bluuebunny/crossref_metadata_2025 huggingface dataset:
Myostatin-induced inhibition of the long noncoding RNA Malat1 is associated with decreased myogenesis
Authors: Watts Rani , Johnsen Virginia L. , Shearer Jane , Hittel Dustin S.
Published: March 2013

Myostatin, a member of the transforming growth factor-β (TGF-β) superfamily of secreted proteins, is a potent negative regulator of myogenesis. Free myostatin induces the phosphorylation of the Smad family of transcription factors, which, in turn, regulates gene expression, via the canonical TGF-β signaling pathway. There is, however, emerging evidence that myostatin can regulate gene expression independent of Smad signaling. As such, we acquired global gene expression data from the gastrocnemius muscle of C57BL/6 mice following a 6-day treatment with recombinant myostatin compared with vehicle-treated animals. Of the many differentially expressed genes, the myostatin-associated decrease (−11.20-fold; P < 0.05) in the noncoding metastasis-associated lung adenocarcinoma transcript 1 (Malat1) was the most significant and the most intriguing because of numerous reports describing its novel role in regulating cell growth. We therefore sought to further characterize the role of Malat1 expression in skeletal muscle myogenesis. RT-PCR-based quantification of C2C12 and primary human skeletal muscle cells revealed a significant and persistent upregulation (4- to 7-fold; P < 0.05) of Malat1 mRNA during the differentiation of myoblasts into myotubes. Conversely, targeted knockdown of Malat1 using siRNA suppressed myoblast proliferation by arresting cell growth in the G0/G1 phase. These results reveal Malat1 as novel downstream target of myostatin with a considerable ability to regulate myogenesis. The identification of new targets of myostatin will have important repercussions for regenerative biology through inhibition and/or reversal of muscle atrophy and wasting diseases.
Physiological characterization of a mouse model of cachexia in colorectal liver metastases
Authors: Murphy Kate T. , Struk Adam , Malcontenti-Wilson Cathy , Christophi Christopher , Lynch Gordon S.
Published: March 2013

Loss of skeletal muscle mass and function (cachexia) is severe in patients with colorectal liver metastases because of the large increase in resting energy expenditure but remains understudied because of a lack of suitable preclinical models. Our aim was to characterize a novel preclinical model of cachexia in colorectal liver metastases. We tested the hypothesis that mice with colorectal liver metastases would exhibit cachexia, as evidenced by a reduction in liver-free body mass, muscle mass, and physiological impairment. Twelve-week-old male CBA mice received an intrasplenic injection of Ringer solution (sham) or murine colorectal cancer cells (MoCR) to induce colorectal liver metastases. At end-point (20–29 days), the livers of MoCR mice were infiltrated completely with metastases, and MoCR mice had reduced liver-free body mass, muscle mass, and epididymal fat mass compared with sham controls ( P < 0.03). MoCR mice exhibited impaired rotarod performance and grip strength ( P < 0.03). Histochemical analyses of tibialis anterior muscles from MoCR mice revealed muscle fiber atrophy and reduced oxidative enzyme activity ( P < 0.001). Adipose tissue remodeling was evident in MoCR mice, with reduced adipocyte diameter and greater infiltration of nonadipocyte tissue ( P < 0.05). These findings reveal the MoCR mouse model exhibits significant cachexia and is a suitable preclinical model of cachexia in colorectal liver metastases. This model should be used for identifying effective treatments for cachexia to improve quality of life and reduce mortality in patients with colorectal liver metastases.
Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS
Authors: Zhang Jiong , Pippin Jeffrey W. , Krofft Ronald D. , Naito Shokichi , Liu Zhi-Hong , Shankland Stuart J.
Published: March 2013

Prednisone is a mainstay of treatment for patients with focal segmental glomerulosclerosis (FSGS), a disease characterized by reduced podocyte number and glomerulosclerosis. Although the systemic immune-modulatory effects of prednisone are well-known, direct tissue effects on glomerular cells are poorly understood. Experimental FSGS was induced in mice with a cytotoxic anti-podocyte antibody, resulting in an abrupt decrease in podocyte number by day 3, proteinuria, and the development of glomerulosclerosis. Administering daily prednisone to mice with FSGS, beginning at day 3, significantly increased podocyte number at weeks 2 and 4. Podocyte number did not increase in control mice with FSGS given DMSO. The increase in podocyte number in prednisone-treated mice correlated significantly with reduced glomerulosclerosis. Prednisone reduced podocyte apoptosis measured by synaptopodin+/caspase-3+ double staining. Additionally, the number of podocyte progenitors, defined as cells expressing both a parietal epithelial cell protein and a podocyte protein, was significantly increased in prednisone-treated mice with FSGS at weeks 2 and 4. This was associated with increased phospho-ERK staining in both parietal epithelial cells (PAX2+/p-ERK+) and in podocyte progenitors (WT-1+/p-ERK+ lining Bowman's capsule). These data show that in this model of experimental FSGS, prednisone augments glomerular repair by increasing podocyte number through direct effects on both glomerular epithelial cells. Prednisone limits podocyte loss by reducing apoptosis, and it increases regeneration by augmenting the number of podocyte progenitors. The data support a direct glomerular cell action for prednisone in improving outcomes in FSGS.
The calcium-binding protein parvalbumin modulates the firing 1 properties of the reticular thalamic nucleus bursting neurons
Authors: Albéri Lavinia , Lintas Alessandra , Kretz Robert , Schwaller Beat , Villa Alessandro E. P.
Published: March 2013

