bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic expression of Hb F in common high Hb F determinants in Thailand: roles of α‐thalassemia, 5′ δ‐globin BCL11A binding region and 3′ β‐globin enhancer
Authors: Prakobkaew Nattaphol , Fucharoen Supan , Fuchareon Goonnapa , Siriratmanawong Nirut 
Published: October 2013

AbstractBackgroundDeletions of δ‐ and β‐globin genes are associated with different Hb F levels. To address this, we have examined hematological and molecular characteristics in a large cohort of high Hb F determinants in Thailand.MethodsA total of 160 unrelated adult subjects with heterozygous trait for high Hb F determinants and another 10 patients with compound heterozygous trait for Hb E were selectively recruited. Hematological parameters and Hb analysis were recorded, and α‐thalassemia mutations were investigated. DNA deletions causing δβ0‐thalassemia and hereditary persistence of fetal hemoglobin (HPFH) were identified using multiplex PCR and denaturing high‐performance liquid chromatography (HPLC) assays developed.ResultsFour different DNA deletions were detected including the 12.6 kb deletion δβ0‐thalassemia (n = 79), 79 kb deletion hereditary persistence of fetal Hb (HPFH)‐6 (n = 65), Indian deletion‐inversion Gγ(Aγδβ)‐thalassemia (n = 15) and 78 kb deletion Chinese Gγ(Aγδβ)‐thalassemia (n = 1). Eighteen cases were found to carry α‐thalassemia with 10 different genotypes. All 10 patients who had similar hematological phenotype with that of Hb E‐β0‐thalassemia were found to be compound Hb E‐δβ0‐thalassemia. Differences in hematological features as well as Hb F levels were noted and are presented comparatively.ConclusionComparison of phenotypes, genotypes, and the deletion breakpoints of these Thai high Hb F determinants indicates that differences in Hb F expression are correlated with the existence of α‐thalassemia, the loss of BCL11A binding region located 5′ to the δ‐globin gene and the 3′ β‐globin enhancer, which confirms their important roles in fetal Hb expression.
Quantification of HBG mRNA in primary erythroid cultures: prediction of the response to hydroxyurea in sickle cell and beta‐thalassemia
Authors: Pecoraro Alice , Rigano Paolo , Troia Antonio , Calzolari Roberta , Scazzone Concetta , Maggio Aurelio , Steinberg Martin H. , Marzo Rosalba Di 
Published: October 2013

AbstractBackground and ObjectiveIncreased expression of fetal hemoglobin (HbF) may ameliorate the clinical course of hemoglobinopathies like sickle cell disease (SCD) and β‐thalassemia. Hydroxyurea (HU) can stimulate HbF production in these diseases but the response is highly variable indicating the utility of developing an in vitro test to predict the patient's response to HU. We assessed whether the HbF response of patients with SCD and thalassemia intermedia (TI) to HU correlates with HBG (both γ‐globin genes) expression in their cultured erythroid progenitors following exposure to HU.Patients and MethodsWe exposed primary erythroid cultures from peripheral blood mononuclear cells from 30 patients with SCD and 15 with TI to HU and measured HBG mRNA by real‐time quantitative PCR. The same patients were then treated with HU and their HbF response after treatment with a stable dose of HU was compared with the mRNA results in cultured cells.Results and ConclusionThe fold increase in HBG mRNA in erythroid progenitors was similar to the fold increase in HbF in vivo. Quantification of HBG mRNA in erythroid progenitor cell cultures from patients with SCD and TI is predictive of their clinical response to HU.
Refractory thrombotic thrombocytopenic purpura in a 16‐year‐old girl: successful treatment with bortezomib
Authors: van Balen Tessa , Schreuder Michiel F. , de Jong Huib , van de Kar Nicole C. A. J. 
Published: October 2013

AbstractWe present a case of a 16‐year‐old girl with autoimmune thrombotic thrombocytopenic purpura (TTP), refractory to plasma exchange and high‐dose prednisone. Despite the additional treatment with rituximab, she developed renal and neurological complications with ongoing hemolysis and thrombocytopenia. Bortezomib, a proteasome inhibitor and thereby blocking plasma cells, was added, and our patient recovered. We suggest that bortezomib can be of additional value in severe immunologically mediated TTP in adolescents. Its use may prevent the necessity of other invasive therapies, such as splenectomy, with significant side effects.
Oral administration of the flavanol (−)‐epicatechin bolsters endogenous protection against focal ischemia through the Nrf2 cytoprotective pathway
Authors: Leonardo Christopher C. , Agrawal Megha , Singh Nilendra , Moore J. Russell , Biswal Shyam , Doré Sylvain 
Published: October 2013

