bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myocardial impulse propagation is impaired in right ventricular tissue of Zucker Diabetic Fatty (ZDF) rats
Authors: Olsen Kristine Boisen , Axelsen Lene Nygaard , Braunstein Thomas Hartig , Sørensen Charlotte Mehlin , Andersen Claus B , Ploug Thorkil , Holstein-Rathlou Niels-Henrik , Nielsen Morten Schak 
Published: January 2013

Abstract

Background
Diabetes increases the risk of cardiovascular complications including arrhythmias, but the underlying mechanisms remain to be established. Decreased conduction velocity (CV), which is an independent risk factor for re-entry arrhythmias, is present in models with streptozotocin (STZ) induced type 1 diabetes. Whether CV is also disturbed in models of type 2 diabetes is currently unknown.

Methods
We used Zucker Diabetic Fatty (ZDF) rats, as a model of type 2 diabetes, and their lean controls Zucker Diabetic Lean (ZDL) rats to investigate CV and its response to the anti-arrhythmic peptide analogue AAP10. Gap junction remodeling was examined by immunofluorescence and western blotting. Cardiac histomorphometry was examined by Masson`s Trichrome staining and intracellular lipid accumulation was analyzed by Bodipy staining.

Results
CV was significantly slower in ZDF rats (56±1.9 cm/s) compared to non-diabetic controls (ZDL, 66±1.6 cm/s), but AAP10 did not affect CV in either group. The total amount of Connexin43 (C×43) was identical between ZDF and ZDL rats, but the amount of lateralized C×43 was significantly increased in ZDF rats (42±12 %) compared to ZDL rats (30±8%), p<0.04. Judged by electrophoretic mobility, C×43 phosphorylation was unchanged between ZDF and ZDL rats. Also, no differences in cardiomyocyte size or histomorphometry including fibrosis were observed between groups, but the volume of intracellular lipid droplets was 4.2 times higher in ZDF compared to ZDL rats (p<0.01).

Conclusion
CV is reduced in type 2 diabetic ZDF rats. The CV disturbance may be partly explained by increased lateralization of C×43, but other factors are likely also involved. Our data indicates that lipotoxicity potentially may play a role in development of conduction disturbances and arrhythmias in type 2 diabetes.
Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells
Authors: Smith Charlotte M , Haucke Volker , McCluskey Adam , Robinson Phillip J , Chircop Megan 
Published: January 2013

Abstract

Background
During metaphase clathrin stabilises the mitotic spindle kinetochore(K)-fibres. Many anti-mitotic compounds target microtubule dynamics. Pitstop 2™ is the first small molecule inhibitor of clathrin terminal domain and inhibits clathrin-mediated endocytosis. We investigated its effects on a second function for clathrin in mitosis.

Results
Pitstop 2 did not impair clathrin recruitment to the spindle but disrupted its function once stationed there. Pitstop 2 trapped HeLa cells in metaphase through loss of mitotic spindle integrity and activation of the spindle assembly checkpoint, phenocopying clathrin depletion and aurora A kinase inhibition.

Conclusions
Pitstop 2 is therefore a new tool for investigating clathrin spindle dynamics. Pitstop 2 reduced viability in dividing HeLa cells, without affecting dividing non-cancerous NIH3T3 cells, suggesting that clathrin is a possible novel anti-mitotic drug target.
Stromal protein degradation is incomplete in Arabidopsis thaliana autophagy mutants undergoing natural senescence
Authors: Lee Travis A , Vande Wetering Scott W , Brusslan Judy A 
Published: January 2013

Abstract

Background
Degradation of highly abundant stromal proteins plays an important role in the nitrogen economy of the plant during senescence. Lines of evidence supporting proteolysis within the chloroplast and outside the chloroplast have been reported. Two extra-plastidic degradation pathways, chlorophagy and Rubisco Containing Bodies, rely on cytoplasmic autophagy.

Results
In this work, levels of three stromal proteins (Rubisco large subunit, chloroplast glutamine synthetase and Rubisco activase) and one thylakoid protein (the major light harvesting complex protein of photosystem II) were measured during natural senescence in WT and in two autophagy T-DNA insertion mutants (atg5 and atg7). Thylakoid-localized protein decreased similarly in all genotypes, but stromal protein degradation was incomplete in the two atg mutants. In addition, degradation of two stromal proteins was observed in chloroplasts isolated from mid-senescence leaves.