The reticular thalamic nucleus (RTN) of the mouse is characterized by an overwhelming majority of GABAergic neurons receiving afferences from both the thalamus and the cerebral cortex and sending projections mainly on thalamocortical neurons. The RTN neurons express high levels of the “slow Ca2+ buffer” parvalbumin (PV) and are characterized by low-threshold Ca2+ currents, IT. We performed extracellular recordings in ketamine/xylazine anesthetized mice in the rostromedial portion of the RTN. In the RTN of wild-type and PV knockout (PVKO) mice we distinguished four types of neurons characterized on the basis of their firing pattern: irregular firing (type I), medium bursting (type II), long bursting (type III), and tonically firing (type IV). Compared with wild-type mice, we observed in the PVKOs the medium bursting (type II) more frequently than the long bursting type and longer interspike intervals within the burst without affecting the number of spikes. This suggests that PV may affect the firing properties of RTN neurons via a mechanism associated with the kinetics of burst discharges. Cav3.2 channels, which mediate the IT currents, were more localized to the somatic plasma membrane of RTN neurons in PVKO mice, whereas Cav3.3 expression was similar in both genotypes. The immunoelectron microscopy analysis showed that Cav3.2 channels were localized at active axosomatic synapses, thus suggesting that the differential localization of Cav3.2 in the PVKOs may affect bursting dynamics. Cross-correlation analysis of simultaneously recorded neurons from the same electrode tip showed that about one-third of the cell pairs tended to fire synchronously in both genotypes, independent of PV expression. In summary, PV deficiency does not affect the functional connectivity between RTN neurons but affects the distribution of Cav3.2 channels and the dynamics of burst discharges of RTN cells, which in turn regulate the activity in the thalamocortical circuit.
Control of layer 5 pyramidal cell spiking by oscillatory inhibition in the distal apical dendrites: a computational modeling study
Authors: Li Xiumin , Morita Kenji , Robinson Hugh P. C. , Small Michael
Published: March 2013

The distal apical dendrites of layer 5 pyramidal neurons receive cortico-cortical and thalamocortical top-down and feedback inputs, as well as local recurrent inputs. A prominent source of recurrent inhibition in the neocortical circuit is somatostatin-positive Martinotti cells, which preferentially target distal apical dendrites of pyramidal cells. These electrically coupled cells can fire synchronously at various frequencies, including over a relatively slow range (5∼30 Hz), thereby imposing oscillatory inhibition on the pyramidal apical tuft dendrites. We examined how such distal oscillatory inhibition influences the firing of a biophysically detailed layer 5 pyramidal neuron model, which reproduced the spatiotemporal properties of sodium, calcium, and N-methyl-d-aspartate receptor spikes found experimentally. We found that oscillatory synchronization strongly influences the impact of distal inhibition on the pyramidal cell firing. Whereas asynchronous inhibition largely cancels out the facilitatory effects of distal excitatory inputs, inhibition oscillating synchronously at around 10∼20 Hz allows distal excitation to drive axosomatic firing, as if distal inhibition were absent. Underlying this is a switch from relatively infrequent burst firing to single spike firing at every period of the inhibitory oscillation. This phenomenon depends on hyperpolarization-activated cation current-dependent membrane potential resonance in the dendrite, but also, in a novel manner, on a cooperative amplification of this resonance by N-methyl-d-aspartate-receptor-driven dendritic action potentials. Our results point to a surprising dependence of the effect of recurrent inhibition by Martinotti cells on their oscillatory synchronization, which may control not only the local circuit activity, but also how it is transmitted to and decoded by downstream circuits.
Increased neural correlations in primate auditory cortex during slow-wave sleep
Authors: Issa Elias B. , Wang Xiaoqin
Published: March 2013

During sleep, changes in brain rhythms and neuromodulator levels in cortex modify the properties of individual neurons and the network as a whole. In principle, network-level interactions during sleep can be studied by observing covariation in spontaneous activity between neurons. Spontaneous activity, however, reflects only a portion of the effective functional connectivity that is activated by external and internal inputs (e.g., sensory stimulation, motor behavior, and mental activity), and it has been shown that neural responses are less correlated during external sensory stimulation than during spontaneous activity. Here, we took advantage of the unique property that the auditory cortex continues to respond to sounds during sleep and used external acoustic stimuli to activate cortical networks for studying neural interactions during sleep. We found that during slow-wave sleep (SWS), local (neuron-neuron) correlations are not reduced by acoustic stimulation remaining higher than in wakefulness and rapid eye movement sleep and remaining similar to spontaneous activity correlations. This high level of correlations during SWS complements previous work finding elevated global (local field potential-local field potential) correlations during sleep. Contrary to the prediction that slow oscillations in SWS would increase neural correlations during spontaneous activity, we found little change in neural correlations outside of periods of acoustic stimulation. Rather, these findings suggest that functional connections recruited in sound processing are modified during SWS and that slow rhythms, which in general are suppressed by sensory stimulation, are not the sole mechanism leading to elevated network correlations during sleep.
Suppression of epileptiform activity by a single short-duration electric field in rat hippocampus in vitro
Authors: Mikkelsen Ronni , Andreasen Mogens , Nedergaard Steen
Published: March 2013

