. This study was designed to investigate the protective effects of macrophage activation in MSC therapy of rhabdomyolysis-induced AKI.

Methods

MSCs were injected into glycerol-induced rhabdomyolysis mice. Renal injury was evaluated using the serum creatinine, urea nitrogen, renal pathology and acute tubular necrosis score. The distribution of MSCs was detected using two-photon fluorescence confocal imaging. Immunofluorescence of anti-F4/80 and anti-CD206 was performed to determine macrophages and M2 macrophages in the tissues of the kidney, and M2 macrophage infiltration was also evaluated using western blotting analyses. After depletion of macrophages using clodronate liposomes at the phase of kidney repair, renal injury was re-evaluated. RAW 264.7 macrophages were incubated with lipopolysaccharide and co-cultured with MSCs and subsequently visualised using immunofluorescence staining and flow cytometry analysis. Finally, disparate phenotype macrophages, including normal macrophages (M0), lipopolysaccharide-stimulated macrophages (M1), and MSC-co-cultured macrophages (M2), were infused into mice with AKI, which were pre-treated with liposomal clodronate.

Results

In vivo infusion of MSCs protected AKI mice from renal function impairment and severe tubular injury, which was accompanied by a time-dependent increase in CD206-positive M2 macrophage infiltration. In addition, depleting macrophages with clodronate delayed restoration of AKI. In vitro, macrophages co-cultured with MSCs acquired an anti-inflammatory M2 phenotype, which was characterised by an increased expression of CD206 and the secretory cytokine interleukin (IL)-10. The concentrations of IL-10, IL-6 and tumor necrosis factor α were evaluated using enzyme-linked immunosorbent assay. Furthermore, macrophage-depleted mice with intramuscular injection of glycerol were subjected to a single injection of different types of RAW 264.7 macrophages. Mice infused with M0 and M1 macrophages suffered a more severe histological and functional injury, while mice transfused with MSC-educated M2 macrophages showed reduced kidney injury.

Conclusions

Our findings suggested that MSCs can ameliorate rhabdomyolysis-induced AKI via the activation of macrophages to a trophic M2 phenotype, which supports the transition from tubule injury to tubule repair.
Dexamethasone potentiates myeloid-derived suppressor cell function in prolonging allograft survival through nitric oxide
Authors: Liao Jiongbo , Wang Xiao , Bi Yujing , Shen Bo , Shao Kun , Yang Hui , Lu Yun , Zhang Zhengguo , Chen Xi , Liu Huanrong , Wang Jian , Chu Yiwei , Xue Lixiang , Wang Xianghui , Liu Guangwei
Published: June 2014

Whereas GCs have been demonstrated to be beneficial for transplantation patients, the pharmacological mechanisms remain unknown. Herein, the role of GR signaling was investigated via a pharmacological approach in a murine allogeneic skin transplantation model. The GC Dex, a representative GC, significantly relieved allograft rejection. In Dex-treated allograft recipient mice, CD11b+Gr1+ MDSCs prolonged graft survival and acted as functional suppressive immune modulators that resulted in fewer IFN-γ-producing Th1 cells and a greater number of IL-4-producing Th2 cells. In agreement, Dex-treated MDSCs promoted reciprocal differentiation between Th1 and Th2 in vivo. Importantly, the GR is required in the Dex-induced MDSC effects. The blocking of GR with RU486 significantly diminished the expression of CXCR2 and the recruitment of CD11b+Gr1+ MDSCs, thereby recovering the increased MDSC-suppressive activity induced by Dex. Mechanistically, Dex treatment induced MDSC iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated the MDSC-suppressive function and the effects on T cell differentiation. This study shows MDSCs to be an essential component in the prolongation of allograft survival following Dex or RU486 treatment, validating the GC–GR–NO signaling axis as a potential therapeutic target in transplantation.
Dose-Finding and Pharmacokinetic Study to Optimize the Dosing of Irinotecan According to the UGT1A1 Genotype of Patients With Cancer
Authors: Innocenti Federico , Schilsky Richard L. , Ramírez Jacqueline , Janisch Linda , Undevia Samir , House Larry K. , Das Soma , Wu Kehua , Turcich Michelle , Marsh Robert , Karrison Theodore , Maitland Michael L. , Salgia Ravi , Ratain Mark J.
Published: June 2014

Purpose

The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes.

