bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization
Authors: Gumy Laura F. , Yeo Giles S.H. , Tung Yi-Chun Loraine , Zivraj Krishna H. , Willis Dianna , Coppola Giovanni , Lam Brian Y.H. , Twiss Jeffery L. , Holt Christine E. , Fawcett James W.
Published: November 2010

mRNAs are transported, localized, and translated in axons of sensory neurons. However, little is known about the full repertoire of transcripts present in embryonic and adult sensory axons and how this pool of mRNAs dynamically changes during development. Here, we used a compartmentalized chamber to isolate mRNA from pure embryonic and adult sensory axons devoid of non-neuronal or cell body contamination. Genome-wide microarray analysis reveals that a previously unappreciated number of transcripts are localized in sensory axons and that this repertoire changes during development toward adulthood. Embryonic axons are enriched in transcripts encoding cytoskeletal-related proteins with a role in axonal outgrowth. Surprisingly, adult axons are enriched in mRNAs encoding immune molecules with a role in nociception. Additionally, we show Tubulin-beta3 (Tubb3) mRNA is present only in embryonic axons, with Tubb3 locally synthesized in axons of embryonic, but not adult neurons where it is transported, thus validating our experimental approach. In summary, we provide the first complete catalog of embryonic and adult sensory axonal mRNAs. In addition we show that this pool of axonal mRNAs dynamically changes during development. These data provide an important resource for studies on the role of local protein synthesis in axon regeneration and nociception during neuronal development.
Plerixafor Dosing and Administration in a Patient with Dialysis-Dependent Renal Failure
Authors: Gregory Kelly M , Rao Kamakshi V , Armistead Paul M
Published: November 2010

Objective:

To report on the use of plerixafor in a patient with multiple myeloma and dialysis-dependent renal failure.

Case Summary:

A 38-year-old man with multiple myeloma and dialysis-dependent renal failure was evaluated for stem cell transplantation. Stem cell mobilization with 6 doses of granulocyte colony-stimulating factor (G-CSF) 10 μg/kg/day yielded an inadequate maximum pre-apheresis CD34+ count of 5.6 cells/μL. The patient was treated with a postdialysis subcutaneous dose of plerixafor 160 μg/kg after 4 days of G-CSF therapy. After a single dose of plerixafor, the patient's pre-apheresis CD34+ count was 125.6 cells/μL. After 1 apheresis session, the stem cell collection yield was 5.33 × 105 CD34+ cells/kg. There were no observed plerixafor toxicities. The patient underwent successful autologous stem cell transplantation. Times to neutrophil and platelet engraftment were 12 and 15 days, respectively. At 100-day follow-up, the patient's myeloma was in remission and he met all criteria for durable engraftment.

Discussion:

Renal impairment is a common comorbidity in patients with multiple myeloma. Plerixafor is a chemokine receptor 4 antagonist approved for use to mobilize stem cells for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. To date, there is limited information on safe and effective dosing and administration of plerixafor in patients who are dialysis-dependent. This report describes the use of plerixafor in a patient with multiple myeloma and dialysis-dependent renal failure.

Conclusions:

Based on our experience, we are instituting a policy to administer plerixafor at Food and Drug Administration–approved renal adjustment doses in patients on hemodialysis, with dialysis sessions scheduled prior to plerixafor administration and repeated as necessary after apheresis and prior to subsequent plerixafor doses. If clinically feasible, dialysis should be held during the days required to collect stem cells.
Antibiotic Prophylaxis for Prevention of Spontaneous Bacterial Peritonitis in Patients Without Gastrointestinal Bleeding
Authors: Segarra-Newnham Marisel , Henneman Amy
Published: November 2010

Objective:

To review relevant studies for both primary and secondary antibiotic prophylaxis of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis without gastrointestinal bleeding.

Data Sources:

A search of PubMed (1980-July 2010) was conducted using the terms prophylaxis, SBP, and antibiotics. A manual review of bibliographies was conducted for inclusion of relevant articles.

Study Selection and Data Extraction:

Prospective studies and meta-analyses published in English were included.