Conclusions
These data suggest that autophagy does contribute to the complete proteolysis of stromal proteins, but does not play a major degenerative role. In addition, support for in organello degradation is provided.
Sodium selenite alters microtubule assembly and induces apoptosis in vitro and in vivo
Authors: Shi Kejian , Jiang Qian , Li Zhushi , Shan Lei , Li Feng , An JiaJia , Yang Yang , Xu Caimin 
Published: January 2013

Abstract

Background
Previous studies demonstrated that selenite induced cancer-cell apoptosis through multiple mechanisms; however, effects of selenite on microtubules in leukemic cells have not been demonstrated.

Methods
The toxic effect of selenite on leukemic HL60 cells was performed with cell counting kit 8. Selenite effects on cell cycle distribution and apoptosis induction were determined by flow cytometry. The contents of cyclin B1, Mcl-1, AIF, cytochrome C, insoluble and soluble tubulins were detected with western blotting. Microtubules were visualized with indirect immunofluorescence microscopy. The interaction between CDK1 and Mcl-1 was assessed with immunoprecipitation. Decreasing Mcl-1 and cyclin B1 expression were carried out through siRNA interference. The alterations of Mcl-1 and cyclin B1 in animal model were detected with either immunohistochemical staining or western blotting. In situ detection of apoptotic ratio was performed with TUNEL assay.

Results
Our current results showed that selenite inhibited the growth of HL60 cells and induced mitochondrial-related apoptosis. Furthermore, we found that microtubule assembly in HL60 cells was altered, those cells were arrested at G2/M phase, and Cyclin B1 was up-regulated and interacted with CDK1, which led to down-regulation of the anti-apoptotic protein Mcl-1. Finally, in vivo experiments confirmed the in vitro microtubule disruption effect and alterations in Cyclin B1 and Mcl-1 levels by selenite.

Conclusions
Taken together, the results from our study indicate that microtubules are novel targets of selenite in leukemic HL60 cells.
Determination of the role of calcium on instability of neurotoxic metabolite of ecstasy by HPTLC-mass
Authors: Jamali Bardia , Ardakani Yalda Hosseinzadeh , Rouini Mohammad-Reza , Foroumadi Alireza , Amidi Salimeh , Aghdam Vahid Hossein Zadeh , Kobarfard Farzad 
Published: January 2013

AbstractBackgroundEcstasy is one of the popular illicit drugs in the world and its usage has been recently increased in Iran. This compound can destroy the serotonergic neurons and produces cognitive and psychopathology diseases. 3,4-dihydroxymethamphetamine (HHMA) which is the main metabolite of this compound, seems to be responsible for this effect. However, no consensus has been reached among the researchers about its role. This disagreement between the researches may be due to failure in determination of HHMA as free form in physiological fluids. In this study, the stability of this crucial metabolite of ecstasy was examined in different mediums.MethodsThe stability of HHMA was studied in the perfusion medium and water at 100 and 10 ng/mL concentrations. Moreover, the effect of temperature (0–25°C), pH (3–10), calcium chloride (0–150 g/L) and ethylenediaminetetraacetic acid (EDTA) on the stability of HHMA was also examined.ResultsOur result suggested that the free form of HHMA could be degraded in the perfusion medium. The rate of this degradation has direct proportion to temperature (at 25°C = 0.037 min-1and at 0°C = 0.002 min-1). Calcium chloride and sodium bicarbonate are two responsible components in this instability. Moreover, the alkaline pHs and increasing the shaking time can accelerate this effect. Although, while degradation was prevented at pH=3, EDTA could only reduce this rate about 30%.ConclusionsCalcium cation can act as an accelerator of HHMA degradation. Therefore, the perfusion medium should not contain Ca2+and the pH of medium is better to be adjusted at acidic range. Since, the internal cellular source of calcium is endoplasmic reticulum system, it can be assumed that, this cation may change HHMA and dopamine to reactive compounds that can bind covalently to the cysteinyl group of biological compounds and damage cellular components.
Scoring radiographic progression in ankylosing spondylitis: should we use the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) or the Radiographic Ankylosing Spondylitis Spinal Score (RASSS)?
Authors: Ramiro Sofia , van Tubergen Astrid , Stolwijk Carmen , Landewé Robert , van de Bosch Filip , Dougados Maxime , van der Heijde Désirée 
Published: January 2013

