bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of NICE (UK) recommendations on outcomes of cardiac pacemaker implantations – a single‐centre, district hospital experience
Authors: Choo Wai Kah , Gupta Sandeep
Published: January 2011

Aims The National Institute for Health and Clinical Excellence (NICE) recommends the use of dual‐chamber pacemakers for all patients with bradycardia with a few exceptions. We aimed to evaluate our compliance to the guidelines and the implications of different pacing modalities on follow‐up outcomes.

Methods We conducted two retrospective studies involving a total of 316 patients. The first study conducted over a 36‐month period examined our performance prior to the introduction of the NICE guidance. The more recent second study conducted over a 12‐month period examined our compliance to the NICE guidance upon its introduction and adoption. Data were analysed in separate groups according to pacemaker types. Symptom control and mortality were measures on follow‐up outcomes.

Results Our compliance to the guidance increased from 72% in the former study to 78% in the latter study (P = 0.17). Symptom control and mortality were not significantly different between the two studies. Combining both studies, fewer NICE‐compliant patients complained of persisting symptoms after 1 year (P = 0.36). Although fewer deaths were observed in the compliant group, this again was not statistically significant (P = 0.10). Although age was not a criteria in selecting a device, younger patients were more likely to receive a pacemaker according to NICE recommendations (P = 0.001).

Conclusions We achieved a near 80% level of compliance to NICE guidance. Our non‐NICE‐compliant patients did not have a poorer outcome than those who were compliant. The decision to insert single‐ or dual‐chamber pacemakers is often multifactorial and individual doctors may have different practices.
Adefovir serum levels do not differ between responders and nonresponders
Authors: Deterding K. , Naesens L. , Buti M. , Janssen H. , Kirschner J. , Guerrero A. , Reijnders J. , Neyts J. , Zoulim F. , Wedemeyer H.
Published: January 2011

Summary.  Primary or secondary failure of adefovir dipivoxil (ADV) therapy of chronic hepatitis B is not infrequent. The reasons for suboptimal responses are not well defined. In HIV and hepatitis C virus infection, failure of antiviral drug therapy has been linked with low blood drug levels. We have studied 20 well‐defined patients with chronic hepatitis B who were treated with ADV for drug and virus kinetics. Importantly, neither Cmax levels (mean 26 ng/mL, range 14–59 ng/mL) nor the time to maximal drug levels (mean 4 h, range 2–8 h) differed between patients showing a complete virological response to adefovir (n = 10), patients with secondary treatment failure (n = 7) and patients with suboptimal primary response (hepatitis B virus‐DNA >10 000 IU/mL after 6 months of treatment; n = 3). Thus, adefovir treatment failure is unlikely to be due to an inability to mount sufficient drug levels in the blood.
Interference of hepatitis C virus replication in cell culture by antisense peptide nucleic acids targeting the X‐RNA
Authors: Ahn D.‐G. , Shim S.‐B. , Moon J.‐E. , Kim J.‐H. , Kim S.‐J. , Oh J.‐W.
Published: January 2011

Summary.  The RNA‐dependent RNA polymerase (RdRp) of hepatitis C virus (HCV) is the essential catalytic enzyme for viral genome replication. It initiates minus‐strand RNA synthesis from a highly conserved 98‐nt sequence, called the X‐RNA, at the 3′‐end of the plus‐strand viral genome. In this study, we evaluated the antiviral effects of peptide nucleic acids (PNAs) targeting the X‐RNA. Our in vitro RdRp assay results showed that PNAs targeting the three major stem‐loop (SL) domains of X‐RNA can inhibit RNA synthesis initiation. Delivery of X‐RNA‐targeted PNAs by fusing the PNAs to cell‐penetrating peptides (CPPs) into HCV‐replicating cells effectively suppressed HCV replication. Electrophoretic mobility shift assays revealed that the PNA targeting the SL3 region at the 5′‐end of X‐RNA dissociated the viral RdRp from the X‐RNA. Furthermore, delivery of the SL3‐targeted PNA into HCV‐infected cells resulted in the suppression of HCV RNA replication without activation of interferon β expression. Collectively, our results indicate that the HCV X‐RNA can be effectively targeted by CPP‐fused PNAs to block RNA–protein and/or RNA–RNA interactions essential for viral RNA replication and identify X‐RNA SL3 as an RdRp binding site crucial for HCV replication. In addition, the ability to inhibit RNA synthesis initiation by targeting HCV X‐RNA using antisense PNAs suggests their promising therapeutic potential against HCV infection.
Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3‐year follow‐up study
Authors: Fung J. , Lai C.‐L. , Wong D. K.‐H. , Seto W.‐K. , Hung I. , Yuen M.‐F.
Published: January 2011

Summary.  For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty‐six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e‐antigen (HBeAg)‐positive, 293 (69%) were HBeAg‐negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow‐up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow‐up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of ≥1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow‐up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow‐up ALT levels were independent significant factors associated with a decline in LSM.
Sequence‐based typing identification of the novel HLA‐A*24:135 variant in a Maldivian family with a bone marrow patient
Authors: Cervelli C. , Canossi A. , Azzarone R. , Scimitarra M. , Papola F.
Published: January 2011