Data Synthesis:

Ten trials and 3 meta-analyses were included. Of the 10 trials, 2 examined the use of secondary prophylaxis for prevention of subsequent episodes of SBP, 4 examined the use of primary prophylaxis to prevent an initial SBP episode, and 4 examined the use of antibiotic prophylaxis in a mixed population. Seven trials evaluated the use of an antibiotic compared to placebo or no treatment. Only 1 trial evaluated norfloxacin versus trimethoprim/sulfamethoxazole. Trial duration varied from 24 days to 12 months. In general, trials examining norfloxacin as secondary prophylaxis found significantly decreased occurrence of SBP but no significant difference in mortality rates. Primary prophylaxis studies found no significant difference in the incidence of infections, including SBP, with norfloxacin or ciprofloxacin treatment but significantly lower incidence of gram-negative infections. Mixed population studies found a significantly decreased incidence of SBP but no significant difference in mortality. In the 3 meta-analyses, a significant decrease in mortality and an overall decrease in SBP incidence in the treatment groups were noted.

Conclusions:

Based on currently available data, the use of prophylactic antibiotic therapy is warranted for the prevention of recurrent SBP in patients with cirrhosis and ascites. In patients with low ascetic fluid protein and at least 1 more risk factor, primary prophylaxis may be considered. Further studies with improved methodology are needed to determine whether prophylactic antibiotic therapy has an impact on mortality.
Cardiology: Pharmacologic Management of Heart Failure with Preserved Ejection Fraction
Authors: Huang Dana , Cheng Judy WM
Published: November 2010

Objective:

To provide an overview of heart failure with preserved ejection fraction (HFPEF), as well as its pathophysiology, diagnosis, and clinical evidence regarding its pharmacologic management.

Data Sources:

Peer-reviewed articles were identified from MEDLINE, International Pharmaceutical Abstracts, and Current Contents (all 1966-August 2010) using the search terms heart failure with preserved ejection fraction, diastolic dysfunction, diastolic heart failure, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), digoxin, β-blockers, calcium-channel blockers, and vasodilators. Citations from available articles were also reviewed for additional references.

Study Selection and Data Extraction:

Fourteen published manuscripts relating to pharmacologic management of HFPEF were identified.

Data Synthesis:

The prevalence of HFPEF has continued to increase. Compared to heart failure with left ventricular systolic dysfunction, HFPEF has been largely understudied. Unlike in the management of heart failure with left ventricular systolic dysfunction, ACE inhibitors, ARBs, β-blockers, and aldosterone antagonists did not demonstrate mortality benefit in HFPEF, with the exception of one small study evaluating the use of propranolol. However, this study enrolled a small number of patients with recent history of myocardial infarction, which limited the generalizability of the results. Most of the current evidence centers on morbidity benefits and symptom reduction. One study showed that treatment with candesartan reduced hospital admissions in this population of patients. Management of HFPEF still focuses on optimally managing underlying diseases (eg, hypertension).

Conclusions:

Much remains to be learned about the appropriate pharmacologic management of patients with HFPEF. Hypertension is in most cases the predominant contributor to its development and progression. For this reason, antihypertensive treatment, including ACE inhibitors, ARBs, β-blockers, and calcium-channel blockers, has been evaluated and is recommended to control the disease in this patient population, although these agents have not demonstrated significant benefit beyond blood pressure control. Further research into the pathophysiology of HFPEF may contribute to identifying the most optimal agent in managing this disease.
Subcutaneous Unfractionated Heparin for Treatment of Venous Thromboembolism in End-Stage Renal Disease
Authors: Metzger Nicole L , Chesson Melissa M
Published: November 2010

Objective:

To report 3 cases of venous thromboembolism (VTE) in patients with end-stage renal disease (ESRD) treated with subcutaneous unfractionated heparin (UFH) bridged with warfarin.

Case Summaries:

Three patients with ESRD were successfully treated for VTE with unmonitored, fixed-dose subcutaneous UFH every 12 hours and doseadjusted warfarin. The first patient was initiated on continuous infusion UFH for deep-vein thrombosis, but due to poor vascular access, nurses were unable to consistently measure anti-Xa levels. Therefore, subcutaneous UFH 17,500 units (~245 units/kg/dose) every 12 hours was initiated. Oral warfarin 5 mg/day was started the following day. The patient received 4 days of inpatient subcutaneous UFH and then was discharged to complete the bridge as an outpatient. The second patient received subcutaneous UFH 10,000 units (~244 units/kg/dose) every 12 hours and oral warfarin 2.5 mg/day to treat a nonocclusive thrombus along her right femoral vein hemodialysis catheter. The patient received 1 day of inpatient subcutaneous UFH treatment prior to discharge and continued bridge therapy with warfarin as an outpatient. The third patient was initiated on subcutaneous UFH 20,000 units (~223 units/kg/dose) every 12 hours and oral warfarin 7.5 mg/day due to a subtherapeutic INR (1.50) 5 days after receiving fresh frozen plasma to reduce her therapeutic INR for a procedure. The patient received 2 doses of subcutaneous UFH as an inpatient before treatment was discontinued because her INR was therapeutic at 2.3.

