bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional, Geographic, and Ethnic Differences in Medication Adherence among Adults with Type 2 Diabetes
Authors: Egede Leonard E , Gebregziabher Mulugeta , Hunt Kelly J , Axon Robert N , Echols Carrae , Gilbert Gregory E , Mauldin Patrick D
Published: February 2011

BACKGROUND:

Medication adherence, a critical component of glycemic control for patients with type 2 diabetes, differs by race/ethnicity. However, few studies have examined regional and rural/urban differences in medication adherence and whether racial/ethnic differences persist after controlling for these differences.

OBJECTIVE:

To examine regional, rural/urban, and racial/ethnic differences in medication adherence in a national sample of veterans with type 2 diabetes.

METHODS:

We performed a cohort study of a national sample of veterans with diabetes (N = 690,968) receiving prescriptions for insulin or oral hypoglycemic agents in 2002. Patients were followed until death, loss to follow-up, or through December 2006. We calculated the annual medication possession ratio (MPR) for each veteran across 4 groups of medication users: individuals using (1) insulin only, (2) oral hypoglycemic agents only, (3) insulin combined with hypoglycemic agents, and (4) insulin or oral hypoglycemic agents (primary analysis).

RESULTS:

In longitudinal models for the primary analysis, adjusting for relevant covariates and time trends, MPR was significantly lower among non-Hispanic blacks (NHBs), Hispanics, and individuals with other/missing/unknown race/ethnicity (6.07%, 1.76%, and 2.83% lower, respectively) relative to non-Hispanic whites (NHWs). MPR was also 2.0% higher in rural versus urban veterans and 1.28% higher in the mid-Atlantic, 2.04% higher in the Midwest, and 0.76% lower in the West, relative to the South. There was a significant race/ethnicity and urban/rural interaction. In NHWs and NHBs, MPR was 1.91 % and 2.00% higher, respectively, in rural versus urban veterans; in contrast, in Hispanics, MPR was 1.0% lower in rural veterans relative to urban veterans.

CONCLUSIONS:

In a national longitudinal cohort of veterans with type 2 diabetes, we found significant regional, rural/urban, and racial/ethnic differences in MPR. Rural/urban residence modified the effect of race/ethnicity on MPR. Recognition of these differences can enable clinicians to better allocate resources and target quality improvement programs.
Impact of Mycophenolate Mofetil Dose Reduction on Allograft Outcomes in Kidney Transplant Recipients on Tacrolimus-Based Regimens: A Systematic Review
Authors: Su Victoria CH , Greanya Erica D , Ensom Mary HH
Published: February 2011

OBJECTIVE:

To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens.

DATA SOURCES:

PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed.

STUDY SELECTION AND DATA EXTRACTION:

Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes.

DATA SYNTHESIS:

Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30–40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation.

CONCLUSIONS:

Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens.
A Comparative Look at the Safety Profiles of Intravenous Iron Products Used in the Hemodialysis Population
Authors: Coppol Elena , Shelly Jamie , Cheng Stephanie , Kaakeh Yaman , Shepler Brian
Published: February 2011

OBJECTIVE:

To review clinical trials conducted in hemodialysis patients of the 4 intravenous iron products available in the US in an attempt to discern strengths and inferiorities between products and evaluate current safety data that can be used to assist the clinician in selecting the most appropriate agent.

DATA SOURCES:

Literature was accessed through PubMed (January 2000-October 2010). In some cases, reference citations from selected review articles were evaluated as well.

STUDY SELECTION AND DATA EXTRACTION:

Clinical trials published in the English language were selected using the search terms iron dextran, iron sucrose, sodium ferric gluconate, and ferumoxytol. Studies were further pared down to include only those enrolling hemodialysis patients.

DATA SYNTHESIS:

There are currently 4 intravenous iron formulations in the US used to treat iron-deficiency anemia in hemodialysis patients. Ferumoxytol has not yet been directly compared to the other 3 agents. Eight studies have been conducted in hemodialysis patients directly comparing iron dextran, iron sucrose, and/or sodium ferric gluconate. These studies were further categorized for evaluation based on iron products compared. Four studies directly compared iron dextran to iron sucrose, 1 study compared iron dextran to sodium ferric gluconate, 1 study compared iron sucrose to sodium ferric gluconate, and 2 studies compared all 3 agents. Of the 3 agents, iron dextran appears to have the least favorable safety profile, while iron sucrose appears most favorable.

CONCLUSIONS:

The newest intravenous iron product, ferumoxytol, has not been directly compared to the other 3 agents. Large well-controlled studies of these products specifically in the hemodialysis population would further help clinicians determine appropriate therapy. Iron sucrose appears to offer the most favorable safety profile when compared to iron dextran and sodium ferric gluconate in treating hemodialysis patients. Oxidative stress and hypersensitivity reactions are common problems encountered when administering intravenous iron.
Impact of Early Postoperative Hydrocortisone Administration in Cardiac Surgical Patients after Cardiopulmonary Bypass
Authors: Ensor Christopher R , Sabo Roy T , Voils Stacy A
Published: February 2011

BACKGROUND:

The usefulness of glucocorticoids after cardiac surgery with cardiopulmonary bypass has been a matter of debate for many years. Exposure to cardiopulmonary bypass evokes the systemic inflammatory response syndrome in patients undergoing cardiac surgery. Intravenous glucocorticoids have been used to reduce proinflammatory cytokine release, slow leukocyte migration, and decrease capillary leak associated with cardiopulmonary bypass.