We describe the identification of the novel HLA‐A*24:135 allele [nucleotide 397 (T→C) in exon 3, Phe→Leu at codon 109 in α2 domain, compared with A*24:02:01] by sequence‐based typing (SBT).
Role of 14‐bp insertion/deletion polymorphism in HLA‐G among Indian women with recurrent spontaneous abortions
Authors: Aruna M. , Sirisha P. V. S. , Andal Bhaskar S. , Tarakeswari S. , Thangaraj K. , Reddy B. M.
Published: January 2011

Human leukocyte antigen (HLA)‐G is predominantly expressed on the extravillous cytotrophoblasts at the fetal–maternal interface. The 14‐bp polymorphism in exon 8 is associated with HLA‐G messenger ribonucleic acid (mRNA) stability and isoform alternative splicing patterns, thereby influencing the functionality of HLA‐G in pregnancy. We analysed the 14‐bp indel polymorphism in 143 recurrent spontaneous abortions (RSAs) and 150 control couples. We did not find any significant difference in the 14‐bp insertion/deletion allele frequencies among the RSA and control couples. Analysis for increased sharing of the polymorphism in the RSA and the control couples also did not show any significant difference. However, we found an increase in the frequency of the 14‐bp deletion homozygotes in the RSA women, which could lead to extremely high levels of soluble HLA‐G (sHLA‐G).
HLA‐DR4 antigen and idiopathic dilated cardiomyopathy susceptibility: a meta‐analysis involving 11,761 subjects
Authors: Jin B. , Ni H. , Geshang Q. , Li Y. , Shen W. , Shi H.
Published: January 2011

Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA‐DR4 antigen and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta‐analysis was performed. Studies in English‐language articles were identified by a search of PubMed and Embase database (inception to June 2010). A total of 19 case–control studies including 1378 cases and 10,383 controls provided data on the association between HLA‐DR4 antigen and genetic susceptibility to IDC. Overall, statistically elevated frequency of HLA‐DR4 allele [OR (odds ratio), 1.58; 95% CI (confidence interval), 1.21–2.07; P = 0.0009] was found in patients with IDC compared with controls. When stratified by myocardial biopsy or non‐biopsy cases, statistically increased risks were found for IDC in both subgroups. In the subgroup analysis by ethnicity, significantly increased risk was found among Europeans from 12 case–control studies (OR, 1.54; 95% CI, 1.11–2.12; P = 0.009). In conclusion, our results suggest that HLA‐DR4 antigen is a low‐penetrant risk factor for developing IDC in Europeans.
Major histocompatibility complex diversity in the endangered Ethiopian wolf (Canis simensis)
Authors: Kennedy L. J. , Randall D. A. , Knobel D. , Brown J. J. , Fooks A. R. , Argaw K. , Shiferaw F. , Ollier W. E. R. , Sillero‐Zubiri C. , Macdonald D. W. , Laurenson M. K.
Published: January 2011

The major histocompatibility complex (MHC) influences immune response to infection and vaccination. In most species, MHC genes are highly polymorphic, but few wild canid populations have been investigated. In Ethiopian wolves, we identified four DLA (dog leucocyte antigen)‐DRB1, two DLA‐DQA1 and five DQB1 alleles. Ethiopian wolves, the world's rarest canids with fewer than 500 animals worldwide, are further endangered and threatened by rabies. Major rabies outbreaks in the Bale Mountains of southern Ethiopia (where over half of the Ethiopian wolf population is located) have killed over 75% of wolves in the affected sub‐populations. In 2004, following a rabies outbreak, 77 wolves were vaccinated, and 19 were subsequently recaptured to monitor the effectiveness of the intervention. Pre‐ and post‐vaccination rabies antibody titres were available for 18 animals, and all of the animals sero‐converted after vaccination. We compared the haplotype frequencies of this group of 18 with the post‐vaccination antibody titre, and showed that one haplotype was associated with a lower response (uncorrected P < 0.03). In general, Ethiopian wolves probably have an adequate amount of MHC variation to ensure the survival of the species. However, we sampled only the largest Ethiopian wolf population in Bale, and did not take the smaller populations further north into consideration.
Identification of a novel HLA‐A*26 allele, A*26:36, by sequence‐based typing
Authors: Li J.‐P. , Li X.‐F. , Chen Y. , Zhang X. , Liu X.‐Z.
Published: January 2011

The novel HLA (human leukocyte angiten)‐A*26 allele differs from A*26:01:01 by a single nucleotide substitution at position 292 of exon 2 where a ‘G’ change to ‘C’.
Gastric cancer with choriocarcinoma and yolk sac tumor components: Case report
Authors: Satake Nobuo , Chikakiyo Motoya , Yagi Toshiyuki , Suzuki Yasuhiro , Hirose Takanori
Published: January 2011

Choriocarcinoma‐ and yolk sac tumor‐like differentiation have rarely been reported in gastric cancers. We report a case of gastric adenocarcinoma, concurrently possessing choriocarcinoma and yolk sac tumor components, of a 74‐year‐old man. A hemorrhagic, 11 × 8 × 3 cm, tumor with ulceration was located in the body and pre‐pylorus of the stomach. Histological examination of the resected specimens demonstrated intermingled proliferation of three different components, namely, adenocarcinoma, choriocarcinoma and yolk sac tumor, which were immunoreactive for carcinoembryonic antigen (CEA), beta‐subunit of human chorionic gonadotropin (HCG) and alpha‐fetoprotein (AFP), respectively. Gastric cancers with germ cell tumor components are uncommon and this is the second reported case of gastric cancer with choriocarcinoma and yolk sac tumor components.
Discovering the value of research supervision
Authors: Severinsson Elisabeth
Published: January 2011