Discussion:

Subcutaneous UFH has been used to treat VTE since the early 1980s; however, with the advent of low-molecular-weight heparin (LMWH), subcutaneous UFH use diminished. Several studies comparing the use of subcutaneous UFH to both continuous infusion UFH and LMWH concluded that subcutaneous UFH is a safe and efficacious alternative. The 2008 Chest Guidelines for Antithrombotic Therapy for Venous Thromboembolic Disease support the use of subcutaneous UFH for the treatment of VTE with a Grade 1A recommendation and provide a Grade 2C recommendation for use of UFH over LMWH for patients with VTE and severe renal failure.

Conclusions:

Safe and convenient treatment options for VTE in patients with ESRD are limited. Fixed-dose, unmonitored subcutaneous UFH as a bridge to warfarin therapy is an effective option in patients with ESRD and those with financial restrictions. The pharmacist plays a key role in identifying patients for whom subcutaneous UFH treatment may be a viable alternative, recommending an appropriate dosing regimen, and educating health-care professionals and patients about safe use.
Task-Dependent Changes in Short-Term Memory in the Prefrontal Cortex
Authors: Warden Melissa R. , Miller Earl K.
Published: November 2010

The prefrontal cortex (PFC) is important for flexible, context-dependent behavioral control. It also plays a critical role in short-term memory maintenance. Though many studies have investigated these functions independently, it is unclear how these two very different processes are realized by a single brain area. To address this, we trained two monkeys on two variants of an object sequence memory task. These tasks had the same memory requirements but differed in how information was read out and used. For the “recognition” task, the monkeys had to remember two sequentially presented objects and then release a bar when a matching sequence was recognized. For the “recall” task, the monkeys had to remember the same sequence of objects but were instead required to recall the sequence and reproduce it with saccadic eye movements when presented with an array of objects. After training, we recorded the activity of PFC neurons during task performance. We recorded 222 neurons during the recognition task, 177 neurons during the recall task, and 248 neurons during the switching task (interleaved blocks of recognition and recall). Task context had a profound influence on neural selectivity for objects. During the recall task, the first object was encoded more strongly than the second object, while during the recognition task, the second object was encoded more strongly. In addition, most of the neurons encoded both the task and the objects, evidence for a single population responsible for these two critical prefrontal functions.
Acute and Sustained Effects of Cognitive Emotion Regulation in Major Depression
Authors: Erk Susanne , Mikschl Alexandra , Stier Sabine , Ciaramidaro Angela , Gapp Volker , Weber Bernhard , Walter Henrik
Published: November 2010

Dysfunctional regulation of mood and emotion is a key component of major depressive disorder and leads to sustained negative feelings. Using functional MRI (fMRI), we investigated the temporal dynamics of emotion regulation in patients with major depressive disorder and in healthy controls, testing for acute and sustained neural effects of active emotion regulation. Moderately depressed individuals (n= 17) and never-depressed healthy control subjects (n= 17) underwent fMRI during performance of an active cognitive emotion regulation task while viewing emotionally arousing pictures. In a second task, completed 15 min later, subjects were presented with the same stimuli in a passive viewing task. Whole-brain analyses and connectivity measures were used to determine acute and sustained effects of emotion regulation on brain activation and coupling between regions. On the group level, patients were able to downregulate negative emotions and corresponding amygdala activation, but this ability decreased with increasing symptom severity. Moreover, only healthy control subjects showed a sustained regulation effect in the amygdala after a 15 min delay, whereas depressed patients did not. Finally, patients exhibited diminished prefrontal activation and reduced prefrontolimbic coupling during active regulation. Although emotion regulation capacity in medicated depressive patients appears to be preserved depending on symptom severity, the effect is not sustained. Correlational analyses provide evidence that this diminished sustained-regulation effect might be related to reduced prefrontal activation during regulation.
Interaction betweenN-Ethylmaleimide-Sensitive Factor and GluR2 Is Essential for Fear Memory Formation in Lateral Amygdala
Authors: Joels Gil , Lamprecht Raphael
Published: November 2010