AbstractConsumption of flavan‐3‐ols, notably (−)‐epicatechin (EC), has been highly recommended in complementary and alternative medicine (CAM) due to reports that flavan‐3‐ols boost antioxidant activity, support vascular function, and prevent cardiovascular disease. To date, in vivo efficacy and mechanisms of action for many CAM therapies, including EC, remain elusive in brain ischemia. In contrast to its purported direct antioxidant role, we hypothesized protection through activation of the endogenous transcriptional factor Nrf2. To screen cellular protection and investigate Nrf2 activation, we adopted a pretreatment paradigm using enriched primary neuronal cultures from mice and washed out EC prior to oxygen glucose deprivation to attenuate direct antioxidant effects. EC protected primary neurons from oxygen glucose deprivation by increasing neuronal viability (40.2 ± 14.1%) and reducing protein oxidation, effects that occurred concomitantly with increased Nrf2‐responsive antioxidant protein expression. We also utilized wildtype and Nrf2 C57BL/6 knockout mice in a permanent model of focal brain ischemia to evaluate glial cell regulation and complex sensorimotor functioning. EC‐treated wildtype mice displayed a reduction or absence of forelimb motor coordination impairments that were evident in vehicle‐treated mice. This protection was associated with reduced anatomical injury (54.5 ± 8.3%) and microglia/macrophage activation/recruitment (56.4 ± 13.0%). The protective effects elicited by EC in both model systems were abolished in tissues and neuronal cultures from Nrf2 knockout mice. Together, these data demonstrate EC protection through Nrf2 and extend the benefits to improved performance on a complex sensorimotor task, highlighting the potential of flavan‐3‐ols in CAM approaches in minimizing subsequent stroke injury.
Blocking brain‐derived neurotrophic factor inhibits injury‐induced hyperexcitability of hippocampal CA3 neurons
Authors: Gill Raminder , Chang Philip K.‐Y. , Prenosil George A. , Deane Emily C. , McKinney Rebecca A. 
Published: October 2013

AbstractBrain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin‐related kinase B (TrkB), a receptor for brain‐derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF‐mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury‐induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB‐Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB‐Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two‐fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB‐Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB‐Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury‐induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post‐traumatic epilepsy. Therefore, our data suggest that blocking the BDNF–TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post‐traumatic epilepsy.
Recent progress in migraine pathophysiology: role of cortical spreading depression and magnetic resonance imaging
Authors: Bhaskar Sonu , Saeidi Kolsoum , Borhani Parvin , Amiri Houshang 
Published: October 2013

AbstractMigraine is characterised by debilitating pain, which affects the quality of life in affected patients in both the western and the eastern worlds. The purpose of this article is to give a detailed outline of the pathophysiology of migraine pain, which is one of the most confounding pathologies among pain disorders in clinical conditions. We critically evaluate the scientific basis of various theories concerning migraine pathophysiology, and draw insights from brain imaging approaches that have unraveled the prevalence of cortical spreading depression (CSD) in migraine. The findings supporting the role of CSD as a physiological substrate in clinical pain are discussed. We also give an exhaustive overview of brain imaging approaches that have been employed to solve the genesis of migraine pain, and its possible links to the brainstem, the neocortex, genetic endophenotypes, and pathogenetic factors (such as dopaminergic hypersensitivity). Furthermore, a roadmap is proposed to provide a better understanding of pain pathophysiology in migraine, to enable the development of strategies using leads from brain imaging studies for the identification of early biomarkers, efficient prognosis, and treatment planning, which eventually may help in alleviating some of the devastating impact of pain morbidity in patients afflicted with migraine.
Multiple sessions of transcranial direct current stimulation to the intact hemisphere improves visual function after unilateral ablation of visual cortex
Authors: Rushmore R. J. , DeSimone C. , Valero‐Cabré A. 
Published: October 2013