The aim of this editorial was to discover the value of research supervision by reflecting on many years of researching the phenomenon. The main benefits of research supervision are improvements in the quality of academic education, the quality of practice, and nursing and midwifery disciplines. Hence, these values must be acknowledged and more resources, both at universities and in clinical practice, are required. The advantages of research supervision are inherent in all its aspects. More education in research supervision is required in order to implement strategies that improve the level of quality in practice, as well as further research in this area. From an ethical perspective, one of the research questions that needs to be addressed is: Which different responsibilities and rights are important in the supervisory process? This question can be answered by using a multidisciplinary perspective for the purpose of enhancing the quality of education and patient care.
Familial colorectal cancer type X: polyp burden and cancer risk stratification via a family history score
Authors: Koh Poh‐Koon , Kalady Matthew , Skacel Marek , Fay Susan , McGannon Ellen , Shenal Janet , Arroyo Loretta , Toderick Kathy , Church James
Published: January 2011

Background:  Patients fulfilling Amsterdam‐1 criteria without mismatch repair deficiency (termed familial colorectal cancer type X (FCC type X)) were reported to have lower cancer risks than classic Lynch syndrome. This study investigates the polyp and cancer burden of this population and demonstrates relationships with a family history score (FHS).

Methods:  The Jagelman Registry was queried for patients meeting Amsterdam criteria with microsatellite stable/low colorectal cancers. The risk of colorectal neoplasia was ascertained using a published FHS. Polyp distribution, histology and cumulative counts as well as extra‐colonic tumours in the pedigree were reviewed.

Results:  Twenty‐one patients (9 males, 12 females) met study criteria. The median lifetime polyp count was 3 (range 1–36). FHS ≥ 8 (80%) was significantly associated with an increased risk of colorectal cancer compared with those with scores <8 who are more likely to develop polyps (P < 0.01). Twelve patients (57%) had predominantly left‐sided polyps. Ten colorectal cancers (7 left‐sided, 3 right‐sided) were diagnosed at a median age of 48 (range 30–74) years. Only three tumours were mucinous or demonstrated tumour‐infiltrating lymphocytes, typical of high microsatellite instability tumours. All patients had family history of colorectal cancers (CRCs) and at least 10 patients had a family history of uterine or breast cancer. One patient was found to have hyperplastic polyposis syndrome.

Conclusions:  FCC type X likely represents a heterogenous group of as yet undefined CRC predispositions. The polyp burden and cancer risk are variable and can be somewhat delineated according to an FHS.
Emergency cricothyrotomy in infants – evaluation of a novel device in an animal model
Authors: Metterlein T. , Frommer M. , Kwok P. , Lyer S. , Graf B.M. , Sinner B.
Published: January 2011

Background:  According to different algorithms of airway management, emergency cricothyrotomy is the final step in managing an otherwise not accessible airway. As an alternative to an open surgical procedure, minimally invasive approaches exist. Quicktrach baby™ is a commercially available set for a minimal invasive cricothyrotomy in infants. The set consists of a plastic cannula over a metal needle for direct placement in the trachea. So far, this device has not been evaluated for its intended use.

Objectives:  We hypothesize that Quicktrach baby™ allows the establishment of an emergency airway. The aim was to prove that the device is easy to handle and the cricothyrotomy fast to perform.

Methods:  After approval of the local ethics committee, the study was performed on the cadavers of 10 adult rabbits. Cricothyrotomy was performed with Quicktrach baby™. Successful placement, performance time, and complication rate were documented. Possible ventilation with a breathing bag was evaluated. Data are reported as mean and interquartile range.

Results:  Successful placement of Quicktrach baby™ was possible in all attempts. The placement took 31 [23–43] s. In two cases, a fracture of the cricoid’s cartilage was seen. In one animal, damage to the posterior wall mucosa was observed. In all cases, sufficient ventilation was possible.

Conclusions:  Quicktrach™ baby proved to be a reliable technique. In the animal model, it is easy and fast to perform. Only a few minor complications occurred. Sufficient ventilation was possible in all attempts.
High‐dose dexmedetomidine sedation for pediatric MRI
Authors: Siddappa Rajashekhar , Riggins Jessica , Kariyanna Shathabish , Calkins Paul , Rotta Alexandre T.
Published: January 2011

Objectives:  To test the hypothesis that high‐dose dexmedetomidine can be successfully used for pediatric magnetic resonance imaging (MRI) sedation without significant hemodynamic compromise.

Background:  The dexmedetomidine dose required to achieve optimal sedation is often higher than its recommended dose. High doses of dexmedetomidine can lead to significant hemodynamic side effects.

Methods:  Dexmedetomidine use for pediatric MRI over a 1‐year period was retrospectively reviewed. A dexmedetomidine bolus of 2 μg·kg−1 intravenous followed by 1 μg·kg−1·h−1 infusion was used. Dexmedetomidine efficacy, side effects, timing of side effects, and additional use of medications were analyzed. Data were compared by t‐test, Mann–Whitney rank‐sum test, Fisher’s exact test, and anova.