Long-term memory formation is believed to involve alterations of synaptic efficacy. It has been shown that GluR1-containing AMPA receptors are inserted into synapses following stimuli leading to plasticity and that GluR2/GluR3-containing receptors replace existing synaptic AMPA receptors continuously and may act to maintain synaptic efficacy. Maintaining GluR2/GluR3 receptors level in synapse requires interactions ofN-ethylmaleimide-sensitive factor (NSF) with GluR2. To assess possible roles of NSF-GluR2 interaction in rat lateral amygdala (LA) in fear memory formation we used a specific GluR2-NSF interaction inhibitory peptide (pep-R845A). This inhibitory peptide, composed of a modified NSF binding site of GluR2, was previously shown to interact specifically with NSF and to affect AMPA-mediated synaptic efficacy. The inhibitory peptide was linked to a TAT peptide (TAT-pep-R845A) to facilitate internalization into LA cells. Infusion of the TAT-pep-R845A inhibitory peptide into LA 30 min before fear conditioning led to a significant impairment of long-term fear memory formation. In contrast, the control TAT peptide alone had no effect on fear memory. Injection of TAT-pep-R845A peptide into LA had no effect on short-term fear memory. In addition, the inhibitory peptide had no effect on memory retrieval when injected into LA 30 min before fear memory test. Furthermore, maintenance of memory was not impaired when the peptide was injected 24 h after fear conditioning and fear memory was tested 48 h afterward. These results show that GluR2-NSF interaction in LA is necessary for fear memory consolidation but not retrieval or persistence.
GABA Depolarizes Immature Neocortical Neurons in the Presence of the Ketone Body β-Hydroxybutyrate
Authors: Kirmse Knut , Witte Otto W. , Holthoff Knut
Published: November 2010

A large body of evidence suggests that the neurotransmitter GABA undergoes a developmental switch from being predominantly depolarizing–excitatory to predominantly hyperpolarizing–inhibitory. Recently published data, however, point to the possibility that the presumed depolarizing mode of GABA action during early development might represent an artifact due to an insufficient energy supply of thein vitropreparations used. Specifically, addition of the ketone bodydl-β-hydroxybutyrate (βHB) to the extracellular medium was shown to prevent GABA from exerting excitatory effects. Applying a complementary set of minimally invasive optical and electrophysiological techniques in brain slices from neonatal mice, we investigated the effects of βHB on GABA actions in immature cells of the upper cortical plate. Fluorescence imaging revealed that GABA-mediated somatic [Ca2+] transients, that required activation of GABAAreceptors and voltage-gated Ca2+channels, remained unaffected by βHB. Cell-attached current-clamp recordings showed that, in the presence of βHB, GABA still induced a membrane potential depolarization. To estimate membrane potential changes quantitatively, we used cell-attached recordings of voltage-gated potassium currents and demonstrated that the GABA-mediated depolarization was independent of supplementation of the extracellular solution with βHB. We conclude that,in vitro, GABA depolarizes immature cells of the upper cortical plate in the presence of the ketone body βHB. Our data thereby support the general concept of an excitatory-to-inhibitory switch of GABA action during early development.
Synaptic Mechanism for the Sustained Activation of Oculomotor Integrator Circuits in the Rat Prepositus Hypoglossi Nucleus: Contribution of Ca2+-Permeable AMPA Receptors
Authors: Saito Yasuhiko , Yanagawa Yuchio
Published: November 2010