The mechanisms behind the therapeutic effects of electrical stimulation of the brain in epilepsy and other disorders are poorly understood. Previous studies in vitro have shown that uniform electric fields can suppress epileptiform activity through a direct polarizing effect on neuronal membranes. Such an effect depends on continuous DC stimulation with unbalanced charge. Here we describe a suppressive effect of a brief (10 ms) DC field on stimulus-evoked epileptiform activity in rat hippocampal brain slices exposed to Cs+ (3.5 mM). This effect was independent of field polarity, was uncorrelated to changes in synchronized population activity, and persisted during blockade of synaptic transmission with Cd2+ (500 μM). Antagonists of A1, P2X, or P2Y receptors were without effect. The suppressive effect depended on the alignment of the external field with the somato-dendritic axis of CA1 pyramidal cells; however, temporal coincidence with the epileptiform activity was not essential, as suppression was detectable for up to 1 s after the field. Pyramidal cells, recorded during epileptiform activity, showed decreased discharge duration and truncation of depolarizing plateau potentials in response to field application. In the absence of hyperactivity, the applied field was followed by slow membrane potential changes, accompanied by decreased input resistance and attenuation of the depolarizing afterpotential following action potentials. These effects recovered over a 1-s period. The study suggests that a brief electric field induces a prolonged suppression of epileptiform activity, which can be related to changes in neuronal membrane properties, including attenuation of signals depending on the persisting Na+ current.
Restoring Poissonian Images by a Combined First-Order and Second-Order Variation Approach
Authors: Jiang Le , Huang Jin , Lv Xiao-Guang , Liu Jun
Published: March 2013

The restoration of blurred images corrupted by Poisson noise is an important topic in imaging science. The problem has recently received considerable attention in recent years. In this paper, we propose a combined first-order and second-order variation model to restore blurred images corrupted by Poisson noise. Our model can substantially reduce the staircase effect, while preserving edges in the restored images, since it combines advantages of the first-order and second-order total variation. We study the issues of existence and uniqueness of a minimizer for this variational model. Moreover, we employ a gradient descent method to solve the associated Euler-Lagrange equation. Numerical results demonstrate the validity and efficiency of the proposed method for Poisson noise removal problem.
Clinical Evaluation of Percutaneous Vertebroplasty in a Patient with Paraplegia and Immobilization Syndrome: A Case Report
Authors: Masala Salvatore , Calabria Eros , Nezzo Marco , De Vivo Dominique , Neroni Luca , Simonetti Giovanni
Published: March 2013

We will discuss a potential role of percutaneous vertebroplasty (PVP) in the management of a patient with immobilization syndrome due to paraplegia and vertebral osteoporotic fractures. While PVP is commonly used for the treatment of osteoporotic thoracolumbar vertebral compression fractures, its role in vertebral stabilization in patient with immobilization syndrome has not been reported in the literature. A 73-year-old woman affected by immobilization syndrome due to paraplegia and vertebral osteoporotic fractures was treated with PVP of vertebrae D12, L1, and L4. After PVP, the patient did not need any antalgic therapy, and there was a significant improvement regarding mobilization, performance of physiological functions, daily management of personal care, and treatment of decubitus ulcers, increasing life quality and psychological well-being.
Mapping Metabolic Brain Activity in Three Models of Hepatic Encephalopathy
Authors: Arias Natalia , Méndez Marta , Fidalgo Camino , Aller María Ángeles , Arias Jaime , Arias Jorge L.
Published: March 2013

Cirrhosis is a common disease in Western countries. Liver failure, hyperammonemia, and portal hypertension are the main factors that contribute to human cirrhosis that frequently leads to a neuropsychiatric disorder known as hepatic encephalopathy (HE). In this study, we examined the differential contribution of these leading factors to the oxidative metabolism of diverse brain limbic system regions frequently involved in memory process by histochemical labelling of cytochrome oxidase (COx). We have analyzed cortical structures such as the infralimbic and prelimbic cotices, subcortical structures such as hippocampus and ventral striatum, at thalamic level like the anterodorsal, anteroventral, and mediodorsal thalamus, and, finally, the hypothalamus, where the mammillary nuclei (medial and lateral) were measured. The severest alteration is found in the model that mimics intoxication by ammonia, followed by the thioacetamide-treated group and the portal hypertension group. No changes were found at the mammillary bodies for any of the experimental groups.
A Technical Note on Fabrication and Thermal Performance Studies of a Solar Pond Model
Authors: Saxena Abhishek , Goel Varun
Published: March 2013

A solar pond has been fabricated to analyze the thermal behavior of it, in the climatic conditions of Moradabad, Uttar Pradesh. Sodium chloride (NaCl) has been used to form a salt gradient for better performance, and a dark-colored (blackened) rigid surface bottom with 1 mm irregularities has been considered for trapping the heat in a good amount. A solar pond with a surface area of 2.56 m2and a depth of 1 m has been filled with salty water of various densities to form three salty water zones (upper convective, nonconvective, and heat storage). A few investigations have been carried out to evaluate the thermal efficiencies of three different zones of the solar pond. An attempt is also made to improve the thermal performance of the salt gradient solar pond.
Multivalued Variational Inequalities with -Pseudomonotone Mappings in Reflexive Banach Spaces
Authors: Saddeek A. M. , Ahmed S. A.
Published: March 2013

This paper is concerned with the study of a class of variational inequalities with multivalued -pseudomonotone mappings in reflexive Banach spaces by using the -antiresolvent technique. An application to the multivalued nonlinear -complementarity problem is also presented. The results coincide with the corresponding results announced by many others for the gradient state.
Nox2 Deficiency Prevents Hypertension-Induced Vascular Dysfunction and Hypertrophy in Cerebral Arterioles
Authors: Chan Siu-Lung , Baumbach Gary L.
Published: March 2013