Abstract
Introduction
Radiographic damage is one of the core outcomes in axial SpA and is usually assessed with the modified Stoke Ankylosing Spondylitis (AS) Spine Score (mSASSS). Alternatively, the Radiographic AS Spinal Score (RASSS) is proposed, which includes the lower thoracic vertebrae, under the hypothesis that most progression occurs in these segments. We aimed to compare the mSASSS and RASSS with regard to performance.

Methods
Two-yearly spinal radiographs from patients followed in the Outcome in AS International Study (OASIS) were used (scored independently by two readers). A total of 195 patients had at least one radiograph (12-year follow-up) to be included. We assessed the accessibility of vertebral corners (VCs) for scoring, as well as status and 2-year progression scores of both scoring methods. To assess the potential additional value of including the thoracic segment in the score, the relative contribution (in %) to the 2-year total RASSS progression of each spinal segment (cervical, thoracic and lumbar) was determined, and compared to the expected contribution, under the assumption that a balanced segmental progression would occur, proportional to the number of sites per segment.

Results
The mSASSS could be scored in a total of 809 radiographs and the RASSS in 78% of these. In 58% of the latter, the score was based on one to two available thoracic VCs scores, and the remaining two to three were imputed because they were missing. There were 520 two-year mSASSS intervals available, and in 63% of them RASSS progression could be assessed. The mean (SD) 2-year interval progression score (330 intervals) was 2.0 (3.6) for the mSASSS and 2.4 (4.4) for the RASSS, yielding a similar effect size (mSASSS 0.57 and RASSS 0.55). Exclusive progression of the thoracic segment occurred in only 5% of the cases. There was no significant difference between the observed (14%) and expected (16%) contribution to progression of the thoracic segment (P = 0.70).

Conclusions
The determination of RASSS for radiographic damage of the spine is frequently impossible or strongly influenced by non-contributory imputation. In comparison to the mSASSS, the contribution of thoracic VCs in the RASSS method is negligible, and does not justify the additional scoring efforts.
The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial
Authors: Wu Jianfeng , Zhou Lixin , Liu Jiyun , Ma Gang , Kou Qiuye , He Zhijie , Chen Juan , Ou-Yang Bin , Chen Minying , Li Yinan , Wu Xiaoqin , Gu Baochun , Chen Lei , Zou Zijun , Qiang Xinhua , Chen Yuanyuan , Lin Aihua , Zhang Guanrong , Guan Xiangdong 
Published: January 2013

Abstract
Introduction
Severe sepsis is associated with a high mortality rate despite implementation of guideline recommendations. Adjunctive treatment may be efficient and require further investigation. In light of the crucial role of immunologic derangement in severe sepsis, thymosin alpha 1 (Tα1) is considered as a promising beneficial immunomodulatory drug. The trial is to evaluate whether Tα1 improves 28-day all-cause mortality rates and immunofunction in patients with severe sepsis.

Methods
We performed a multicenter randomized controlled trial in six tertiary, teaching hospitals in China between May 12, 2008 and Dec 22, 2010. Eligible patients admitted in ICU with severe sepsis were randomly allocated by a central randomization center to the control group or Tα1 group (1:1 ratio). The primary outcome was death from any cause and was assessed 28 days after enrollment. Secondary outcomes included dynamic changes of Sequential Organ Failure Assessment (SOFA) and monocyte human leukocyte antigen-DR (mHLA-DR) on day 0, 3, 7 in both groups. All analyses were done on an intention-to-treat basis.