Sustained neural activity is involved in several brain functions. Although recurrent/feedback excitatory networks are proposed as a neural mechanism for this sustained activity, the synaptic mechanisms have not been fully clarified. To address this issue, we investigated the excitatory synaptic responses of neurons in the prepositus hypoglossi nucleus (PHN), a brainstem structure involved as an oculomotor neural integrator, using whole-cell voltage-clamp recordings in rat slice preparations. Under a blockade of inhibitory synaptic transmissions, the application of “burst stimulation” (100 Hz, 20 pulses) to a brainstem area projecting to the PHN induced an increase in the frequency of EPSCs in PHN neurons that lasted for several seconds. Sustained EPSC responses were observed even when the burst stimulation was applied in the vicinity of a recorded neuron within the PHN that was isolated from the slices. Pharmacologically, the sustained EPSC responses were reduced by 1-naphthyl acetyl spermine (50 μm), a blocker of Ca2+-permeable AMPA (CP-AMPA) receptors. Analysis of the current–voltage (I–V) relationship of the current responses to iontophoretic application of kainate revealed that more than one-half of PHN neurons exhibited an inwardly rectifyingI–Vrelationship. Furthermore, PHN neurons exhibiting inwardly rectifying current responses showed higher Ca2+permeability. The sustained EPSC responses were also reduced by flufenamic acid (200 μm), a blocker of Ca2+-activated nonselective cation (CAN) channels. These results indicate that the sustained EPSC responses are attributable to the sustained activation of local excitatory networks in the PHN, which arises from the activation of CP-AMPA receptors and CAN channels in PHN neurons.
Aberrant Frontal and Temporal Complex Network Structure in Schizophrenia: A Graph Theoretical Analysis
Authors: van den Heuvel Martijn P. , Mandl René C. W. , Stam Cornelis J. , Kahn René S. , Hulshoff Pol Hilleke E.
Published: November 2010

Brain regions are not independent. They are interconnected by white matter tracts, together forming one integrative complex network. The topology of this network is crucial for efficient information integration between brain regions. Here, we demonstrate that schizophrenia involves an aberrant topology of the structural infrastructure of the brain network. Using graph theoretical analysis, complex structural brain networks of 40 schizophrenia patients and 40 human healthy controls were examined. Diffusion tensor imaging was used to reconstruct the white matter connections of the brain network, with the strength of the connections defined as the level of myelination of the tracts as measured through means of magnetization transfer ratio magnetic resonance imaging. Patients displayed a preserved overall small-world network organization, but focusing on specific brain regions and their capacity to communicate with other regions of the brain revealed significantly longer node-specific path lengths (higherL) of frontal and temporal regions, especially of bilateral inferior/superior frontal cortex and temporal pole regions. These findings suggest that schizophrenia impacts global network connectivity of frontal and temporal brain regions. Furthermore, frontal hubs of patients showed a significant reduction of betweenness centrality, suggesting a less central hub role of these regions in the overall network structure. Together, our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regions.
Participation of Transmembrane Domain 1 of Presenilin 1 in the Catalytic Pore Structure of the γ-Secretase
Authors: Takagi Shizuka , Tominaga Aya , Sato Chihiro , Tomita Taisuke , Iwatsubo Takeshi
Published: November 2010

γ-Secretase is an intramembrane-cleaving protease that is responsible for the generation of amyloid-β peptides linked to the pathogenesis of Alzheimer's disease. Using a substituted cysteine accessibility method, we have previously shown that the hydrophilic “catalytic pore” structure of γ-secretase is formed by the transmembrane domains (TMDs) 6, 7, and 9 of presenilin 1 (PS1), the catalytic subunit of γ-secretase, within the membrane. Here, we analyzed the structure in and around the first hydrophobic region, the putative TMD1, of PS1, of which the precise function as well as three-dimensional location within γ-secretase remained unknown. We found that TMD1 is located in proximity to the catalytic GxGD and PAL motifs within the C-terminal fragment of PS1, facing directly the catalytic pore. Competition experiments using known γ-secretase inhibitors suggested that the N-terminal region of TMD1 functions as a subsite during proteolytic action of the γ-secretase. Intriguingly, binding of inhibitors affected water accessibility of residues at the membrane border of TMD1, suggesting the possibility of a dynamic motion of TMD1 during the catalytic process. Our results provide mechanistic insights into the functional role of TMD1 of PS1 in the intramembrane-cleaving activity of the γ-secretase.
Left Dorsomedial Frontal Brain Damage Is Associated with Insomnia
Authors: Koenigs Michael , Holliday Jessica , Solomon Jeffrey , Grafman Jordan
Published: November 2010

Insomnia is a common sleep disorder, yet its pathophysiological basis remains poorly understood. Studying a group of 192 patients with focal brain lesions, we show a significant association between insomnia and left dorsomedial prefrontal damage. Our findings are the first to demonstrate a link between insomnia and a discrete locus of brain damage, providing novel insight into the neurobiological mechanisms of sleep maintenance.
Gating of Signal Propagation in Spiking Neural Networks by Balanced and Correlated Excitation and Inhibition
Authors: Kremkow Jens , Aertsen Ad , Kumar Arvind
Published: November 2010