Oxidative stress is involved in many hypertension-related vascular diseases in the brain, including stroke and dementia. Thus, we examined the role of genetic deficiency of NADPH oxidase subunit Nox2 in the function and structure of cerebral arterioles during hypertension. Arterial pressure was increased in right-sided cerebral arterioles with transverse aortic banding for 4 weeks in 8-week-old wild-type (WT) and Nox2-deficient (-/y) mice. Mice were givenNG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or vehicle to drink. We measured the reactivity in cerebral arterioles through open cranial window in anesthetized mice and wall cross-sectional area and superoxide levelsex vivo. Aortic constriction increased systolic and pulse pressures in right-sided carotid arteries in all groups of mice. Ethidium fluorescence showed increased superoxide in right-sided cerebral arterioles in WT, but not in Nox2-/y mice. Dilation to acetylcholine, but not sodium nitroprusside, was reduced, and cross-sectional areas were increased in the right-sided arterioles in WT, but were unchanged in Nox2-/y mice. L-NAME reduced dilation to acetylcholine but did not result in hypertrophy in right-sided arterioles of Nox2-/y  mice. In conclusion, hypertension-induced superoxide production derived from Nox2-containing NADPH oxidase promotes hypertrophy and causes endothelial dysfunction in cerebral arterioles, possibly involving interaction with nitric oxide.
Evaluate the Impact of Cold Wave on Face Slab Cracking Using Fuzzy Finite Element Method
Authors: Zheng Dongjian , Cheng Lin , Xu Yanxin
Published: March 2013

We use fuzzy finite element method (FEM) to analyze the impact of cold wave on face slab cracking of a concrete-faced rockfill dam (CFRD). The static response of dam and the temperature field of face slab are calculated using deterministic FEM since some observed and test data can be obtained. Some parameters of Goodman contact element between face slabs and cushion material are selected as fuzzy variables, and the fuzzy FEM is used to calculate fuzzy stress of face slab. The fuzzy FEM is implemented using vertex method based on the extension principle. Through the analysis of two selected calculation cases of cold wave, it is shown that the calculated cracking direction and cracking zone caused by thermal stress are similar to those of the observed cracks. This proves that the cold wave that caused swift air temperature drop is an important reason for the cracking of face slab. According to these analysis results, some cracking prevention measures are then proposed.
Annoying Hiccups following Intra-Articular Corticosteroid Injection of Betamethasone Acetate/Betamethasone Sodium Phosphate at the Knee Joint
Authors: Habib George , Artul Suheil , Hakim Geries
Published: March 2013

Hiccups is a type of reflex that could happen secondary to different causes including drugs, especially systemic corticosteroids. Usually, high rather than regular doses of systemic steroids are incriminated, and this could explain the fact that very few cases of hiccups following regional corticosteroid treatment were reported. Here, we report the first case of hiccups in the English literature following intra-articular corticosteroid injection (IACI) at the knee joint and review all the previous reported cases of hiccups following regional corticosteroid treatment. Usually, this phenomenon of hiccups responds to regular antihiccups treatment; however, it is recommended not to repeat an IACI in a patient who had this adverse effect before due to an expected severe recurrent attack of hiccups afterwards.
Fault Diagnosis in Dynamic Systems Using Fuzzy Interacting Observers
Authors: Kolesov N. V.
Published: March 2013

A method of fault diagnosis in dynamic systems based on a fuzzy approach is proposed. The new method possesses two basic specific features which distinguish it from the other known fuzzy methods based on the application of fuzzy logic and a bank of state observers. First, this method uses a bank of interacting observers instead of traditional independent observers. The second specific feature of the proposed method is the assumption that there is no strict boundary between the serviceable and disabled technical states of the system, which makes it possible to specify a decision making rule for fault diagnosis.
Mechanical Thrombectomy with the Solitaire Stent at Lyon, France
Authors: Apetse Kossivi , Mechtouff Laura , Cho Tae-Hee , Derex Laurent , Nighoghossian Norbert , Turjman Francis
Published: March 2013

Background/Aims: The Solitaire stent has been suggested as a promising device to perform intracranial thrombectomy in large vessels. We report our experience. Methods: Consecutive patients in whom a thrombectomy with Solitaire stent had been performed for acute ischemic stroke in the Lyon Stroke Unit, France, from November 2009 to November 2010 were enrolled. Results: There were 12 patients with a mean age of 66 years and a mean baseline National Institutes of Health Stroke Scale score of 17.5. There were 10 cases of anterior cerebral artery and 2 cases of basilar artery occlusion. The mean time from onset of symptoms to recanalization was 306 min. Partial or total recanalization was obtained in 91.6% of patients. One case of periprocedural asymptomatic arterial dissection and 1 case of symptomatic cerebral hemorrhage occurred. At 90 days, 4 patients (33.3%) were dead and 5 patients (41.6%) had a modified Rankin Scale ≤2. Conclusions: In this case series, thrombectomy using Solitaire stent in stroke related to large vessel occlusion appears to be feasible, safe and potentially effective. Randomized controlled trials are needed to demonstrate the superiority of thrombectomy alone or in combination with intravenous tPA over intravenous tPA alone in ischemic stroke patients with large intracranial arterial occlusion.
Prophylactic Effects of Duloxetine on Post-Stroke Depression Symptoms: An Open Single-Blind Trial
Authors: Zhang Li-San , Hu Xing-Yue , Yao Lin-Yan , Geng Yu , Wei Li-Li , Zhang Jin-Hua , Chen Wei
Published: March 2013