AbstractDamage to cerebral systems is frequently followed by the emergence of compensatory mechanisms, which serve to reduce the effects of brain damage and allow recovery of function. Intrinsic recovery, however, is rarely complete. Non‐invasive brain stimulation technologies have the potential to actively shape neural circuits and enhance recovery from brain damage. In this study, a stable deficit for detecting and orienting to visual stimuli presented in the contralesional visual hemifield was generated by producing unilateral brain damage of the right posterior parietal and contiguous visual cortical areas. A long regimen of inhibitory non‐invasive transcranial direct‐current stimulation (cathodal tDCS, 2 mA, 20 min) was applied to the contralateral (intact) posterior parietal cortex over 14 weeks (total of 70 sessions, one per day, 5 days per week) and behavioral outcomes were periodically assessed. In three out of four stimulated cats, lasting recovery of visuospatial function was observed. Recovery started after 2–3 weeks of stimulation, and recovered targets were located first in the periphery, and moved to more central visual field locations with the accrual of stimulation sessions. Recovery for moving tasks followed a biphasic pattern before reaching plateau levels. Recovery did not occur for more difficult visual tasks. These findings highlight the ability of multiple sessions of transcranial direct‐current stimulation to produce recovery of visuospatial function after unilateral brain damage.
Avoidance‐based human Pavlovian‐to‐instrumental transfer
Authors: Lewis Andrea H. , Niznikiewicz Michael A. , Delamater Andrew R. , Delgado Mauricio R. 
Published: October 2013

AbstractThe Pavlovian‐to‐instrumental transfer (PIT) paradigm probes the influence of Pavlovian cues over instrumentally learned behavior. The paradigm has been used extensively to probe basic cognitive and motivational processes in studies of animal learning. More recently, PIT and its underlying neural basis have been extended to investigations in humans. These initial neuroimaging studies of PIT have focused on the influence of appetitively conditioned stimuli on instrumental responses maintained by positive reinforcement, and highlight the involvement of the striatum. In the current study, we sought to understand the neural correlates of PIT in an aversive Pavlovian learning situation when instrumental responding was maintained through negative reinforcement. Participants exhibited specific PIT, wherein selective increases in instrumental responding to conditioned stimuli occurred when the stimulus signaled a specific aversive outcome whose omission negatively reinforced the instrumental response. Additionally, a general PIT effect was observed such that when a stimulus was associated with a different aversive outcome than was used to negatively reinforce instrumental behavior, the presence of that stimulus caused a non‐selective increase in overall instrumental responding. Both specific and general PIT behavioral effects correlated with increased activation in corticostriatal circuitry, particularly in the striatum, a region involved in cognitive and motivational processes. These results suggest that avoidance‐based PIT utilizes a similar neural mechanism to that seen with PIT in an appetitive context, which has implications for understanding mechanisms of drug‐seeking behavior during addiction and relapse.
Transporter‐mediated replacement of extracellular glutamate for GABA in the developing murine neocortex
Authors: Unichenko Petr , Dvorzhak Anton , Kirischuk Sergei 
Published: October 2013

AbstractDuring early development, cortical neurons migrate from their places of origin to their final destinations where they differentiate and establish synaptic connections. During corticogenesis, radially migrating cells move from deeper zone to the marginal zone, but they do not invade the latter. This “stop” function of the marginal zone is mediated by a number of factors, including glutamate and γ‐aminobutyric acid (GABA), two main neurotransmitters in the central nervous system. In the marginal zone, GABA has been shown to be released via GABA transporters (GAT)‐2/3, whereas glutamate transporters (EAATs) operate in the uptake mode. In this study, GABAergic postsynaptic currents (GPSCs) were recorded from Cajal‐Retzius cells in the marginal zone of murine neonatal neocortex using a whole‐cell patch‐clamp technique. Minimal electrical stimulation was applied to elicit evoked GPSCs using a paired‐pulse protocol. EAAT blockade with dl‐threo‐b‐benzyloxyaspartic acid (dl‐TBOA), a specific non‐transportable EAAT antagonist, abolishes constitutive GAT‐2/3‐mediated GABA release. In contrast to dl‐TBOA, d‐aspartate, an EAAT substrate, fails to block GAT‐2/3‐mediated GABA release. SNAP‐5114, a specific GAT‐2/3 antagonist, induced an elevation of intracellular sodium concentration ([Na+]i) under resting conditions and in the presence of d‐aspartate, indicating that GAT‐2/3 operates in reverse mode. In the presence of dl‐TBOA, however, SNAP‐5114 elicited a [Na+]i decrease, demonstrating that GAT‐2/3 operates in uptake mode. We conclude that EAATs via intracellular Na+ signaling and/or cell depolarization can govern the strength/direction of GAT‐mediated GABA transport.
Phagocytic microglial phenotype induced by glibenclamide improves functional recovery but worsens hyperalgesia after spinal cord injury in adult rats
Authors: Redondo‐Castro Elena , Hernández Joaquim , Mahy Nicole , Navarro Xavier 
Published: October 2013