OBJECTIVE:

To assess the impact of early postoperative hydrocortisone administration on duration of vasoactive medication administration and the incidence of postoperative atrial fibrillation in cardiac surgical patients after cardiopulmonary bypass.

METHODS:

A retrospective cohort study (between July 1, 2004, and June 30, 2008) was conducted at a large, university-affiliated, tertiary-care medical center. One-hundred forty-seven patients who underwent cardiac surgery with cardiopulmonary bypass, 72 of whom received at least 1 dose of hydrocortisone (treatment), and 75 similar patients who did not receive hydrocortisone (control), were randomly selected.

RESULTS:

Cardiopulmonary bypass and aortic cross-clamp times were similar between treatment and control groups (128 vs 124 minutes, p = 0.56; 103 vs 98 minutes, p = 0.39). Patients who received hydrocortisone had a significantly shorter time to discontinuation of all vasoactive medications (79.6 vs 21.1 hours, p < 0.001), and less postoperative atrial fibrillation (OR 0.28, 95% CI 0.14 to 0.56, p < 0.001). Patients in the treatment group experienced significantly more hyperglycemia (89 vs 71%, p = 0.006); however, major and minor bleeding or infection rates did not differ significantly between groups.

CONCLUSIONS:

Patients treated with hydrocortisone after cardiac surgery with cardiopulmonary bypass experienced a significantly shorter time to discontinuation of all vasoactive medications and less postoperative atrial fibrillation than patients not treated with hydrocortisone. These benefits came at the expense of significantly more hyperglycemia.
The Pharmacogenetic Rescue of Side-Lined Anticancer Drugs to the Front-Line: Gefitinib as a Case Example
Authors: Li-Wan-Po Alain , Farndon Peter A , Kobayashi Susumu , Mitsudomi Tetsuya , Potter Vanessa A
Published: February 2011

OBJECTIVE:

To illustrate the increasing importance of pharmacogenetics in drug development and clinical practice through a critical analysis of the validation and licensing of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as a treatment for non–small cell lung cancer (NSCLC).

DATA SOURCES:

Journal articles and the “grey” literature were identified through a systematic search of MEDLINE (to June 2010) and the Web sites of the major drug regulators. References identified through the reference lists of major published reviews of gefitinib and Erb receptors, including EGFR, were also reviewed.

STUDY SELECTION AND DATA EXTRACTION:

A broad appraisal of the titles and abstracts of articles on gefitinib and tyrosine kinase inhibitors in lung cancer was undertaken to identify pertinent concepts and relevant publications for further analysis. Articles deemed particularly relevant were retrieved for detailed appraisal. Dossiers on the licensing of gefitinib from the Food and Drug Administration Web site and major published reviews were retrieved. Relevant pharmacogenetic issues were identified and the clinical studies addressing these were evaluated.

DATA SYNTHESIS:

Initial promising trial data for gefitinib in NSCLC led to its conditional marketing approval. When the drug's efficacy was not confirmed in a pivotal Phase 3 trial, its prescribing was restricted. Subsequent discovery of activating mutations in the tyrosine kinase domain of EGFR led to further retrospective and prospective evaluation of the drug in patients with those mutations. The new evidence was sufficiently robust to persuade the drug regulators to license the drug as first-line treatment for patients with locally advanced or metastatic NSCLC who test positive for those mutations.

CONCLUSIONS:

Pharmacogenetic evidence has played a key role in rescuing gefitinib for front-line treatment of NSCLC. This case-example portends what will be increasingly likely scenarios in the regulation and clinical validation of targeted drug therapies.
Impact of a Pharmacist-Directed Anticoagulation Service on the Quality and Safety of Heparin-Induced Thrombocytopenia Management
Authors: To Long , Schillig Jessica M , DeSmet Brian D , Kuriakose Philip , Szandzik Edward G , Kalus James S
Published: February 2011

BACKGROUND:

The use of anticoagulant medications is complex and prone to error in the inpatient setting. Patients with heparin-induced thrombocytopenia (HIT) must receive treatment with alternative anticoagulant agents to ensure optimal patient outcomes.

OBJECTIVE:

To evaluate the impact of an inpatient pharmacist-directed anticoagulation service (PDAS) on the safety and efficiency of direct thrombin inhibitor use in patients with HIT.

METHODS:

This was a quasi-experimental pre/postintervention study comparing patients with HIT managed with usual care to patients managed with a focused inpatient anticoagulation service. The primary endpoints of the study were the percent of time that the activated partial thromboplastin time (aPTT) remained within the therapeutic range and time to achievement of a therapeutic aPTT. Bleeding and appropriateness of warfarin initiation were evaluated as secondary endpoints.