Post-stroke depression (PSD) is a common yet severe sequela of stroke, and is often accompanied with somatic symptoms. Duloxetine, a new serotonin-norepinephrine reuptake inhibitor, may help to prevent depression after stroke. 95 ischemic stroke patients without depression were randomly divided into two groups: duloxetine group (n = 47) and control group (n = 48). Patients in the control group received routine ischemic stroke therapy, whereas patients in the duloxetine group received duloxetine (dose range 30–90 mg) for 12 weeks in addition to routine therapy. Follow-up observations lasted for 24 weeks. The Hamilton Depression Scale was used to measure depression, and the National Institute of Stroke Scale, Mini-Mental State Examination, Activities of Daily Living Scale (Chinese version) and Short Form 36 Health Survey Questionnaire were used to assess neurological function, cognitive function, rehabilitation from stroke and quality of life. Results showed that in general, duloxetine spared ischemic stroke patients from both minor and major depression by 16%. In addition, duloxetine helped patients to rehabilitate more rapidly from stroke, and was associated with better cognitive function and quality of life. In conclusion, the prophylactic use of duloxetine not only decreased the incidence of PSD, but also promoted rehabilitation, cognitive function and quality of life.
NeuroAiD: Properties for Neuroprotection and Neurorepair
Authors: Heurteaux C. , Widmann C. , Moha ou Maati H. , Quintard H. , Gandin C. , Borsotto M. , Veyssiere J. , Onteniente B. , Lazdunski M.
Published: March 2013

Background: Treatments for stroke and other brain injuries are limited. NeuroAiD has been shown to be beneficial in clinical studies. We reviewed the pharmacological effects of NeuroAiD on the normal and ischemic brain and neurons. Methods: In vivo and in vitro experiments using mouse model of stroke (focal ischemia), rat model of cardiac arrest (global ischemia) and cortical neurons in culture were reviewed and summarized. Results: NeuroAiD improved survival, attenuated infarct size, improved functional recovery in the model of focal ischemia, and protected neurons against glutamate-induced injury. Furthermore, it enhanced cognitive recovery by reducing hippocampal CA1 cell degeneration, DNA fragmentation, Bax expression and ma-londialdehyde release in the model of global ischemia. Ac-tivation of the Akt survival pathway and opening of KATP channels may contribute to the neuroprotective properties of NeuroAiD. NeuroAiD increased BDNF expression and induced proliferation of cells which differentiate and mature into neurons. It enhanced rosette formation of human embryonic stem cells. NeuroAiD-treated embryonic cortical neurons developed into neurons with longer neurites, denser outgrowths and networks, and more synaptic release sites. Conclusions: NeuroAiD demonstrated both neuroprotective and neuroregenerative properties in rodent models of focal and global ischemia and in cortical cell cultures. These properties would be important for developing a treatment strategy in reducing the long-term disability of stroke, cardiac arrest and other brain injuries.
Chinese Medicine NeuroAiD Efficacy Stroke Recovery - Extension Study (CHIMES-E Study): An Observational Multicenter Study to Investigate the Longer-Term Efficacy of NeuroAiD in Stroke Recovery
Authors: Venketasubramanian N. , Young Sherry , Tay San San , Chang Hui Meng , Umapathi T. , Chan Bernard , de Silva Asita , Wong Lawrence , Navarro Jose , Zhao Yu-Dong , Tan Say Beng , Chen Christopher
Published: March 2013

Background: Stroke carries a poor long-term prognosis for death and disability. There are few acute treatments that reduce death and disability after stroke. The ongoing international, multicenter, randomized, placebo-controlled, double-blind CHIMES trial is currently testing the hypothesis that a 3-month course of the traditional Chinese medicine MLC601 (NeuroAiD) is superior to placebo in reducing neurological deficit and improving functional outcome after acute ischemic stroke in patients receiving standard stroke care. This extension study tests the hypothesis that at 2 years, an initial 3-month administration of NeuroAiD is superior to placebo in reducing neurological deficit and improving functional outcome in patients with cerebral infarction of an intermediate range of severity. Methods: Study subjects will be those who are already participants in CHIMES - aged above 21 years, had signs and symptoms of acute stroke, 6 ≤ NIHSS ≤ 14, neuroimaging consistent with ischemic stroke, and received study medication within 72 h of stroke onset. A subject will not be eligible for inclusion in CHIMES-E if they have withdrawn consent from all participation and follow-up for CHIMES. Subjects will be contacted at 6, 12, 18 and 24 months after CHIMES enrolment. After verbal consent is obtained, subjects will be assessed for functional state by the modified Rankin scale (mRS) and Barthel Index (BI), and a history of recurrent vascular events as well as medical events. The primary outcome measure will be the mRS at month 24. Secondary outcome measures will be mRS and BI at 6, 12 and 18 months, and BI at 24 months. Analysis will be based on the intention-to-treat principle. If the number of patients lost to follow-up is substantial, a sensitivity analysis based on the last observation carried forward method will be carried out, to compare the results with those from the main analysis without imputation. Based on a cumulative odds ratio of 1.5 for the NeuroAiD group, a two-sided test of 5% type I error and an expected 30% dropout rate after 2 years of follow-up for the 1,100 patients recruited into CHIMES, the 770 subjects with mRS data expected to be available at year 2 yields an 89% power to detect a difference in efficacy between NeuroAiD and placebo. Conclusions: This study will provide evidence for the longer-term efficacy of an initial course of a neurorestorative therapy after acute ischemic stroke of intermediate severity.
NeuroAiD® (MLC601) and Amyloid Precursor Protein Processing
Authors: Lim Y.A. , Murray L.A. , Lai M.K.P. , Chen C.
Published: March 2013