Patients and Methods

Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1.

Results

In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r2 = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r2 = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response.

Conclusion

The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan.
Thermal limitation of performance and biogeography in a free-ranging ectotherm: insights from accelerometry
Authors: Ruan Gannon , Taylor Matthew D. , Suthers Iain M. , Gray Charles A. , van der Meulen Dylan E. , Smith James A. , Payne Nicholas L.
Published: June 2014

Theoretical and laboratory studies generally show ectotherm performance increases with temperature to an optimum, and subsequently declines. Several physiological mechanisms likely shape thermal performance curves, but responses of free-ranging animals to temperature variation will represent a compromise between these mechanisms and ecological constraints. Thermal performance data from wild animals balancing physiology and ecology is rare, and this represents a hindrance for predicting population impacts of future temperature change. We used internally-implanted accelerometers near the middle of a species' geographical distribution and gill-net catch data near the species' latitudinal extremes to quantify temperature-related activity levels of a wild predatory fish (Platycephalus fuscus). We examined our data in the context of established models of thermal performance, and the relationship between thermal performance thresholds and biogeography. Acceleration data approximated a thermal performance curve, with activity peaking at 23°C, but declining rapidly at higher temperatures. Gill-net catch data displayed a similar trend, with a temperature-associated increase and decrease in catch rates in temperate and tropical regions, respectively. Extrapolated estimates of zero activity (CTmin and CTmax) from the accelerometers were similar to the minimum and maximum mean monthly water temperatures experienced at the southern and northern (respectively) limits of the species distribution, consistent with performance-limited biogeography in this species. These data highlight the fundamental influence of temperature on ectotherm performance, and how thermal performance limits may shape biogeography. Biologging approaches are rarely used to examine thermal performance curves in free-ranging animals, but these may be central to understanding the trade-offs between physiology and ecology that constrain species' biogeographies and determine the susceptibility of ectotherms to future increases in temperature.
Aquaporin expression in the Japanese medaka (Oryzias latipes, Temminck & Schlegel) in FW and SW: challenging the paradigm for intestinal water transport?
Authors: Madsen Steffen S. , Bujak Joanna , Tipsmark Christian K.
Published: June 2014

We investigated the salinity dependent expression dynamics of 7 aquaporin paralogs (aqp1a, -3a, -7, -8ab, -10a, -10b and -11a) in several tissues of euryhaline Japanese medaka (Oryzias latipes). All paralogs except aqp7 and -10a had a broad tissue distribution and several were affected by salinity in both osmoregulatory and non-osmoregulatory tissues. In the intestine, aqp1a, -7, -8ab and -10a decreased upon seawater (SW)-acclimation, both when comparing long-term acclimated fish and during 1-3 days of the transition period (freshwater (FW)-to-SW and SW-to-FW). In the gill, aqp3a was lower and aqp10a higher in SW than in FW. In the kidney no aqps were affected by salinity. In the skin, aqp1a and -3a were lower in SW than in FW. In the liver aqp8ab and -10a were lower in SW than in FW. Further, 6 Na+,K+-ATPase α-subunit isoform transcripts were analyzed in the intestine but showed no consistent response to salinity, suggesting that water transport is not regulated at this level. In contrast, mRNA of the Na+,K+, 2Cl--cotransporter type-2 showed a strong increase in the intestine in SW compared to FW fish. Using custom made antibodies, we localized Aqp1a, -8ab and -10a proteins in the apical region of enterocytes of FW fish. Apical staining intensity strongly decreased, vanished or moved to sub apical regions, when fish were acclimated to SW, supporting the lower mRNA expression in SW. Western blots confirmed the decrease in Aqp1a and -10a protein in SW. The strong decrease in aquaporin expression in the intestine of SW fish is surprising and challenges the paradigm for transepithelial intestinal water absorption in SW fishes.
Adult somatic progenitor cells and hematopoiesis in oyster
Authors: Jemaà Mohamed , Morin Nathalie , Cavelier Patricia , Cau Julien , Strub Jean-Marc , Delsert Claude
Published: June 2014