Results:  High‐dose dexmedetomidine was used in 77 patients, and MRI was completed in 76 (99%) patients. A second bolus of dexmedetomidine was required in 28 (36%) patients, and 22 (29%) patients required additional medications (midazolam, fentanyl, or ketamine) for adequate sedation. A 25% decrease in blood pressure (BP) was observed in 10.5%, a transient increase in BP in 3.9%, and a heart rate <60 min−1 in 7.9% of cases. These side effects resolved spontaneously. There were no apneas or respiratory depression. Vital sign changes, recovery time, and discharge time were not significantly different in subgroups of patients receiving one or two boluses of dexmedetomidine with or without additional medications. Transient hypertension was more common in patients receiving two boluses of dexmedetomidine (P = 0.048).

Conclusions:  High‐dose dexmedetomidine can be successfully used for pediatric MRI sedation, but a significant number of children require additional medications for optimal control. Hemodynamic side effects resolved spontaneously. High‐dose dexmedetomidine did not result in respiratory depression.
Genetic Information: Comparing Alternative Regulatory Approaches When Prevention Matters
Authors: BARIGOZZI FRANCESCA , HENRIET DOMINIQUE
Published: January 2011

We compare the alternative approaches used for regulating genetic information in the health insurance market when prevention measures are available. In the model, firms offer insurance contracts to consumers who are initially uninformed of their risk type but can obtain such information by performing a costless genetic test. A crucial ingredient of our analysis is that information has decision‐making value since it allows for the optimal choice of a self‐insurance action (secondary prevention). We focus on the welfare properties of market equilibria obtained under the different regulatory schemes and, by using an intuitive graphical analysis, we rank them unambiguously. Our results show that Disclosure Duty weakly dominates the other regulatory schemes and that Strict Prohibition represents the worst regulatory approach.
Optimal Nonlinear Redistributive Taxation and Public Good Provision in an Economy with Veblen Effects
Authors: MICHELETTO LUCA
Published: January 2011

This paper deals with the consequences of the assumption of negatively interdependent preferences for the shape of the optimal nonlinear income tax and the efficient level of public good provision in a setting where the agents' market ability is private information. The analysis points out that the terms added in the tax formulas due to the presence of Veblen effects might justify a reduction in the optimal marginal tax rates faced by the different individuals. Also, the desirability of negative marginal tax rates cannot be ruled out. With respect to the issue of the optimal level of public good provision, I derive a modified Samuelson rule and highlight the fact that the Veblen‐based part of the formula might require to distort downwards the efficient level of public good provision.
Pathological significance of ganglioside clusters in Alzheimer’s disease
Authors: Yanagisawa Katsuhiko
Published: January 2011

J. Neurochem. (2011) 116, 806–812.

One of the key questions regarding the pathogenesis of Alzheimer’s disease (AD) is how amyloid β‐protein (Aβ), a proteinaceous component of senile plaques, starts to assemble into amyloid fibrils in the brain. A body of evidence is growing to suggest that Aβ binds to ganglioside on neuronal membranes, and then, is converted to an endogenous seed with an altered conformation (ganglioside‐bound Aβ, GAβ) for amyloid fibril formation in the brain. Notably, the risk factors for the development of AD, including aging and apolipoprotein E4, likely facilitate the formation of ganglioside clusters in lipid raft‐like membrane microdomains at pre‐synaptic terminals, which provide a favorable milieu for the GAβ generation. Furthermore, it has also been suggested that endocytic pathway abnormality of neurons is involved in the formation of the ganglioside clusters. In this review, the nature of the ganglioside clusters and how gangliosides behave in the clusters leading to the GAβ generation are discussed.
Reggie/flotillin and the targeted delivery of cargo
Authors: Stuermer Claudia A. O.
Published: January 2011

J. Neurochem. (2011) 116, 708–713.

The two proteins reggie‐1/flotillin‐2 and reggie‐2/flotillin‐1 form microdomains at the plasma membrane and at intracellular compartments where src tyrosine kinases associate with them. Specific GPI‐anchored proteins, in particular prion protein and Thy‐1, co‐cluster with reggie microdomains at the plasma membrane and elicit signal transduction in association with reggies which regulates the activation of several GTPases involved in the recruitment of specific membrane proteins from intracellular carriers to target sites of the cell membrane in a cell type‐specific manner. For example, prion protein and reggie regulate the recruitment and targeted delivery of the T cell receptor complex to the T cell cap, of E‐cadherin to cell–cell contact sites in epithelial cells, and of bulk membrane and growth receptors to the growth cone in developing neurons. Evidence is accumulating that reggies are involved in guiding the cell‐type‐specific membrane proteins from the intracellular compartments to their target sites at the cell membrane, a function required in all cells which explains why reggies are expressed in many or all cells in invertebrates and vertebrates.
Cellular prion protein is implicated in the regulation of local Ca2+ movements in cerebellar granule neurons
Authors: Lazzari Cristian , Peggion Caterina , Stella Roberto , Massimino Maria Lina , Lim Dmitry , Bertoli Alessandro , Sorgato Maria Catia
Published: January 2011