Background: Amyloid precursor protein (APP) undergoes cleavage under physiological conditions, predominantly by α- and γ-secretases, to form the nonpathogenic sAPPα and p3 fragments. By contrast, amyloid-beta (Aβ) is produced via proteolytic cleavage by β- and γ-secretases. In Alzheimer's disease (AD), APP is preferentially processed via the amyloidogenic pathway, producing large amounts of Aβ that form the major constituent of senile plaques and tau-containing neurofibrillary tangles. Similarly, stroke patients have a higher level of Aβ around the area of infarct, suggesting that Aβ may mediate at least some of the secondary neurotoxicity observed in stroke patients. Methods: To investigate the effects of MLC601 (NeuroAiD®) on regulation of APP processing, the human neuroblastoma cell line SH-SY5Y was used for all experiments. Stocks of MLC601 were prepared at a final concentration of 50 mg/ml. Cells were treated with different concentrations of MLC601 before assessing changes in the levels of released lactate dehydrogenase (LDH), full-length APP and secreted sAPPα. Results: Concentrations of MLC601 between 1 and 1,000 µg/ml significantly lowered the levels of LDH released into the media when compared to control cells. In contrast, MLC601 concentrations at 5,000 and 10,000 µg/ml resulted in a significant increase in the LDH release. Treatment with 100, 500 and 1,000 μg/ml of MLC601 significantly increases the levels of sAPPα secreted by SH-SY5Y into the media. Treatment with 1,000 μg/ml of MLC601 significantly decreased the levels of full-length APP. Conclusion: MLC601 is a possible modulator of APP processing and has implications as a putative therapeutic strategy for the treatment of poststroke dementia and AD.
Isolated Cortical Vein Thrombosis: A Widely Variable Clinicoradiological Spectrum
Authors: Xue S.F. , Ma Q.F. , Ma X. , Jia J.P.
Published: March 2013

Background/Aims: The aim of this study is to highlight the variable clincoradiological spectrum of isolated cortical vein thrombosis (ICoVT), which seems to remain a challenge to clinicians. Cases Reports: We reported 3 patients with this diagnosis. One presented with only an epileptic seizure, one with worsening headache, seizures, mental disorder, speech disturbance and right-sided weakness, and the other with seizures and fluctuating paralysis in her left-sided limbs. Brain images were manifested with a strand-like abnormal signal, a large hemorrhagic infarction and a continuously enlarged space-occupying massive edema, respectively. Conclusions: Neurologic features and brain imaging of ICoVT are highly variable, which might be partly responsible for the underestimation of ICoVT. Clinical diagnosis should probably be evoked more often.
The c.7409G>A (p.Cys2470Tyr) Variant of FBN1: Phenotypic Variability across Three Generations
Authors: Potter K.J. , Creighton S. , Armstrong L. , Eydoux P. , Duncan W. , Penny D.J. , Fan Y. , Gibson W.T.
Published: March 2013

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin gene FBN1, which encodes an extracellular matrix glycoprotein. Major features of Marfan syndrome occur in the ocular, cardiovascular, and skeletal systems as well as in the dura mater. Approximately 60% of known disease-causing mutations are missense mutations of single amino acid residues. Effects on the cardiovascular system are classically associated with mutations in exons 24-32 of the 65 FBN1 exons and many, though not all, reports associate missense mutations in exons 59-65 with a mild cardiovascular phenotype. Here we present 5 related individuals among whom a c.7409G>A (p.Cys2470Tyr) missense variant in exon 59 of FBN1 is associated with significant cardiovascular features. The index case also had an apparently de novo 46,XX,del(5)(q33.1q33.3) deletion on chromosome 5. This family demonstrates skeletal, dermatological and neurological features consistent with Marfan syndrome but lacks significant ophthalmological findings to date. These findings suggest that FBN1 C-terminal missense mutations may not confer the ophthalmological features of Marfan syndrome, but they also confer a more significant risk for cardiovascular pathology than that suggested by previous studies. Furthermore, clinical data from this family supports the previously reported association of dural ectasia with C-terminal mutations.
Neue Arzneimittel in der Onkologie: Merkmale klinischer Zulassungsstudien und Argumente für die rasche Durchführung unabhängiger klinischer Studien nach der Zulassung
Authors: Ludwig Wolf-Dieter , Schott Gisela
Published: March 2013

Die Zulassung bzw. Indikationserweiterung für alle onkologischen Arzneimittel erfolgt heute in Europa basierend auf der Verordnung (EG) Nr. 726/2004 in einem zentralisierten Verfahren der European Medicines Agency (EMA). Untersuchungen der letzten Jahre haben Mängel in den Zulassungsstudien aufgezeigt. So werden beispielsweise die Vorgaben der EMA nicht immer konsequent beachtet und Studien werden nach Zwischenanalysen, die zu diesem Zeitpunkt eine bessere Wirksamkeit gegenüber dem Vergleichsarm zeigen, vorzeitig abgebrochen. Unsere aktuelle Auswertung der Europäischen Bewertungsberichte (Auswertungszeitraum: 01.01.2009 bis 13.08.2012) zu 29 Wirkstoffen für 39 onkologische Indikationen ergibt, dass sich die Qualität der Zulassungsstudien in verschiedener Hinsicht verbessert hat. So wurden meist die von der EMA und der Food and Drug Administration (FDA) empfohlenen primären Endpunkte - Gesamtüberleben und progressionsfreies Überleben - verwendet und nur eine Studie wurde als Phase-II-Studie ohne Vergleichsarm durchgeführt. Demgegenüber werden die onkologischen Arzneimittel zur Behandlung seltener Leiden (Orphan Drugs) auf der Basis von kleinen Studien zugelassen, die vielfach offen und nicht randomisiert durchgeführt werden und Surrogatendpunkte unter suchen. Nach der Zulassung ist für die Beantwortung der noch offenen patientenrelevanten Fragen die Durchführung von unabhängigen klinischen Studien erforderlich, für die verstärkt öffentliche Gelder bereitgestellt und bürokratische Hürden abgebaut werden müssen. Nur so kann ein effizienter Umgang mit begrenzten Gesundheitsressourcen ermöglicht und die Versorgungsqualität von Tumorpatienten verbessert werden.
Akademische multizentrische Studien im Fokus: Auswirkungen der Arzneimittelgesetzgebung auf Therapieoptimierungsstudien in der Hämatologie/Onkologie
Authors: Ihrig Kristina , Fath Birgit , Fuchs Michael , Hallek Michael , Marschner Norbert , Naumann Ralph , Röllig Christoph , Saußele Susanne , Tesch Hans , Gökbuget Nicola
Published: March 2013