Long-lived animals show a non-observable age-related decline in immune defense, which is provided by blood cells that derive from self-renewing stem cells. The oldest living animals are bivalves. Yet, the origin of hemocytes, the cells involved in innate immunity, is unknown in bivalves and current knowledge about mollusk adult somatic stem cells is scarce. Here we identify a population of adult somatic precursor cells and show their differentiation into hemocytes. Oyster gill contains an as yet unreported irregularly folded structure (IFS) with stem-like cells bathing into the hemolymph. BrdU labeling revealed that the stem-like cells in the gill epithelium and in the nearby hemolymph replicate DNA. Proliferation of this cell population was further evidenced by phosphorylated-histone H3 mitotic staining. Finally, these small cells most abundant in the IFS epithelium were found positive for the stemness marker Sox2. We provide evidence for hematopoiesis by showing that co-expression of Sox2 and Cu/Zn SOD, a hemocyte-specific enzyme, does not occur in the gill epithelial cells but rather in the underlying tissues and vessels. We further confirm the hematopoietic features of these cells by the detection of Filamin, a protein specific for a sub-population of hemocytes, in large BrdU-labeled cells bathing into gill vessels. Altogether, our data show that progenitor cells differentiate into hemocytes in gill, which suggests that hematopoiesis occurs in oyster gills.
Computational Mutation Design of Diol Dehydratase: Catalytic Ability toward Glycerol beyond the Wild-Type Enzyme
Authors: Doitomi Kazuki , Tanaka Hiromasa , Kamachi Takashi , Toraya Tetsuo , Yoshizawa Kazunari
Published: June 2014

A computational mutation analysis based on quantum mechanical/molecular mechanical (QM/MM) calculations is performed for the elucidation of catalytic functions of amino acid residues at the active site of diol dehydratase in the dehydration of glycerol to afford 3-hydroxypropionaldehyde. While the wild-type diol dehydratase is subject to suicide inactivation in the dehydration process, mutants Gln336Ala and Ser301Ala are more resistant to the inactivation by glycerol (Yamanishi et al., FEBS J.2012, 279, 793). In the present study the impact of the mutation is discussed on the basis of energy profiles of two reaction pathways for the dehydration of glycerol and the inactivation of the enzyme. Both the mutants efficiently distinguish between two possible binding conformations of glycerol, the GS and GR conformations, where the former is known to mainly contribute to the inactivation of the enzyme. The improved resistance to the inactivation observed for the mutants can be explained by a hydrogen-bonding interaction between an OH group of glycerol and Ser301 as well as steric repulsion between glycerol and Val300. The computational mutation analysis first unveils the vital role of Val300 in the discrimination of the GS and GR conformations, which was not clearly viewed in the wild-type enzyme. The present findings will encourage the application of computational mutation approach to the rational design of enzymes optimized for desired organic synthesis.
A pre-ribosomal RNA interaction network involving snoRNAs and the Rok1 helicase
Authors: Martin Roman , Hackert Philipp , Ruprecht Maike , Simm Stefan , Brüning Lukas , Mirus Oliver , Sloan Katherine E. , Kudla Grzegorz , Schleiff Enrico , Bohnsack Markus T.
Published: June 2014

Ribosome biogenesis in yeast requires 75 small nucleolar RNAs (snoRNAs) and a myriad of cofactors for processing, modification, and folding of the ribosomal RNAs (rRNAs). For the 19 RNA helicases implicated in ribosome synthesis, their sites of action and molecular functions have largely remained unknown. Here, we have used UV cross-linking and analysis of cDNA (CRAC) to reveal the pre-rRNA binding sites of the RNA helicase Rok1, which is involved in early small subunit biogenesis. Several contact sites were identified in the 18S rRNA sequence, which interestingly all cluster in the “foot” region of the small ribosomal subunit. These include a major binding site in the eukaryotic expansion segment ES6, where Rok1 is required for release of the snR30 snoRNA. Rok1 directly contacts snR30 and other snoRNAs required for pre-rRNA processing. Using cross-linking, ligation and sequencing of hybrids (CLASH) we identified several novel pre-rRNA base-pairing sites for the snoRNAs snR30, snR10, U3, and U14, which cluster in the expansion segments of the 18S rRNA. Our data suggest that these snoRNAs bridge interactions between the expansion segments, thereby forming an extensive interaction network that likely promotes pre-rRNA maturation and folding in early pre-ribosomal complexes and establishes long-range rRNA interactions during ribosome synthesis.
Additive effects of β-adrenergic and cytokine signaling on lipolytic activation
Authors: Card Nicholas , Garver William S. , Orlando Robert A.
Published: June 2014