J. Neurochem. (2011) 116, 881–890.

The cellular prion protein (PrPC) is a cell‐surface glycoprotein mainly expressed in the CNS. The structural conversion of PrPC generates the prion, the infectious agent causing transmissible spongiform encephalopathies, which are rare and fatal diseases affecting animals and humans. Despite decades of intensive research, the mechanism of prion‐associated neurodegeneration and the physiologic role of PrPC are still obscure. Recent evidence, however, supports the hypothesis that PrPC may be involved in the control of Ca2+ homeostasis. Given the universal significance of Ca2+ as an intracellular messenger for both the life and death of cells, this possibility may help explain the complex, often controversial, dataset accumulated on PrPC physiology, and the events leading to prion‐associated neuronal demise. In this study, we have compared local Ca2+ movements in cerebellar granule neurons (CGN) derived from wild‐type (WT), or PrP‐knockout (KO), mice, by means of the Ca2+‐sensitive photo‐probe, aequorin, genetically targeted to specific intracellular domains and delivered to CGN by lentiviral vectors. The use of an aequorin that localizes to the cytosolic domains proximal to the plasma membrane has allowed us to demonstrate that there was a dramatic increase of store‐operated Ca2+ entry in PrP‐KO CGN compared to WT neurons. Notably, this phenotype was rescued upon restoring PrPC expression. The Ca2+‐phenotype of PrP‐KO neurons can in part be explained by the lower expression of two major Ca2+‐extruding proteins, namely the plasma membrane and the sarco‐endoplasmic reticulum Ca2+‐ATPases. The lower sarco‐endoplasmic reticulum Ca2+‐ATPase content may also contribute to explain why PrP‐KO CGN accumulated less Ca2+ in the endoplasmic reticulum than the WT counterpart.
Cholesterol asymmetry in synaptic plasma membranes
Authors: Gibson Wood W. , Igbavboa Urule , Müller Walter E. , Eckert Gunter P.
Published: January 2011

J. Neurochem.(2011)116, 684–689.

Lipids are essential for the structural and functional integrity of membranes. Membrane lipids are not randomly distributed but are localized in different domains. A common characteristic of these membrane domains is their association with cholesterol. Lipid rafts and caveolae are examples of cholesterol enriched domains, which have attracted keen interest. However, two other important cholesterol domains are the exofacial and cytofacial leaflets of the plasma membrane. The two leaflets that make up the bilayer differ in their fluidity, electrical charge, lipid distribution, and active sites of certain proteins. The synaptic plasma membrane (SPM) cytofacial leaflet contains over 85% of the total SPM cholesterol as compared with the exofacial leaflet. This asymmetric distribution of cholesterol is not fixed or immobile but can be modified by different conditionsin vivo: (i) chronic ethanol consumption; (ii) statins; (iii) aging; and (iv) apoE isoform. Several potential candidates have been proposed as mechanisms involved in regulation of SPM cholesterol asymmetry: apoE, low‐density lipoprotein receptor, sterol carrier protein‐2, fatty acid binding proteins, polyunsaturated fatty acids, P‐glycoprotein and caveolin‐1. This review examines cholesterol asymmetry in SPM, potential mechanisms of regulation and impact on membrane structure and function.
Roles of sphingolipids in Drosophila development and disease
Authors: Kraut Rachel
Published: January 2011

J. Neurochem. (2011) 116, 764–778.

The last 10 years have seen a rebirth of interest in lipid biology in the fields of Drosophila development and neurobiology, and sphingolipids have emerged as controlling many processes that have not previously been studied from the viewpoint of lipid biochemistry. Mutations in sphingolipid regulatory enzymes have been pinpointed as affecting cell survival and growth in tissues ranging from muscle to retina. Specification of cell types are also influenced by sphingolipid regulatory pathways, as genetic interactions of glycosphingolipid biosynthetic enzymes with many well‐known signaling receptors such as Notch and epidermal growth factor receptor reveal. Furthermore, studies in flies are now uncovering unexpected roles of sphingolipids in controlling lipid storage and response to nutrient availability. The sophisticated genetics of Drosophila is particularly well suited to uncover the roles of sphingolipid regulatory enzymes in development and metabolism, especially in light of conserved pathways that are present in both flies and mammals. The challenges that remain in the field of sphingolipid biology in Drosophila are to combine traditional developmental genetics with more analytical biochemical and biophysical methods, to quantify and localize the responses of these lipids to genetic and metabolic perturbations.
Purinergic signalling at the plasma membrane: a multipurpose and multidirectional mode to deal with amyotrophic lateral sclerosis and multiple sclerosis
Authors: Amadio Susanna , Apolloni Savina , D’Ambrosi Nadia , Volonté Cinzia
Published: January 2011

J. Neurochem. (2011) 116, 796–805.

ATP is a widespread and multipurpose signalling molecule copiously released in the extracellular environment of the whole nervous system upon cell activation, stress, or damage. Extracellular ATP is also a multidirectional information molecule, given the concurrent presence at the plasma membrane of various targets for ATP. These include ectonucleotidases (metabolizing ATP down to adenosine), ATP/adenosine transporters, P2 receptors for purine/pyrimidine nucleotides (ligand‐gated ion channels P2X receptors and G‐protein‐coupled P2Y receptors), in addition to metabotropic P1 receptors for nucleosides. All these targets rarely operate as single units, rather they associate with each other at the plasma membrane as multi‐protein complexes. Altogether, they control the duration, magnitude and/or direction of the signals triggered and propagated by purine/pyrimidine ligands, and the impact that each single ligand has on a variety of short‐ and long‐term functions. A strict control system allows assorted, even divergent, biological outcomes. Among these, we enumerate cell‐to‐cell communication, tropic, trophic, but also noxious actions causing the insurgence/progression of pathological conditions. Here, we show that purinergic signalling in the nervous system can be instrumental for instance to neurodegenerative and neuroinflammatory diseases such as amyotrophic lateral sclerosis and multiple sclerosis.
Cannabinoid 1 receptor‐dependent transactivation of fibroblast growth factor receptor 1 emanates from lipid rafts and amplifies extracellular signal‐regulated kinase 1/2 activation in embryonic cortical neurons
Authors: Asimaki Olga , Leondaritis George , Lois Giannis , Sakellaridis Nikos , Mangoura Dimitra
Published: January 2011