RESULTS:

A total of 193 patients were included in the study. Percent of time that aPTT was in the therapeutic range was 32% higher with the PDAS (p < 0.001) and time to therapeutic aPTT was shortened by approximately 12.5 hours in patients managed by the PDAS (p < 0.001). There was a trend for more bleeding events, regardless of severity, among control patients (p = 0.130). Rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeding was lower in the PDAS group (p = 0.006), but there was no significant difference between groups in GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate/severe bleeding (p = 0.679). Appropriateness of warfarin initiation was also similar between groups.

CONCLUSIONS:

Implementation of a focused inpatient PDAS was associated with improved efficiency of dosing, improved monitoring, and low bleeding risk.
S100B protein in neurodegenerative disorders
Authors: Steiner Johann , Bogerts Bernhard , Schroeter Matthias L. , Bernstein Hans-Gert
Published: February 2011

“Classic” neurodegenerative disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis share common pathophysiological features and involve progressive loss of specific neuronal populations, axonal or synaptic loss and dysfunction, reactive astrogliosis, and reduction in myelin. Furthermore, despite the absence of astrogliosis, impaired expression of astrocyte- and oligodendrocyte-related genes has been observed in patients with major psychiatric disorders, including schizophrenia and mood disorders. Because S100B is expressed in astrocytes and oligodendrocytes, its concentration in cerebrospinal fluid (CSF) or serum has been considered a suitable surrogate marker for the diagnostic or prognostic assessment of neurodegeneration. This review summarizes previous postmortem, CSF and serum studies regarding the role of S100B in this context. A general drawback is that only small single-center studies have been performed. Many potential confounding factors exist because of the wide extra-astrocytic and extracerebral expression of S100B. Due to lack of disease specificity, reliance on S100B concentrations for differential diagnostic purposes in cases of suspected neurodegenerative disorders is not recommended. Moreover, there is no consistent evidence for a correlation between disease severity and concentrations of S100B in CSF or serum. Therefore, S100B has limited usefulness for monitoring disease progression.
Inflammatory markers in childhood asthma
Authors: Dodig Slavica , Richter Darko , Zrinski-Topić Renata
Published: February 2011

The major characteristic of asthma is persistent airway inflammation that fails to resolve spontaneously. Dysregulation of pro- and anti-inflammatory mechanisms is responsible for the development of chronic inflammation. The inflammatory reaction is mediated by numerous cells and their mediators. Detection and quantification of airway inflammation in children are subject to many requirements, e.g., use of biologic samples obtained in a non-invasive way; use of standardized analytical methods to determine biomarkers that can identify inflammation processes (inflammation itself, oxidative stress, apoptosis and remodelling); determining the role of systemic inflammation; assessment of correlation of various biomarkers of inflammation with clinical parameters and their diagnostic efficacy; providing a tool(s) to monitor diseases, and to evaluate adequacy of therapy; and predicting the clinical course of inflammation and prognosis of asthma. Using standardized analyses, it is now possible to determine direct markers of local inflammation, i.e., fractional nitric oxide (marker of oxidative stress) in exhaled breath, pH (marker of acid stress) in breath condensate, and indirect markers in blood/serum, i.e., eosinophil granulocytes (indicating migration), eosinophil cationic protein (marker of activated eosinophil granulocytes) and C-reactive protein (marker of systemic inflammation). However, none of these biomarkers are specific for asthma. Further standardization of the known pulmonary biomarkers of local inflammation and identification of new ones will allow for longitudinal follow-up of inflammation in children with asthma.
High frequency of inadequate test requests for antiphospholipid antibodies in daily clinical practice
Authors: Mameli Antonella , Barcellona Doris , Vannini Maria Luigia , Marongiu Francesco
Published: February 2011

Background: We have empirically noted that many physicians routinely request anti-phospholipid antibodies (aPL) without a correct clinical indication. The aim of this study was to evaluate retrospectively whether aPL testing at our Thrombosis Centre was justified.

Methods: Medical records from 520 subjects for aPL screening tests for various clinical conditions were reviewed. The aPL screening tests were: lupus anticoagulant (LA), anti-cardiolipin antibodies (aCL) and anti-β2 glycoptotein I (aβ2 GPI). Requests for aPL screening were divided into justified, potentially justified or not adequately justified.

Results: aPL testing requests were considered justified in 358 (69%) patients, potentially justified in 66 (12.6%) and not adequately justified in 96 (18.4%). LA was positive in 65 (18%) of justified requests and in only one (1%) of the 96 potentially justified requests. None of the 66 not adequately justified for aPL testing was positive for LA. aβ2 GPI was positive in 63 (17.6%) of the 358 justified, in four (6%) of the 66 potentially justified and in five (5.2%) of the 96 not adequately justified requests; aCL IgG were positive in 59 (16.4%) of the 358 justified and in five (7.5%) and six (6.2%) of the potentially justified and not adequately justified requests, respectively. The presence of the triple aPL positivity was found exclusively in the justified requests.