AbstractMicroglial cell plays a crucial role in the development and establishment of chronic neuropathic pain after spinal cord injuries. As neuropathic pain is refractory to many treatments and some drugs only present partial efficacy, it is essential to study new targets and mechanisms to ameliorate pain signs. For this reason we have used glibenclamide (GB), a blocker of KATP channels that are over expressed in microglia under activation conditions. GB has already been used to trigger the early scavenger activity of microglia, so we administer it to promote a better removal of dead cells and myelin debris and support the microglia neuroprotective phenotype. Our results indicate that a single dose of GB (1 μg) injected after spinal cord injury is sufficient to promote long‐lasting functional improvements in locomotion and coordination. Nevertheless, the Randall–Selitto test measurements indicate that these improvements are accompanied by enhanced mechanical hyperalgesia. In vitro results indicate that GB may influence microglial phagocytosis and therefore this action may be at the basis of the results obtained in vivo.
Experimental evidence that evolutionary relatedness does not affect the ecological mechanisms of coexistence in freshwater green algae
Authors: Narwani Anita , Alexandrou Markos A. , Oakley Todd H. , Carroll Ian T. , Cardinale Bradley J. 
Published: October 2013

AbstractThe coexistence of competing species depends on the balance between their fitness differences, which determine their competitive inequalities, and their niche differences, which stabilise their competitive interactions. Darwin proposed that evolution causes species' niches to diverge, but the influence of evolution on relative fitness differences, and the importance of both niche and fitness differences in determining coexistence have not yet been studied together. We tested whether the phylogenetic distances between species of green freshwater algae determined their abilities to coexist in a microcosm experiment. We found that niche differences were more important in explaining coexistence than relative fitness differences, and that phylogenetic distance had no effect on either coexistence or on the sizes of niche and fitness differences. These results were corroborated by an analysis of the frequency of the co‐occurrence of 325 pairwise combinations of algal taxa in > 1100 lakes across North America. Phylogenetic distance may not explain the coexistence of freshwater green algae.
High frequency of intrathecal immunoglobulin synthesis in epilepsy so far classified cryptogenic
Authors: Kowski A. B. , Volz M. S. , Holtkamp M. , Prüss H. 
Published: October 2013

Background and purposeThe influence of the immune system on seizures and epileptogenesis has been increasingly considered, in particular the role of autoantibodies. In this study, we aimed to determine the frequency of intrathecal antibody synthesis in the cerebrospinal fluid (CSF) compartment of patients with epilepsy.MethodsIn a retrospective cohort study trial in a university hospital neurology department, 164 well‐characterized patients with different etiologies of seizures and epilepsies, and 77 control patients were included.ResultsCSF‐specific immunoglobulin (IgG, IgM and IgA) synthesis was significantly (P < 0.0001) more frequent in patients with epilepsy (34.1%) compared with age‐ and sex‐matched controls (2.6%). The highest incidence of intrathecal Ig synthesis was detected in patients with encephalitis‐related acute symptomatic seizures (86.7%), but also in patients with focal epilepsy so far classified cryptogenic (45.2%). Antibody synthesis was not related to the number of CSF white blood cells.ConclusionsHumoral immune activation in the CSF compartment was detected in one‐third of patients with epilepsy, besides acute symptomatic seizures particularly frequent in cryptogenic epilepsy – an etiology so far defined as not having a detectable cause. Systematic prospective clinical and experimental trials are required to identify antigenic targets and select appropriate patients for which immunotherapy might offer new causal therapeutic options.
Lipid profile and thyroid hormone concentrations in children with epilepsy treated with oxcarbazepine monotherapy: a prospective long‐term study
Authors: Garoufi A. , Koemtzidou E. , Katsarou E. , Dinopoulos A. , Kalimeraki I. , Fotinou A. , Drakatos A. , Attilakos A. 
Published: October 2013