J. Neurochem. (2011) 116, 866–873.

G‐protein coupled receptors may mediate their effects on neuronal growth and differentiation through activation of extracellular signal‐regulated kinases 1/2 (ERK1/2), often elicited by transactivation of growth factor receptor tyrosine kinases. This elaborate signaling process includes inducible formation and trafficking of multiprotein signaling complexes and is facilitated by pre‐ordained membrane microdomains, in particular lipid rafts. In this study, we have uncovered novel signaling interactions of cannabinoid receptors with fibroblast growth factor receptors, which depended on lipid rafts and led to ERK1/2 activation in primary neurons derived from chick embryo telencephalon. More specifically, the cannabinoid 1 receptor (CB1R) agonist methanandamide induced tyrosine phosphorylation and transactivation of fibroblast growth factor receptor (FGFR)1 via Src and Fyn, which drove an amplification wave in ERK1/2 activation. Transactivation of FGFR1 was accompanied by the formation of a protein kinase C ε‐dependent multiprotein complex that included CB1R, Fyn, Src, and FGFR1. Recruitment of molecules increased with time of exposure to methanandamide, suggesting that in addition to signaling it also served trafficking of receptors. Upon agonist stimulation we also detected a rapid incorporation of CB1R, as well as activated Src and Fyn, and FGFR1 in lipid rafts. Most importantly, lipid raft integrity was a pre‐requisite for CB1R‐dependent complex formation. Our data provide evidence that lipid rafts may organize CB1 receptor proximal signaling events, namely activation of Src and Fyn, and transactivation of FGFR1 towards activation of ERK1/2 and induction of neuronal differentiation.
Functional characterization of putative cholesterol binding sequence (CRAC) in human type‐1 cannabinoid receptor
Authors: Oddi Sergio , Dainese Enrico , Fezza Filomena , Lanuti Mirko , Barcaroli Daniela , De Laurenzi Vincenzo , Centonze Diego , Maccarrone Mauro
Published: January 2011

J. Neurochem. (2011) 116, 858–865.

Endocannabinoid signaling modulates a variety of neuroinflammatory and neurodegenerative diseases, mainly through the activation of type‐1 and type‐2 (CB1R and CB2R) cannabinoid receptors. CB1R is negatively regulated by membrane cholesterol, while CB2R is unaffected. Here, we identified in the transmembrane helix 7 of human CBRs a consensus sequence already known in other proteins as cholesterol recognition/interaction amino acid sequence and consensus pattern. As this motif is different in the two CBR subtypes, we mutated lysine 402 of CB1R into glycine, to obtain a cholesterol recognition/interaction amino acid sequence and consensus similar to that of CB2R. Both mutated and wild‐type receptors were transiently expressed in human neuronal SH‐SY5Y cells, and their localization and functioning were investigated using biochemical assays and immunofluorescence labelling. We found a reduced propensity of the mutant CB1R to reside in cholesterol‐rich microdomains and, by means of fluorescence recovery after photobleaching analysis, we documented its loss of sensitivity to increased membrane cholesterol content. These results seem to uncover the existence of a new structural determinant in cannabinoid receptors, that is likely implicated in directing their interaction with cholesterol‐rich microdomains of cell membranes.
Histone acetylation‐mediated glycosyltransferase gene regulation in mouse brain during development
Authors: Suzuki Yusuke , Yanagisawa Makoto , Ariga Toshio , Yu Robert K.
Published: January 2011

J. Neurochem. (2011) 116, 874–880.

Gangliosides are sialic acid‐containing glycosphingolipids abundant in the central nervous tissues. The quantity and expression pattern of gangliosides in brain change drastically during early development and are mainly regulated through stage‐specific expression of glycosyltransferase (ganglioside synthase) genes. It is still unclear, however, how the transcriptional activation of glycosyltransferase genes is regulated during development. In this study, we investigated the epigenetic regulation of two key glycosyltransferases, N‐acetylgalactosaminyltransferase I (GA2/GM2/GD2/GT2‐synthase) and sialyltransferase II (GD3‐synthase), in embryonic, postnatal, and adult mouse brains. Combined bisulfite restriction analysis assay showed that DNA methylation in the 5′ regions of these glycosyltransferase genes was not associated with their expression patterns. On the other hand, chromatin immunoprecipitation assay of both glycosyltransferase genes showed that their histone H3 acetylation was highly correlated to their mRNA expression levels during development. In fact, we confirmed that the expression patterns of gangliosides and glycosyltransferases in neuroepithelial cells were changed after treatment with a histone deacetylase inhibitor, sodium butyrate. Our studies provide the first evidence that efficient histone acetylation of the glycosyltransferase genes in mouse brain contributes to the developmental alteration of ganglioside expression.
Myelin‐associated glycoprotein protects neurons from excitotoxicity
Authors: Lopez Pablo H. H. , Ahmad Abdullah S. , Mehta Niraj R. , Toner Mayu , Rowland Elizabeth A. , Zhang Jiangyang , Doré Sylvain , Schnaar Ronald L.
Published: January 2011