Conclusions: This study suggests that requests for aPL tests should be addressed more adequately. This work could be an example of how to focus attention on requests for laboratory tests especially on the basis of valid clinical criteria before the analyte is measured.
Biomarkers in Alzheimer’s disease
Authors: Demarin Vida , Zavoreo Iris , Kes Vanja Bašić , Šimundić Ana Marija
Published: February 2011

Dementia is a growing public health concern because of the lack of effective curative treatment options and a rising global prevalence. Alzheimer’s disease (AD) is the most common type of dementia, affecting 60%–70% of all patients with dementia. The main pathological features of Alzheimer’s dementia are neurofibrillary tangles and senile plaques caused by progressive deposition of β-amyloid in the brain, but its underlying pathological basis is unclear. In common late onset AD sporadic forms (95% of all AD cases), a major genetic risk factor is the apolipoproteinE-ɛ4 (ApoE-ɛ4) alleles, and other genetic determinants have also been proposed to play causative role. This review focuses on biomarkers and subsequent changes in continuous measurement of cognitive and functional abilities in patients with mild cognitive impairment (MCI) and AD that aim to achieve a higher diagnostic accuracy for AD along with clinical assessment, neuropsychological testing and neuroimaging.
Activation of pine kraft lignin by Fenton-type oxidation for cross-linking with oligo(oxyethylene) diglycidyl ether
Authors: Passauer Lars , Fischer Klaus , Liebner Falk
Published: February 2011

Mechanically stable hydrogels featuring water absorption capacities of up to 75 gH2O ggel
-1 can be obtained by cross-linking of activated technical lignins with poly(ethylene) glycol diglycidyl ether under strong alkaline conditions. Fenton oxidation prior to cross-linking by hydrogen peroxide and catalytic amounts of ferrous chloride has been found to be superior to an alkaline H2O2 pre-treatment with respect to gel formation, water sorption, and rheological properties of the resulting oligo(oxyethylene) lignin gels. Purified pine kraft lignin undergoes in the course of Fenton oxidation hydroxylation of both aliphatic and aromatic moieties. This is the main reason for the enhanced cross-linking density obtained after treatment with poly(ethylene) glycol diglycidyl ether. The oxidative changes have been demonstrated by principal component analysis of Curie point pyrograms, wet chemical methods, FT-IR, and 31P NMR spectroscopy. Cleavage of side-chains, radical 5,5′-coupling of phenylpropane units, formation of carbonyl and carboxyl groups, and cleavage of aromatic rings were observed. These structural changes may increase or decrease the water sorption capability of the cross-linked products.
Two-step hydrolysis of nipa (Nypa fruticans) frond as treated by semi-flow hot-compressed water
Authors: Phaiboonsilpa Natthanon , Tamunaidu Pramila , Saka Shiro
Published: February 2011

Two-step hydrolysis of nipa (Nypa fruticans) frond, one of the monocotyledonous angiosperms, was studied in a semi-flow hot-compressed water treatment at 230°C/10 MPa/15 min (first stage) and 270°C/10 MPa/30 min (second stage). In the first stage, hemicelluloses such as O-acetyl-4-O-methylglucuronoarabinoxylan and pectin and para-crystalline cellulose were selectively hydrolyzed, as well as lignin, which was partially decomposed. In the second stage, hydrolysis of crystalline cellulose and some additional decomposition of lignin were observed. In addition, inorganic constituents and free sugars, composed mainly of glucose, fructose, and sucrose, were recovered in cold water (20°C/10 MPa/30 min) prior to these 2 stages. In total, 97.3% of oven-dried nipa frond sample could be solubilized into cold and hot-compressed water. The degradation products in the water-soluble portion were primarily recovered as various saccharides (hydrolyzed moieties of the polyoses), which were later dehydrated, fragmented and isomerized partly. The residual (2.7%) is composed mainly of lignin associated with 0.4% of Si. A decomposition pathway is proposed for O-acetyl-4-O-methylglucuronoarabinoxylan as the major hemicellulose based on its various hydrolyzed products.
Direct Corticospinal Control of Force Derivative
Authors: Soto Oscar , Cros Didier
Published: February 2011

During simultaneous generation of static and dynamic forces, motor cortical signals only predict the dynamic components, suggesting a key role in the coding of force changes. However, such a role is obscured by uncertainties regarding the representation of dynamic force signals in corticospinal outputs. We used transcranial magnetic stimulation (TMS) of the motor cortex in humans during a task that dissociated the direction of instantaneous net force and that of force derivative. The direction of TMS-evoked force outputs was closely associated with that of the force derivative, and had no relationship with that of the net force generated simultaneously, even though the magnitude of the instantaneous net force largely exceeded that of the force derivative. This observation supports the hypothesis that during dynamic force generation, the motor cortex and the corticospinal system assume a pivotal role in coding the direction of force changes, through selective recruitment of spinal motoneurons.
Activity-Dependent Regulation of Surface Glucose Transporter-3
Authors: Ferreira Jainne M. , Burnett Arthur L. , Rameau Gerald A.
Published: February 2011

Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation of intracellular glucose. The effect was blocked by NMDA receptor (NMDAR) and neuronal nitric oxide synthase (nNOS) inhibition. The Akt inhibitor I (Akt-I) blocked NMDAR-induced GLUT3 surface expression while a nNOS-phosphomimetic mutant (S1412D) enhanced GLUT3 expression at cell surface. These results suggest that NMDAR/Akt-dependent nNOS phosphorylation is coupled to GLUT3 trafficking. We demonstrated that activation of cGMP-dependent protein kinase (cGK) increased the surface expression of GLUT3, which was repressed by Rp-8-pCPT-cGMPS, a potent cell-permeable inhibitor of cGKs. These studies characterize the molecular basis for activity-dependent increases in surface GLUT3 after stimulation of the NMDARs. NMDAR-induced increase in surface GLUT3 represents a novel pathway for control of energy supply during neuronal activity that is critical for maintaining glucose homeostasis during neuronal transmission.
Spinal Phosphinositide 3-Kinase–Akt–Mammalian Target of Rapamycin Signaling Cascades in Inflammation-Induced Hyperalgesia
Authors: Xu Qinghao , Fitzsimmons Bethany , Steinauer Joanne , Neill Audrey O' , Newton Alexandra C. , Hua Xiao-Ying , Yaksh Tony L.
Published: February 2011

Phosphinositide 3-kinase (PI3K), Akt, and their downstream kinase, mammalian target of rapamycin (mTOR), are implicated in neural plasticity. The functional linkages of this signaling cascade in spinal dorsal horn and their role in inflammatory hyperalgesia have not been elucidated. In the present work, we identified the following characteristics of this cascade. (1) Local inflammation led to increase in rat dorsal horn phosphorylation (activation) of Akt (pAkt) and mTOR (pmTOR), as assessed by Western blotting and immunocytochemistry. (2) Increased pAkt and pmTOR were prominent in neurons in laminae I, III, and IV, whereas pmTOR and its downstream targets (pS6, p4EBP) were also observed in glial cells. (3) Intrathecal treatment with inhibitors to PI3K or Akt attenuated Formalin-induced second-phase flinching behavior, as well as carrageenan-induced thermal hyperalgesia and tactile allodynia. (4) Intrathecal rapamycin (an mTORC1 inhibitor) displayed anti-hyperalgesic effect in both inflammatory pain models. Importantly, intrathecal wortmannin at anti-hyperalgesic doses reversed the evoked increase not only in Akt but also in mTORC1 signaling (pS6/p4EBP). (5) pAkt and pmTOR are expressed in neurokinin 1 receptor-positive neurons in laminae I–III after peripheral inflammation. Intrathecal injection of Substance P activated this cascade (increased phosphorylation) and resulted in hyperalgesia, both of which effects were blocked by intrathecal wortmannin and rapamycin. Together, these findings reveal that afferent inputs trigged by peripheral inflammation initiate spinal activation of PI3K–Akt–mTOR signaling pathway, a component of which participates in neuronal circuits of facilitated pain processing.
A Circuit Model for Saccadic Suppression in the Superior Colliculus
Authors: Phongphanphanee Penphimon , Mizuno Fengxia , Lee Psyche H. , Yanagawa Yuchio , Isa Tadashi , Hall William C.
Published: February 2011

Attenuation of visual activity in the superficial layers (SLs), stratum griseum superficiale and stratum opticum, of the superior colliculus during saccades may contribute to reducing perceptual blur during saccades and also may help prevent subsequent unwanted saccades. GABAergic neurons in the intermediate, premotor, layer (SGI), stratum griseum intermedium, send an inhibitory input to SL. This pathway provided the basis for a model proposing that the SGI premotor cells that project to brainstem gaze centers and discharge before saccades also activate neighboring GABAergic neurons that suppress saccade-induced visual activity in SL.

Thein vitromethod allowed us to test this model. We made whole-cell patch-clamp recordings in collicular slices from either rats or GAD67–GFP knock-in mice, in which GABAergic neurons could be identified by their expression of green fluorescence protein (GFP). Antidromic electrical stimulation of SGI premotor cells was produced by applying pulse currents in which their axons congregate after exiting the superior colliculus. The stimulation evoked monosynaptic EPSCs in SGI GABAergic neurons that project to SL, as would be predicted if these neurons receive excitatory input from the premotor cells. Second, IPSCs were evoked in SL neurons, some of which project to the visual thalamus. These IPSCs were polysynaptically mediated by the GABAergic neurons that were excited by the antidromically activated SGI neurons. These results support the hypothesis that collaterals of premotor neuron axons excite GABAergic neurons that inhibit SL visuosensory cells.
Heparan Sulfate Sugar Modifications Mediate the Functions ofSlitsand Other Factors Needed for Mouse Forebrain Commissure Development
Authors: Conway Christopher D. , Howe Kathy M. , Nettleton Nicole K. , Price David J. , Mason John O. , Pratt Thomas
Published: February 2011