Background and purposeTo evaluate prospectively the changes and possible associations in lipid and thyroid profiles in children treated with oxcarbazepine (OXC) monotherapy.MethodsSerum total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TGs), lipoprotein (a) [Lp(a)], free thyroxine (FT4), free triiodothyronine (FT3), thyrotropin (TSH) and gamma‐glutamyltransferase (GGT) concentrations were measured in 23 children with epilepsy, before and at 8 and 18 months of OXC monotherapy.ResultsTotal cholesterol was significantly increased at 8 months (P = 0.033), whereas LDL‐C was significantly increased at 8 and 18 months (P < 0.001 and P = 0.004, respectively) of treatment. Lp(a) was significantly increased at 8 months (P = 0.042) and borderline significantly increased at 18 months (P = 0.050) of treatment. FT4 was significantly decreased at 8 and 18 months (P < 0.001 and P = 0.002, respectively), and TSH levels were significantly increased at 8 and 18 months (P = 0.002 and P = 0.001, respectively) of OXC monotherapy. GGT levels were significantly increased at 8 and 18 months (P < 0.001) of treatment. There were no significant alterations in HDL‐C, TGs and FT3 levels during the study. Significant positive correlations were found between GGT and LDL‐C levels at 8 (r = 0.468, P = 0.024) and 18 months (r = 0.498, P = 0.016), and between TSH and TC at 18 months (r = 0.508, P = 0.013) of treatment.ConclusionsOXC monotherapy may cause significant and persistent alterations in lipid and thyroid profiles in children with epilepsy. The increase in LDL‐C and TC levels may be associated with liver enzymes induction and thyroid dysfunction. Further long‐term prospective studies are required to confirm these findings and to determine their clinical significance.
Diabetes and thrombolysis for acute stroke: a clear benefit for diabetics
Authors: Reiter M. , Teuschl Y. , Matz K. , Seyfang L. , Brainin M. ,   the Austrian Stroke Unit Registry Collaborators
Published: October 2013

Background and purposeDiabetes is a predictor for poor outcome after thrombolysis in stroke patients, and early post‐stroke glycaemia is associated with higher rates of post‐thrombolytic symptomatic intracerebral haemorrhages (SICHs). Diabetic stroke patients may nevertheless profit from thrombolysis. Here, we compared outcome data of matched thrombolysed and non‐thrombolysed diabetic and non‐diabetic stroke patients from a national database.MethodsThe outcomes of 1079 matched quadruples, each consisting of a thrombolysed diabetic, a non‐thrombolysed diabetic, a thrombolysed non‐diabetic and a non‐thrombolysed non‐diabetic case (a total of 4316 cases), enrolled in the Austrian Stroke Unit Registry (2004–2013), were compared. Patients were matched according to sex, age, stroke severity, pre‐stroke disability and prior stroke.ResultsA regression model with improvement as depending variable found no effect of diabetes (P = 0.158) or the interaction diabetes × thrombolysis (P = 0.507), whereas the effect of thrombolysis itself was highly significant (P < 0.001). Functional outcome (modified Rankin Scale) was significantly better in thrombolysed than in non‐thrombolysed diabetic patients at discharge from the stroke‐unit (P < 0.001) and 3 months later (P = 0.006). No significant differences were found in the number of SICHs after thrombolytic treatment between diabetic (4.9%) and non‐diabetic strokes (3.5%). Both groups had a higher risk of SICH compared with the non‐thrombolysed groups (diabetics 2.6%, non‐diabetics 2.5%). Due to lack of documentation, the effect of admission blood glucose on SICH was not investigated.ConclusionsData from this nationwide survey show that diabetic stroke patients receive a substantial benefit from thrombolysis, and therefore diabetic strokes should not be excluded from thrombolytic treatment.