J. Neurochem. (2011) 116, 900–908.

In addition to supporting rapid nerve conduction, myelination nurtures and stabilizes axons and protects them from acute toxic insults. One myelin molecule that protects and sustains axons is myelin‐associated glycoprotein (MAG). MAG is expressed on the innermost wrap of myelin, apposed to the axon surface, where it interacts with axonal receptors that reside in lateral membrane domains including gangliosides, the glycosylphosphatidylinositol‐anchored Nogo receptors, and β1‐integrin. We report here that MAG protection extends beyond the axon to the neurons from which those axons emanate, protecting them from excitotoxicity. Compared to wild type mice, Mag‐null mice displayed markedly increased seizure activity in response to intraperitoneal injection of kainic acid, an excitotoxic glutamate receptor agonist. Mag‐null mice also had larger lesion volumes in response to intrastriatal injection of the excitotoxin NMDA. Prior injection of a soluble form of MAG partially protected Mag‐null mice from NMDA‐induced lesions. Hippocampal neurons plated on proteins extracted from wild‐type rat or mouse myelin were resistant to kainic acid‐induced excitotoxicity, whereas neurons plated on proteins from Mag‐null myelin were not. Protection was reversed by anti‐MAG antibody and replicated by addition of soluble MAG. MAG‐mediated protection from excitotoxicity was dependent on Nogo receptors and β1‐integrin. We conclude that MAG engages membrane‐domain resident neuronal receptors to protect neurons from excitotoxicity, and that soluble MAG mitigates excitotoxic damage in vivo.
Plasmalogen synthesis is regulated via alkyl‐dihydroxyacetonephosphate‐synthase by amyloid precursor protein processing and is affected in Alzheimer’s disease
Authors: Grimm Marcus O. W. , Kuchenbecker Johanna , Rothhaar Tatjana L. , Grösgen Sven , Hundsdörfer Benjamin , Burg Verena K. , Friess Petra , Müller Ulrike , Grimm Heike S. , Riemenschneider Mathias , Hartmann Tobias
Published: January 2011

J. Neurochem. (2011) 116, 916–925.

Lipids play an important role as risk or protective factors in Alzheimer’s disease, which is characterized by amyloid plaques composed of aggregated amyloid‐beta. Plasmalogens are major brain lipids and controversially discussed to be altered in Alzheimer’s disease (AD) and whether changes in plasmalogens are cause or consequence of AD pathology. Here, we reveal a new physiological function of the amyloid precursor protein (APP) in plasmalogen metabolism. The APP intracellular domain was found in vivo and in vitro to increase the expression of the alkyl‐dihydroxyacetonephosphate‐synthase (AGPS), a rate limiting enzyme in plasmalogen synthesis. Alterations in APP dependent changes of AGPS expression result in reduced protein and plasmalogen levels. Under the pathological situation of AD, increased amyloid‐beta level lead to increased reactive oxidative species production, reduced AGPS protein and plasmalogen level. Accordingly, phosphatidylethanol plasmalogen was decreased in the frontal cortex of AD compared to age matched controls. Our findings elucidate that plasmalogens are decreased as a consequence of AD and regulated by APP processing under physiological conditions.
Ganglioside GD3 monoclonal antibody‐induced paxillin tyrosine phosphorylation and filamentous actin assembly in cerebellar growth cones
Authors: Yuyama Kohei , Sekino‐Suzuki Naoko , Yamamoto Naomasa , Kasahara Kohji
Published: January 2011

J. Neurochem. (2011) 116, 845–850.

We have demonstrated that antibody to ganglioside GD3 (R24) immunoprecipitates src‐family tyrosine kinase Lyn from primary cerebellar granule cells and R24 treatment of the intact cells induces Lyn activation and rapid tyrosine phosphorylation of several substrates, suggesting the functional association of ganglioside GD3 with Lyn. In this study, R24 treatment of primary cerebellar granule cells enhances phosphorylation of paxillin at tyrosine residue 118 and induces filamentous actin assembly and neurite outgrowth. R24 treatment of cerebellar growth cone membrane fraction induces prominent tyrosine phosphorylation of 68 kDa protein which comigrates with phosphopaxillin at tyrosine residue 118. Tyrosine phosphorylation of paxillin is known to regulate actin cytoskeleton‐dependent changes in cell morphology. Signal transduction by ganglioside GD3 is involved in growth cone morphology via tyrosine phosphorylation of paxillin.
Regulation of tyrosine kinase B activity by the Cyp46/cholesterol loss pathway in mature hippocampal neurons: relevance for neuronal survival under stress and in aging
Authors: Sodero Alejandro O. , Trovò Laura , Iannilli Francesca , Van Veldhoven Paul , Dotti Carlos G. , Martin Mauricio G.
Published: January 2011