Obesity often leads to increased systemic inflammation which is now thought to play a causative role in the development of atherosclerotic disease and insulin resistance.  This inflammatory response originates within large adipose tissue depots and is initiated by classically activated macrophages that infiltrate the tissue from the circulation.  The large number of macrophages residing in obese adipose tissue leads to significant increases in interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) secretion; achieving levels sufficient to elevate circulating plasma concentrations.  These cytokines activate potent signals to initiate lipolysis, to release free fatty acids from triacylglycerol stores and contribute to hyperlipidemia in obese individuals.  Obese adipose tissue responds to normal β-adrenergic and glucagon stimuli to recover from negative energy balance by inducing lipolysis.  However, it is not clear what quantitative influence additional lipolytic stimulation by IL-6 and TNFα has on normal β-adrenergic activity.  Although, β-adrenergic and cytokine signaling activate separate pathways for lipolytic activation, it is undefined whether the effects of multiple signaling events on lipolysis are additive or coincident.  To clarify this issue, we measured lipolytic activity in 3T3-L1-derived adipocytes stimulated by a β-adrenergic agonist (isoproterenol), IL-6 or TNFα individually and in combinations as co- and tri-stimulation.  Treatment of adipocytes with isoproterenol and either IL-6 or TNFα as co-stimulants increased lipolytic activation by approximately the sum of the individual ligands, suggesting contributions from two independent pathways.  Co-stimulation with IL-6 and TNFα provided slightly more than an additive response indicating signaling contributions from independent and common pathways.  Tri-stimulation resulted in the largest level of lipolytic activation with a value approximate to adding isoproterenol stimulation to a combined treatment of IL-6 and TNFα.  The additive nature of cytokine signaling to β-adrenergic activity suggests its therapeutic inhibition will prevent excessive lipolysis, yet minimally interfere with maintaining normal responses to varying energy demands.
Novel somatic single nucleotide variants within the RNA binding protein hnRNP A1 in multiple sclerosis patients
Authors: Lee Sangmin , Levin Michael
Published: June 2014

Some somatic single nucleotide variants (SNVs) are thought to be pathogenic, leading to neurological disease. We hypothesized that heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), an autoantigen associated with multiple sclerosis (MS) would contain SNVs. MS patients develop antibodies to hnRNP A1293-304, an epitope within the M9 domain (AA268-305) of hnRNP A1. M9 is hnRNP A1’s nucleocytoplasmic transport domain, which binds transportin-1 (TPNO-1) and allows for hnRNP A1’s transport into and out of the nucleus. Genomic DNA sequencing of M9 revealed nine novel SNVs that resulted in an amino acid substitution in MS patients that were not present in controls. SNVs occurred within the TPNO-1 binding domain (hnRNP A1268-289) and the MS IgG epitope (hnRNP A1293-304), within M9.  In contrast to the nuclear localization of wild type (WT) hnRNP A1, mutant hnRNP A1 mis-localized to the cytoplasm, co-localized with stress granules and caused cellular apoptosis. Whilst WT hnRNP A1 bound TPNO-1, mutant hnRNP A1 showed reduced TPNO-1 binding. These data suggest SNVs in hnRNP A1 might contribute to pathogenesis of MS.
The study of hypolipidemias properties of garlic, vegetable oils ( olive, flax and amaranth) and dietary fiber on the example of pectin, alginate and chitosan
Authors: Мухаммед  , Mukhammed A. , Максимов  , Maksimov M.
Published: June 2014