Heparan sulfate proteoglycans are cell surface and secretory proteins that modulate intercellular signaling pathways including Slit/Robo and FGF/FGFR. The heparan sulfate sugar moieties on HSPGs are subject to extensive postsynthetic modification, generating enormous molecular complexity that has been postulated to provide increased diversity in the ability of individual cells to respond to specific signaling molecules. This diversity could help explain how a relatively small number of axon guidance molecules are able to instruct the extremely complex connectivity of the mammalian brain. Consistent with this hypothesis, we previously showed that mutant mice lacking the heparan sulfotransferases (Hsts) Hs2st or Hs6st1 display major axon guidance defects at the developing optic chiasm. Here we further explore the role of these Hsts at the optic chiasm and investigate their function in corpus callosum development. Each Hst is expressed in a distinct pattern and each mutant displays a specific spectrum of axon guidance defects. ParticularHs2st−/−andHs6st1−/−phenotypes closely match those ofSlit1−/−andSlit2−/−embryos respectively, suggesting possible functional relationships. To test functional interactions betweenHs2storHs6st1andSlitswe examined optic chiasm and corpus callosum phenotypes in a panel of genotypes whereHs2storHs6st1andSlit1orSlit2function were simultaneously reduced or absent. We find examples ofHs2standHs6st1having epistatic, synergistic, and antagonistic genetic relationships withSlit1and/orSlit2depending on the context. At the corpus callosum we find thatHs6st1hasSlit-independent functions and our data indicate additional roles in FGF signaling.
TheCaenorhabditis elegansJIP3 Protein UNC-16 Functions As an Adaptor to Link Kinesin-1 with Cytoplasmic Dynein
Authors: Arimoto Makoto , Koushika Sandhya P. , Choudhary Bikash C. , Li Chris , Matsumoto Kunihiro , Hisamoto Naoki
Published: February 2011

Kinesin-1 is a microtubule plus-end-directed motor that transports various cargos along the axon. Previous studies have elucidated the physical and genetic interactions between kinesin-1 and cytoplasmic dynein, a microtubule minus-end-directed motor, in neuronal cells. However, the physiological importance of kinesin-1 in the dynein-dependent retrograde transport of cargo molecules remains obscure. Here, we show thatCaenorhabditis eleganskinesin-1 forms a complex with dynein via its interaction with UNC-16, which binds to the dynein light intermediate (DLI) chain. Both kinesin-1 and UNC-16 are required for localization of DLI-1 at the plus ends of nerve process microtubules. In addition, retrograde transport of APL-1 depends on kinesin-1, UNC-16, and dynein. These results suggest that kinesin-1 mediates the anterograde transport of dynein using UNC-16 as a scaffold and that dynein in turn mediates the retrograde transport of cargo moleculesin vivo. Thus, UNC-16 functions as an adaptor for kinesin-1-mediated transport of dynein.
p75NTR Regulates Aβ Deposition by Increasing Aβ Production But Inhibiting Aβ Aggregation with Its Extracellular Domain
Authors: Wang Yan-Jiang , Wang Xin , Lu Jian-Jun , Li Qiao-Xin , Gao Chang-Yue , Liu Xiao-Hong , Sun Yin , Yang Miao , Lim Yoon , Evin Genevieve , Zhong Jin-Hua , Masters Colin , Zhou Xin-Fu
Published: February 2011

Accumulation of toxic amyloid-β (Aβ) in the cerebral cortex and hippocampus is a major pathological feature of Alzheimer's disease (AD). The neurotrophin receptor p75NTR has been proposed to mediate Aβ-induced neurotoxicity; however, its role in the development of AD remains to be clarified. The p75NTR/ExonIII−/− mice and APPSwe/PS1dE9 mice were crossed to generate transgenic AD mice with deletion of p75NTR gene. In APPSwe/PS1dE9 transgenic mice, p75NTR expression was localized in the basal forebrain neurons and degenerative neurites in neocortex, increased with aging, and further activated by Aβ accumulation. Deletion of the p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Aβ levels in the brain and serum, but increased the accumulation of insoluble Aβ and Aβ plaque formation. There was no change in the levels of amyloid precursor protein (APP) and its proteolytic derivatives, or α-, β-, and γ-secretase activities, or in levels of BACE1, neprilysin (NEP), and insulin-degrading enzyme (IDE) proteins. Aβ production by cortical neurons of APPSwe/PS1dE9 mice was reduced by deletion of p75NTR genein vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Aβ42peptidein vitro, and reduced local Aβ plaques after hippocampus injectionin vivo. In addition, deletion of p75NTR attenuated microgliosis but increased the microhemorrhage profiles in the brain. The deletion of p75NTR did not significantly change the cognitive function of the mice up to the age of 9 months. Our data suggest that p75NTR plays a critical role in regulating Aβ levels by both increasing Aβ production and attenuating its aggregation, and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology.
Spike-Train Communities: Finding Groups of Similar Spike Trains
Authors: Humphries Mark D.
Published: February 2011