J. Neurochem. (2011) 116, 747–755.

It is well established that memory formation and retention involve the coordinated flow of information from the post‐synaptic site of particular neuronal populations to the nucleus, where short and long‐lasting modifications of gene expression occur. With age, mnemonic, motor and sensorial alterations occur, and it is believed that extra failures in the mechanisms used for memory formation and storage are the cause of neurodegenerative pathologies like Alzheimer’s disease. A prime candidate responsible for damage and loss of function during aging is the accumulation of reactive oxygen species, derived from normal oxidative metabolism. However, dysfunction in the aged brain is not paralleled by an increase in neuronal death, indicative that the brain is better suited to fight against the death signals generated from reactive oxygen species than against loss‐of‐function stimuli. A main aim of this laboratory is to understand how neurons perform and survive in the constitutive stress background represented by aging. In this report, we summarize our recent findings in relation to survival.
Assessment of abuse of tianeptine from a reimbursement database using ‘doctor‐shopping’ as an indicator
Authors: Rouby Frank , Pradel Vincent , Frauger Elisabeth , Pauly Vanessa , Natali François , Reggio Patrick , Thirion Xavier , Micallef Joëlle
Published: January 2011

Doctor‐shopping is a patient behaviour characterized by simultaneous consultations of several physicians during the same period. Some case reports have described an abuse of tianeptine, an atypical antidepressant. Our objective was to assess the extent of abuse of this drug with a method quantifying doctor‐shopping in comparison with other antidepressants and benzodiazepines (BZD). All dispensations of antidepressants and BZD during the year 2005 in a French area of 4.5 million inhabitants were extracted from a reimbursement database. For each patient, two quantities were computed: quantity dispensed and obtained by doctor‐shopping. Tianeptine and other drugs were compared using their doctor‐shopping indicator (DSI), defined as the percentage of drug obtained by doctor‐shopping among dispensed quantity; 410 525 patients received at least one antidepressant dispensation during the year 2005. Tianeptine was the sixth most dispensed antidepressant. The DSI of tianeptine was 2.0%, ranking it first among antidepressant (the second being mianserine with a DSI of 1%). Flunitrazepam has the highest DSI (30.2%), the DSI of the five following BZD (clonazepam, zolpidem, oxazepam, diazepam, bromazepam) range from 3.0% to 2.0%. Tianeptine is associated with higher DSI, compared with other antidepressants, suggesting that it may be subject to abuse in the population. Moreover, its DSI as a measure of diversion is similar to the DSI of diazepam or bromazepam.
Protective effect of antioxidants on blood oxidative stress caused by arginine
Authors: de Lima Daniela Delwing , Delwing Fábio , da Cruz José Geraldo Pereira , Wyse Angela Terezinha Souza , Magro Débora Delwing‐Dal
Published: January 2011

In this study, we investigated in vivo and in vitro effect of arginine on parameters of oxidative stress namely thiobarbituric acid‐reactive substances (TBA‐RS) and total radical‐trapping antioxidant parameter (TRAP) in plasma and on the antioxidant enzymes activities catalase (CAT), glutathione peroxidase (GSH‐Px), and superoxide dismutase (SOD) in erythrocytes of rats. Results showed that acute administration reduced TRAP and CAT activity and increased TBA‐RS. Furthermore, in vitro studies did not alter oxidative parameters studied. The influence of Nω‐nitro‐l‐arginine methyl ester (l‐NAME) and antioxidants (α‐tocopherol plus ascorbic acid) on the effects elicited by arginine was also studied. In addition, simultaneous injection of l‐NAME or treatment with antioxidants prevented the alteration on TRAP, TBA‐RS, and CAT activity caused by arginine. Data indicate that oxidative stress induction is probably mediated by the generation of NO and/or ONOO− and other free radicals, because l‐NAME and these antioxidants prevented these effects caused by arginine.
Diverse modulating effects of estradiol and progesterone on the monophasic action potential duration in Langendorff‐perfused female rabbit hearts
Authors: Cheng Jianhua , Ma Xiaohong , Zhang Juan , Su Dan
Published: January 2011

This study aimed to comparatively investigate the acute modulating effects of oestrogen and progesterone on the repolarization and the susceptibility of female rabbits to class III anti‐arrhythmic agents. The acute influence of estradiol and progesterone on the cardiac repolarization and the drug sensitivity of the rapidly activating delayed rectifier K+channel to sotalol was comparatively studied in Langendorff‐perfused rabbit hearts at pharmacological concentrations through recording of epicardial monophasic action potentials. In Langendorff‐perfused rabbit hearts, estradiol (1–30 μm) concentration‐dependently prolonged the monophasic action potential durations (MAPD30and MAPD90) (P < 0.05); while the effects of progesterone on MAPD were biphasic: it prolonged MAPD30and MAPD90at lower concentrations (1–3 μm) but shortened MAPD30and MAPD90at higher concentrations (10–30 μm). Sotalol‐induced prolongation of MAPD90was significantly less in the hearts pretreated with progesterone than those treated with estradiol (P < 0.05). The incidence of the pro‐arrhythmic events induced by sotalol in the hearts pretreated with progesterone was also significantly lower than those pretreated with estradiol (P < 0.05). In conclusion, estradiol and progesterone have different modulating effects on cardiac repolarization: estradiol can concentration‐dependently prolong the cardiac repolarization time and thus may reduce the repolarization reserve and increase the susceptibility of female rabbits to sotalol‐induced arrhythmias, whereas progesterone may shorten the cardiac repolarization time at concentrations above 10 μm, thus protecting the heart from drug‐induced arrhythmias.