Hintergrund: Zweck dieser Erhebung war die Erfassung der Auswirkungen gesetzlicher Rahmenbedingungen für klinische Studien auf Prüfzentren hämatologisch-onkologischer Investigator-initiierter Studien (IIT). Methode: Fragebögen wurden an Leitungen hämatologisch-onkologischer Prüfzentren versandt. Ergebnisse: Teilnehmende Zentren an IIT weisen eine gute Infrastruktur und umfassende Studienerfahrung auf. Je nach Erkrankung wird ein hoher Anteil der Patienten in Studien behandelt, um Therapieergebnisse zu verbessern. Dennoch werden 35% der Umfrageteilnehmer ihre Teilnahme an IIT reduzieren, da unter anderem für die aufwendige Organisation keine ausreichende Finanzierung für Studienpersonal besteht. Schlussfolgerungen: Die Studienlandschaft der Hämatologie/Onkologie mit ihren aka-demischen Multicenterstudien ist gefährdet. Dies hat weitreichende Folgen für Patienten, da qualitativ hochwertige Studien an vielen Standorten nicht aktiviert werden und so wertvolle Daten für die Optimierung der Therapien verloren gehen. Um diese Entwicklung zu stoppen, ist eine Änderung der Rahmenbedingungen durch Gesetzgeber, Überwachungsbehörden und Kostenträger erforderlich.
Das ökonomische Dilemma
Authors: Overkamp Friedrich , Bröker Anja
Published: March 2013

Die Bereitschaft von Praxen und Kliniken für ein Engagement im Bereich der Klinischen Forschung ist in den letzten 10 Jahren deutlich gestiegen. Es macht sich jedoch zunehmend Ernüchterung breit im Hinblick auf die eklatante Unterfinanzierung klinischer Studien. Der vorliegende Beitrag möchte aufgrund praktischer Erfahrungen Denkanstöße und Impulse für eine Neuorientierung der Vergütung setzen. Ursachen und Hintergründe der Unterfinanzierung werden erläutert, insbesondere werden die anfallenden Kosten eingehend dargelegt. Die Etablierung von Werkzeugen zur Kostenkalkulation erscheint dringend notwendig, erste Ansätze dazu gibt es bereits.
Beantragung der Bewilligung von akademischen Multicenterstudien bei deutschen Ethikkommissionen
Authors: Gökbuget Nicola , Naumann Ralph ,   für den Arbeitskreis AMG der DGHO
Published: March 2013

Für klinische Studien muss vor Beginn ein positives Votum der zuständigen Ethikkommissionen eingeholt werden. In Deutschland gibt es fast 50 unabhängige Ethikkommissionen, die für die einzelnen Standorte in Multicenterstudien zuständig sein können. Da gerade bei Studien an seltenen Erkrankungen eine Beteiligung von vielen Zentren notwendig ist, stellt das Beantragungsverfahren bei akademischen Multicenterstudien für maligne hämatologische Erkrankungen häufig einen bürokratischen Albtraum dar. Einzelne Aspekte der Antragstellung sowie Ansätze für mögliche Verbesserungen werden dargestellt.
Transient heparin-induced platelet activation linked to generation of platelet 12-lipoxygenase
Authors: McMahon Greg S. , Jones Chris I. , Hayes Paul D. , Naylor A. Ross , Goodall Alison H.
Published: March 2013

Previously we demonstrated that heparin administration during carotid endarterectomy (CEA) caused a marked, but transient increase in platelet aggregation to arachidonic acid (AA) and adenosine diphosphate (ADP), despite effective platelet cyclo-oxygenase-1 (COX-1) inhibition with aspirin. Here we investigated the metabolism of AA via platelet 12-lipoxygenase (12-LOX) as a possible mediator of the observed transient aspirin resistance, and compared the effects of unfractionated (UFH) and low-molecular-weight (LMWH) heparin. A total of 43 aspirinated patients undergoing CEA were randomised in the trial to 5,000 IU UFH (n=22) or 2,500 IU LMWH (dalteparin, n=21). Platelet aggregation to AA (4×10–3) and ADP (3×10–6) was determined, and the products of the COX-1 and 12-LOX pathways; thromboxane B2 (TXB2) and 12-hydroxyeicosatretraenoic acid (12-HETE) were measured in plasma, and in material released from aggregating platelets. Aggregation to AA increased significantly (∼10-fold) following heparinisation (p<0.0001), irrespective of heparin type (p=0.33). Significant, but smaller (∼2-fold) increases in aggregation to ADP were also seen, which were significantly lower in the platelets of patients randomised to LMWH (p<0.0001). Plasma levels of TxB2 did not rise following heparinisation (p=0.93), but 12-HETE increased significantly in the patients’ plasma, and released from platelets stimulated in vitro with ADP, with both heparin types (p<0.0001). The magnitude of aggregation to ADP correlated with 12-HETE generation (p=0.03). Heparin administration during CEA generates AA that is metabolised to 12-HETE via the 12-LOX pathway, possibly explaining the phenomenon of transient heparin-induced platelet activation. LMWH has less effect on aggregation and 12-HETE generation than UFH when the platelets are stimulated with ADP.
Structure of plasma and tissue kallikreins
Authors: Pathak Monika , Shen Wong Szu , Dreveny Ingrid , Emsley Jonas
Published: March 2013