Identifying similar spike-train patterns is a key element in understanding neural coding and computation. For single neurons, similar spike patterns evoked by stimuli are evidence of common coding. Across multiple neurons, similar spike trains indicate potential cell assemblies. As recording technology advances, so does the urgent need for grouping methods to make sense of large-scale datasets of spike trains. Existing methods require specifying the number of groups in advance, limiting their use in exploratory analyses. I derive a new method from network theory that solves this key difficulty: it self-determines the maximum number of groups in any set of spike trains, and groups them to maximize intragroup similarity. This method brings us revealing new insights into the encoding of aversive stimuli by dopaminergic neurons, and the organization of spontaneous neural activity in cortex. I show that the characteristic pause response of a rat's dopaminergic neuron depends on the state of the superior colliculus: when it is inactive, aversive stimuli invoke a single pattern of dopaminergic neuron spiking; when active, multiple patterns occur, yet the spike timing in each is reliable. In spontaneous multineuron activity from the cortex of anesthetized cat, I show the existence of neural ensembles that evolve in membership and characteristic timescale of organization during global slow oscillations. I validate these findings by showing that the method both is remarkably reliable at detecting known groups and can detect large-scale organization of dynamics in a model of the striatum.
Membrane Penetration by Synaptotagmin Is Required for Coupling Calcium Binding to Vesicle FusionIn Vivo
Authors: Paddock Brie E. , Wang Zhao , Biela Laurie M. , Chen Kaiyun , Getzy Michael D. , Striegel Amelia , Richmond Janet E. , Chapman Edwin R. , Featherstone David E. , Reist Noreen E.
Published: February 2011

The vesicle protein synaptotagmin I is the Ca2+sensor that triggers fast, synchronous release of neurotransmitter. Specifically, Ca2+binding by the C2B domain of synaptotagmin is required at intact synapses, yet the mechanism whereby Ca2+binding results in vesicle fusion remains controversial. Ca2+-dependent interactions between synaptotagmin and SNARE (solubleN-ethylmaleimide-sensitive fusion protein attachment receptor) complexes and/or anionic membranes are possible effector interactions. However, no effector-interaction mutations to date impact synaptic transmission as severely as mutation of the C2B Ca2+-binding motif, suggesting that these interactions are facilitatory rather than essential. Here we useDrosophilato show the functional role of a highly conserved, hydrophobic residue located at the tip of each of the two Ca2+-binding pockets of synaptotagmin. Mutation of this residue in the C2A domain (F286) resulted in a ∼50% decrease in evoked transmitter release at an intact synapse, again indicative of a facilitatory role. Mutation of this hydrophobic residue in the C2B domain (I420), on the other hand, blocked all locomotion, was embryonic lethal even in syt I heterozygotes, and resulted in less evoked transmitter release than that insytnullmutants, which is more severe than the phenotype of C2B Ca2+-binding mutants. Thus, mutation of a single, C2B hydrophobic residue required for Ca2+-dependent penetration of anionic membranes results in the most severe disruption of synaptotagmin functionin vivoto date. Our results provide direct support for the hypothesis that plasma membrane penetration, specifically by the C2B domain of synaptotagmin, is the critical effector interaction for coupling Ca2+binding with vesicle fusion.
Visuotopic Organization of Macaque Posterior Parietal Cortex: A Functional Magnetic Resonance Imaging Study
Authors: Arcaro Michael J. , Pinsk Mark A. , Li Xin , Kastner Sabine
Published: February 2011

Macaque anatomy and physiology studies have revealed multiple visual areas in posterior parietal cortex (PPC). While many response properties of PPC neurons have been probed, little is known about PPC's large-scale functional topography—specifically related to visuotopic organization. Using high-resolution functional magnetic resonance imaging at 3 T with a phase–encoded retinotopic mapping paradigm in the awake macaque, a large-scale visuotopic organization along lateral portions of PPC anterior to area V3a and extending into the lateral intraparietal sulcus (LIP) was found. We identify two new visual field maps anterior to V3a within caudal PPC, referred to as caudal intraparietal-1 (CIP-1) and CIP-2. The polar angle representation in CIP-1 extends from regions near the upper vertical meridian (that is the shared border with V3a and dorsal prelunate) to those within the lower visual field (that is the shared border with CIP-2). The polar angle representation in CIP-2 is a mirror reversal of the CIP-1 representation. CIP-1 and CIP-2 share a representation of central space on the lateral border. Anterior to CIP-2, a third polar angle representation was found within LIP, referred to as visuotopic LIP. The polar angle representation in LIP extends from regions near the upper vertical meridian (that is the shared border with CIP-2) to those near the lower vertical meridian. Representations of central visual space were identified within dorsal portions of LIP with peripheral representations in ventral portions. We also consider the topographic large-scale organization found within macaque PPC relative to that observed in human PPC.
Polarization-Sensitive Descending Neurons in the Locust: Connecting the Brain to Thoracic Ganglia
Authors: Träger Ulrike , Homberg Uwe
Published: February 2011