The atherosclerosis as the etiological basis of most cardiovascular diseases, is now recognized as the most common and socially significant pathology in the world. In addition to age, sex, diabetes, smoking, hypertension, the atherosclerosis nowadays is increasingly associated with lipid metabolism disorders such as dyslipidemia and hyperlipidemia. Among potential lipid-lowering drugs the traditional natural products have been rightfully occupying a special place. According to literature data, the use of natural preparations on the basis of garlic, vegetable oils (amaranth, flax and olive), and dietary fiber (pectin, alginate and chitosan) is relevant. In this study, the natural drugs used in rats with experimental hyperlipidemia, the results of use of garlic powder (300mg/kg) showed the most significant decrease of TG (-23.7%, -22.8%). The use of chitosan (300mg/kg) better lowered total choles-terol (-19,1%, 20, 8C%), amaranth oil (5ml/kg) significantly better lowered LDL (-14,3%, -15,0%) and increased HDL (+13,6%, +12,5%) at the significance level of p<0.05. The synergism is manifested when combined application of natural components and allows to enhancing the beneficial properties of each component, so the use of natural multicomponent complex on the basis of the most effective combinations of the studied objects is relevant. A comparative study of lipid-lowering properties of paired combinations of studied preparations on experimental hyperlipidemia models in rats allowed to revealing best lipid-lowering effect in combinations of garlic powder / amaranth oil (300mg/5ml) (KA = 0,98 ± 0,02, 1,11 ± 0,01); and chitosan / amaranth oil (300mg/5ml) (KA=1,01±0,03, 1,19±0,02) at p<0.05. Further study of lipid-lowering properties of complex garlic powder/ amaranth oil/ chitosan (300 mg/5ml/300mg) in experimental models hyperlipidemia rats was revealed significantly better lipid-lowering effect. The complex was significantly reduced levels of total cholesterol (-21,7%, -23,0%), TG (-20%, -20,9%), LDL (-16,5%, -16,0%) and increased levels of HDL (+12,3%, +12,6%) at the significance level of p<0.05.
Modern problems of morphological studying of the human cortex cytoarchitecture in norm and during ischemia
Authors: Мыцик  , Mytsik A. , Акулинин  , Akulinin V. , Сергеев  , Sergeev A. , Степанов  , Stepanov S.
Published: June 2014

Study of the human cortex morphology in norm and at the ischemia is due to the desire to identify common patterns and specific features of compensatory neural networks reorganization, seeking means of regulation of destructive and regenerative processes. The emergence of a large amount of information on the nervous tissue mor-phology is the need for increasing the accuracy of morphometric analysis. This requires an assessment of the overall methodological level of modern morphological studies of the human cortex. The authors analyzed the literature and their own data obtained from a morphological study of the human cortex. The main tendencies, current methodological issues and perspective directions of study the structural and functional state of neurons in norm and ischemia are presented. Great attention is paid to the immunohistochemical and morphometric methods of obtaining objective information. Currently there are methodological and methodical basis for further study of the human brain morphology. However, the total number of articles on the study of human brain morphology earned far less than the experimental works. For the fullest use of biopsy material is offered a comprehensive approach, including method of computer-aided analysis of images, immunohistochemistry, morphometry and statistical analysis.
The efficiency of correction conorary and heart failure by means of the ivabradine in the patients with coronary heart disease and low contractile function of the left ventricle needing surgical myocardial revascularization
Authors: Белов  , Belov V. , Ковалев  , Kovalev S. , Белова  , Belova E.
Published: June 2014

The study involved 24 patients with coronary heart disease (CHD) and chronic heart failure II-IV FC according to NYHA, also the systolic dysfunction of the left ventricle and sinus tachycardia needing surgical myocardial revascularization in EC conditions (extracorporeal circulation). All patients had II-IV functional class (FC) of CHF (chronic heart failure) according to NYHA (average 2,8±0,6). FC of effort angina was 2,6±0,4 (CCS). 92% of patients had a history of myocardial infarction and sinus rhythm. To correct CHF, coronary insufficiency and to prepare for CABG in EC conditions, the drug therapy by means of ACE-inhibitors of angiotensin-receptor blockers, beta- blockers, calcium channel blockers, diuretics, digoxin and aldosterone antagonists was carried out all patients. Average heart rate (HR) at rest was 98±6 per minute. To achieve further normal HR in the drug therapy was added the Ivabradine in the dose of 10-15 mg per day for 18-38 days prior to myocardial revascularization. The use of the Ivabradine in the dose of 13±1 mg per day allows to decrease FC of CHF and coronary insufficiency in the patients with low contractile ability of the myocardium and hemodynamically significant stenosis of coronary arteries and to achieve normal HR in 75 % of patients with good tolerability.