Results
A total of 361 patients were allocated to either the control group (n = 180) or Tα1 (n = 181) group. The mortalities from any cause within 28 days in the Tα1 group and control group were 26.0% and 35.0% respectively with a marginal P value (nonstratified analysis, P = 0.062; log rank, P = 0.049); the relative risk of death in the Tα1 group as compared to the control group was 0.74 (95% CI 0.54 to 1.02). Greater improvement of mHLA-DR was observed in the Tα1 group on day 3 (mean difference in mHLA-DR changes between the two groups was 3.9%, 95% CI 0.2 to 7.6%, P = 0.037) and day 7 (mean difference in mHLA-DR changes between the two groups was 5.8%, 95% CI 1.0 to 10.5%, P = 0.017) than in the control group. No serious drug-related adverse event was recorded.

Conclusions
The use of Tα1 therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis.

Trial registration
ClinicalTrials.gov NCT00711620.
Haloperidol prophylaxis in critically ill patients with a high risk for delirium
Authors: van den Boogaard Mark , Schoonhoven Lisette , van Achterberg Theo , van der Hoeven Johannes G , Pickkers Peter 
Published: January 2013

Abstract
Introduction
Delirium is associated with increased morbidity and mortality. We implemented a delirium prevention policy in intensive care unit (ICU) patients with a high risk of developing delirium, and evaluated if our policy resulted in quality improvement of relevant delirium outcome measures.

Methods
This study was a before/after evaluation of a delirium prevention project using prophylactic treatment with haloperidol. Patients with a predicted risk for delirium of ≥ 50%, or with a history of alcohol abuse or dementia, were identified. According to the prevention protocol these patients received haloperidol 1 mg/8 h. Evaluation was primarily focused on delirium incidence, delirium free days without coma and 28-day mortality. Results of prophylactic treatment were compared with a historical control group and a contemporary group that did not receive haloperidol prophylaxis mainly due to non-compliance to the protocol mostly during the implementation phase.

Results
In 12 months, 177 patients received haloperidol prophylaxis. Except for sepsis, patient characteristics were comparable between the prevention and the historical (n = 299) groups. Predicted chance to develop delirium was 75 ± 19% and 73 ± 22%, respectively. Haloperidol prophylaxis resulted in a lower delirium incidence (65% vs. 75%, P = 0.01), and more delirium-free-days (median 20 days (IQR 8 to 27) vs. median 13 days (3 to 27), P = 0.003) in the intervention group compared to the control group. Cox-regression analysis adjusted for sepsis showed a hazard rate of 0.80 (95% confidence interval 0.66 to 0.98) for 28-day mortality. Beneficial effects of haloperidol appeared most pronounced in the patients with the highest risk for delirium. Furthermore, haloperidol prophylaxis resulted in less ICU re-admissions (11% vs. 18%, P = 0.03) and unplanned removal of tubes/lines (12% vs. 19%, P = 0.02). Haloperidol was stopped in 12 patients because of QTc-time prolongation (n = 9), renal failure (n = 1) or suspected neurological side-effects (n = 2). No other side-effects were reported. Patients who were not treated during the intervention period (n = 59) showed similar results compared to the untreated historical control group.

Conclusions
Our evaluation study suggests that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects. These results warrant confirmation in a randomized controlled trial.

Trial registration
clinicaltrial.gov Identifier: NCT01187667.
Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis
Authors: Ware Lorraine B , Magarik Jordan A , Wickersham Nancy , Cunningham Gary , Rice Todd W , Christman Brian W , Wheeler Arthur P , Bernard Gordon R , Summar Marshall L 
Published: January 2013

Abstract
Introduction
The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis.

Methods
Plasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions.

Results
Plasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness.

Conclusions
In severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function.
Role of kinin B2 receptors in opioid-induced hyperalgesia in inflammatory pain in mice
Authors: Grastilleur Sébastien , Mouledous Lionel , Bedel Jerome , Etcheverry Jonathan , Bader Michael , Girolami Jean-Pierre , Fourcade Olivier , Frances Bernard , Minville Vincent 
Published: January 2013