Many animal species, in particular insects, exploit theE-vector pattern of the blue sky for sun compass navigation. Like other insects, locusts detect dorsal polarized light via photoreceptors in a specialized dorsal rim area of the compound eye. Polarized light information is transmitted through several processing stages to the central complex, a brain area involved in the control of goal-directed orientation behavior. To investigate how polarized light information is transmitted to thoracic motor circuits, we studied the responses of locust descending neurons to polarized light. Three sets of polarization-sensitive descending neurons were characterized through intracellular recordings from axonal fibers in the neck connectives combined with single-cell dye injections. Two descending neurons from the brain, one with ipsilaterally and the second with contralaterally descending axon, are likely to bridge the gap between polarization-sensitive neurons in the brain and thoracic motor centers. In both neurons,E-vector tuning changed linearly with daytime, suggesting that they signal time-compensated spatial directions, an important prerequisite for navigation using celestial signals. The third type connects the suboesophageal ganglion with the prothoracic ganglion. It showed no evidence for time compensation inE-vector tuning and might play a role in flight stabilization and control of head movements.
LRRK2 Controls Synaptic Vesicle Storage and Mobilization within the Recycling Pool
Authors: Piccoli Giovanni , Condliffe Steven B. , Bauer Matthias , Giesert Florian , Boldt Karsten , De Astis Silvia , Meixner Andrea , Sarioglu Hakan , Vogt-Weisenhorn Daniela M. , Wurst Wolfgang , Gloeckner Christian Johannes , Matteoli Michela , Sala Carlo , Ueffing Marius
Published: February 2011

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the single most common cause of inherited Parkinson's disease. Little is known about its involvement in the pathogenesis of Parkinson's disease mainly because of the lack of knowledge about the physiological role of LRRK2. To determine the function of LRRK2, we studied the impact of short hairpin RNA-mediated silencing of LRRK2 expression in cortical neurons. Paired recording indicated that LRRK2 silencing affects evoked postsynaptic currents. Furthermore, LRRK2 silencing induces at the presynaptic site a redistribution of vesicles within the bouton, altered recycling dynamics, and increased vesicle kinetics. Accordingly, LRRK2 protein is present in the synaptosomal compartment of cortical neurons in which it interacts with several proteins involved in vesicular recycling. Our results suggest that LRRK2 modulates synaptic vesicle trafficking and distribution in neurons and in consequence participates in regulating the dynamics between vesicle pools inside the presynaptic bouton.
Network Oscillations in Rod-Degenerated Mouse Retinas
Authors: Menzler Jacob , Zeck Günther
Published: February 2011

In the mammalian retina, excitatory and inhibitory circuitries enable retinal ganglion cells (RGCs) to signal the occurrence of visual features to higher brain areas. This functionality disappears in certain diseases of retinal degeneration because of the progressive loss of photoreceptors. Recent work in a mouse model of retinal degeneration (rd1) found that, although some intraretinal circuitry is preserved and RGCs maintain characteristic physiological properties, they exhibit increased and aberrant rhythmic activity. Here, extracellular recordings were made to assess the degree of aberrant activity in adultrd1retinas and to investigate the mechanism underlying such behavior. A multi-transistor array with thousands of densely packed sensors allowed for simultaneous recordings of spiking activity in populations of RGCs and of local field potentials (LFPs). The majority of identified RGCs displayed rhythmic (7–10 Hz) but asynchronous activity. The spiking activity correlated with the LFPs, which reflect an average synchronized excitatory input to the RGCs. LFPs initiated from random positions and propagated across the retina. They disappeared when ionotrophic glutamate receptors or electrical synapses were blocked. They persisted in the presence of other pharmacological blockers, including TTX and inhibitory receptor antagonists. Our results suggest that excitation—transmitted laterally through a network of electrically coupled interneurons—leads to large-scale retinal network oscillations, reflected in the rhythmic spiking of mostrd1RGCs. This result may explain forms of photopsias reported by blind patients, while the mechanism involved should be considered in future treatment strategies targeting the disease of retinitis pigmentosa.
Cations But Not Anions Regulate the Responsiveness of Kainate Receptors
Authors: MacLean David M. , Wong Adrian Y. C. , Fay Anne-Marie , Bowie Derek
Published: February 2011

Kainate-selective ionotropic glutamate receptors are unique among ligand-gated ion channels in their obligate requirement of external anions and cations for activation. Although it is established that the degree of kainate receptor (KAR) activation is shaped by the chemical nature of the agonist molecule, the possible complementary role of external ions has yet to be examined. Here we show that external cations but not anions regulate the responsiveness to a range of full and partial agonists acting on rat GluK2 receptors. This observation is unexpected as previous work has assumed anions and cations affect KARs in an identical manner through functionally coupled binding sites. However, our data demonstrate that anion- and cation-binding pockets behave discretely. We suggest cations uniquely regulate a pregating or flipping step that impacts the closed-cleft stability of the agonist-binding domain (ABD). This model departs from a previous proposal that KAR agonist efficacy is governed by the degree of closure elicited in the ABD by ligand binding. Our findings are, however, in line with recent studies on Cys-loop ligand-gated ion channels suggesting that the “flipping” mechanism has been conserved by structurally diverse ligand-gated ion channel families as a common means of regulating neurotransmitter behavior.