The kallikrein kinin system (KKS) consists of serine proteases involved in the production of peptides called kinins, principally bradykinin and Lys-bradykinin (kallidin). The KKS contributes to a variety of physiological processes including inflammation, blood pressure control and coagulation. Here we review the protein structural data available for these serine proteases and examine the molecular mechanisms of zymogen activation and substrate recognition focusing on plasma kallikrein (PK) and tissue kallikrein (KLK1) cleavage of kininogens. PK circulates as a zymogen bound to high-molecular-weight kininogen (HK). PK is activated by coagulation factor XIIa and then cleaves HK to generate bradykinin and factor XII to generate further XIIa. A structure has been described for the activated PK protease domain in complex with the inhibitor benzamidine. Kallikrein-related peptidases (KLKs) have a distinct domain structure and exist as a family of 15 genes which are differentially expressed in many tissues and the central nervous system. They cleave a wide variety of substrates including low-molecular-weight kininogen (LK) and matrix proteins. Crystal structures are available for KLK1, 3, 4, 5, 6 and 7 activated protease domains typically in complex with S1 pocket inhibitors. A substrate mimetic complex is described for KLK3 which provides insight into substrate recognition. A zymogen crystal structure determined for KLK6 reveals a closed S1 pocket and a novel mechanism of zymogen activation. Overall these structures have proved highly informative in understanding the molecular mechanisms of the KKS and provide templates to design inhibitors for treatment of a variety of diseases.
Regulation of Cardiac Hypertrophic Signaling by Prolyl Isomerase Pin1
Authors: Toko Haruhiro , Konstandin Mathias H. , Doroudgar Shirin , Ormachea Lucia , Joyo Eri , Joyo Anya Y. , Din Shabana , Gude Natalie A. , Collins Brett , Völkers Mirko , Thuerauf Donna J. , Glembotski Christopher C. , Chen Chun-Hau , Lu Kun Ping , Müller Oliver J. , Uchida Takafumi , Sussman Mark A.
Published: March 2013

Rationale:

Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based on the phosphorylation status of involved signaling molecules. Although numerous critical regulatory kinases and phosphatases have been identified in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the nonmyocyte context, control of folding, activity, and stability of proteins is mediated by the prolyl isomerase Pin1, but the role of Pin1 in the heart is unknown.

Objective:

To establish the role of Pin1 in the heart.

Methods and Results:

Here, we show that either genetic deletion or cardiac overexpression of Pin1 blunts hypertrophic responses induced by transaortic constriction and consequent cardiac failure in vivo. Mechanistically, we find that Pin1 directly binds to Akt, mitogen activated protein kinase (MEK), and Raf-1 in cultured cardiomyocytes after hypertrophic stimulation. Furthermore, loss of Pin1 leads to diminished hypertrophic signaling of Akt and MEK, whereas overexpression of Pin1 increases Raf-1 phosphorylation on the autoinhibitory site Ser259, leading to reduced MEK activation.

Conclusions:

Collectively, these data support a role for Pin1 as a central modulator of the intensity and duration of 2 major hypertrophic signaling pathways, thereby providing a novel target for regulation and control of cardiac hypertrophy.
Macroeconomic Effects of the CGIF Scheme Using a Multi-Country Dynamic General Equilibrium Model
Authors: Park Young-Joon , Rhee Dong-Eun
Published: March 2013

As a regional credit mechanism, the Credit Guarantee Investment Facility (CGIF) has been developed in East Asia, and its first credit guarantee is on the cards in 2012. This paper analyzes the potential macroeconomic benefits from CGIF on the basis of simulated scenarios using an ASEAN+3 version of the Global Integrated Monetary and Fiscal model. The results show that even if CGIF enhances several, but not all, of the ASEAN+3 members' credit fundamentals, it helps increase not only the credit-beneficiary countries' investment and real GDP, but also those of the other ASEAN+3 countries.
Capital Formation and Agricultural Growth in China
Authors: Ma Hengyun , Huang Jikun , Oxley Les
Published: March 2013

The paper considers the role and determinants of capital formation in Chinese agriculture and, in particular, the effects of capital formation on agricultural total factor productivity (TFP) growth. The results show that capital investment in agriculture by both government and farmers has risen significantly in the past two and a half decades, particularly in recent years. As China remains in the early stages of agricultural policy transition, its political economy would suggest that there will likely be more public investment in, and more subsidies to, agriculture in the coming years. Increased public investment in agriculture appears to have also induced increased farmers' capital formation in agriculture. Credit policy, the overall growth of farmer's income, rural wages, and comparative advantage of commodities are important factors that may facilitate farmers' investment in agriculture. The results also show that the successful growth of China's agriculture has been associated with its high TFP growth. Both public and private agricultural capital formations have played an important role in raising China's agricultural productivity. The TFP decomposition analyses show that technological change is a primary driver of the TFP growth in China's agriculture.