Abstract
Postoperative pain management is a clinical challenge that can be complicated by opioid-induced hyperalgesia (OIH). Kinin receptors could mediate both the acute and chronic phases of inflammation and pain. A few recent studies suggest that dynorphin A could maintain neuropathic pain by activating the bradykinin (BK) receptor. Thus, the effect of a single administration of sufentanil (a μ-opioid receptor agonist) was investigated in a model of carrageenan-induced inflammatory pain using three strains of mice, i.e., knockout mice for one kinin receptor, B1R or B2R (B1KO, B2KO), and wild-type C57/BL6J mice (WT) treated with either a B1R (R954) or a B2R antagonist (HOE140) or a KKS inhibitor (aprotinin). Pain was assessed and compared between the different groups using two behavioral tests exploring mechanical (von Frey filaments) and thermal (Hargreaves test) sensitivity. Pretreatment with sufentanil induced a sustained increase in pain sensitivity with a delayed return to baseline values characterizing an OIH in carrageenan-injected mice only. Sufentanil-induced OIH was not observed in B2KO but persisted in B1KO and was blunted by aprotinin and the B2R antagonist only. Collectively, our data indicate that the B2R receptor and BK synthesis or availability are essential peripheral steps in the mechanism leading to OIH in a pain context.
The unique activity of bone morphogenetic proteins in bone: a critical role of the Smad signaling pathway
Authors: Katagiri Takenobu , Tsukamoto Sho 
Published: January 2013

Abstract
Bone morphogenetic proteins (BMPs) are multifunctional cytokines that belong to the transforming growth factor-β family. BMPs were originally identified based on their unique activity, inducing heterotopic bone formation in skeletal muscle. This unique BMP activity is transduced by specific type I and type II transmembrane kinase receptors. Among the downstream pathways activated by these receptors, the Smad1/5/8 transcription factors appear to play critical roles in BMP activity. Smad1/5/8 transcription factors are phosphorylated at the C-terminal SVS motif by BMP type I receptors and then induce the transcription of early BMP-responsive genes by binding to conserved sequences in their enhancer regions. The linker regions of Smad1/5/8 contain multiple kinase phosphorylation sites, and phosphorylation and dephosphorylation of these sites regulate the transcriptional activity of Smad proteins. Gain-of-function mutations in one BMP type I receptor have been identified in patients with fibrodysplasia ossificans progressiva, a rare genetic disorder that is characterized by progressive heterotopic bone formation in the skeletal muscle. The mutant receptors activate the Smad signaling pathway even in the absence of BMPs, therefore novel inhibitors for the BMP receptor – Smad axis are being developed to prevent heterotopic bone formation in fibrodysplasia ossificans progressiva. Taken together, the data in the literature show that the BMP type I receptor – Smad signaling axis is the critical pathway for the unique activity of BMPs and is a potential therapeutic target for pathological conditions caused by inappropriate BMP activity.
Hypoxia-inducible factor prolyl 4-hydroxylases: common and specific roles
Authors: Myllyharju Johanna , Koivunen Peppi 
Published: January 2013

Abstract
Hypoxia-inducible transcription factor (HIF), an αβ dimer, is the key inducer of hypoxia-responsive genes that operate both during normal development and pathological processes in association with decreased oxygen availability. The products of HIF target genes function in, e.g., hematopoiesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumorigenesis and metastasis. HIF is accumulated in hypoxia, whereas it is rapidly degraded in normoxic cells. The oxygen-sensing mechanism behind this phenomenon is provided by HIF prolyl 4-hydroxylases (HIF-P4Hs, commonly known as PHDs and EglNs) that require oxygen in their reaction. In normoxia, two prolines in the oxygen-dependent degradation domain of the HIFα subunit become hydroxylated by the HIF-P4Hs. The 4-hydroxyproline residues formed serve as recognition sites for the von Hippel-Lindau E3 ubiquitin ligase complex and result in subsequent ubiquitination and instant proteasomal degradation of HIFα in normoxia. The HIF-P4H reaction is inhibited in hypoxia. HIFα evades degradation and forms a functional dimer with HIFβ, leading to activation of the HIF target genes. The central role of HIF-P4Hs in the regulation of the hypoxia response pathway has provided an attractive possibility as a drug candidate for treatment of, e.g., severe anemias and ischemic conditions, and several companies are currently carrying out clinical studies on the use of HIF-P4H inhibitors to treat anemia in patients with a kidney disease. Therefore, it is important to understand the effects of individual HIF-P4H isoenzymes on the hypoxia response and potential other pathways in vivo. The common and specific functions of the HIF-P4H isoenzymes are discussed in this review on the basis of available data from cell biological studies and gene-modified animals.