Both ongoing and natural stimulus driven neuronal activity are dominated by transients. Selective gating of these transients is mandatory for proper brain function and may, in fact, form the basis of millisecond-fast decision making and action selection. Here we propose that neuronal networks may exploit timing differences between correlated excitation and inhibition (temporal gating) to control the propagation of spiking activity transients. When combined with excitation–inhibition balance, temporal gating constitutes a powerful mechanism to control the propagation of mixtures of transient and tonic neural activity components.
Selective Participation of Somatodendritic HCN Channels in Inhibitory But Not Excitatory Synaptic Integration in Neurons of the Subthalamic Nucleus
Authors: Atherton Jeremy F. , Kitano Katsunori , Baufreton Jerome , Fan Kai , Wokosin David , Tkatch Tatiana , Shigemoto Ryuichi , Surmeier D. James , Bevan Mark D.
Published: November 2010

The activity patterns of subthalamic nucleus (STN) neurons are intimately linked to motor function and dysfunction and arise through the complex interaction of intrinsic properties and inhibitory and excitatory synaptic inputs. In many neurons, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play key roles in intrinsic excitability and synaptic integration both under normal conditions and in disease states. However, in STN neurons, which strongly express HCN channels, their roles remain relatively obscure. To address this deficit, complementary molecular and cellular electrophysiological, imaging, and computational approaches were applied to the rat STN. Molecular profiling demonstrated that individual STN neurons express mRNA encoding several HCN subunits, with HCN2 and 3 being the most abundant. Light and electron microscopic analysis showed that HCN2 subunits are strongly expressed and distributed throughout the somatodendritic plasma membrane. Voltage-, current-, and dynamic-clamp analysis, two-photon Ca2+imaging, and computational modeling revealed that HCN channels are activated by GABAAreceptor-mediated inputs and thus limit synaptic hyperpolarization and deinactivation of low-voltage-activated Ca2+channels. Although HCN channels also limited the temporal summation of EPSPs, generated through two-photon uncaging of glutamate, this action was largely shunted by GABAergic inhibition that was necessary for HCN channel activation. Together the data demonstrate that HCN channels in STN neurons selectively counteract GABAAreceptor-mediated inhibition arising from the globus pallidus and thus promote single-spike activity rather than rebound burst firing.
The Absence of Eye Muscle Fatigue Indicates That the Nervous System Compensates for Non-Motor Disturbances of Oculomotor Function
Authors: Prsa Mario , Dicke Peter W. , Thier Peter
Published: November 2010

The physical properties of our bodies are subject to change (due to fatigue, heavy equipment, injury or aging) as we move around in the surrounding environment. The traditional definition of motor adaptation dictates that a mechanism in our brain needs to compensate for such alterations by appropriately modifying neural motor commands, if the vitally important accuracy of executed movements is to be preserved. In this article we describe how a repetitive eye movement task brings about changes in eye saccade kinematics that compromise accurate motor performance in the absence of a proper compensatory response. Surgical lesions in animals and human patient studies have previously demonstrated that an intact cerebellum is necessary for the compensation to arise and prevent the occurrence of hypometric movements. Here we identified the dynamic properties of the eye plant by recording from abducens motoneurons responsible for the required movement and measured the muscle response to microstimulation of the abducens nucleus in rhesus monkeys. The ensuing results demonstrate that the muscular periphery remains intact during the fatiguing eye movement task, while internal sources of noise (drowsiness, attentional modulation, neuronal fatigue etc.) must be responsible for a diminished oculomotor performance. This finding leads to the important realization that while supervising the accuracy of our movements, the nervous system takes additionally into account and adapts to any disruptive processes within the brain itself, clearly unrelated to the dynamical behavior of muscles or the environment. The existence of this supplementary mechanism forces a reassessment of traditional views of cerebellum-dependent motor adaptation.
Permeability of the Paranodal Junction of Myelinated Nerve Fibers
Authors: Mierzwa Amanda , Shroff Seema , Rosenbluth Jack
Published: November 2010

We have used fluorescent dextran tracers to test the tightness of the paranodal junction of living or fixed myelinated fibers in mouse sciatic nerve. Both 3 and 70 kDa tracers are able to penetrate from the perinodal space symmetrically into the paranodes on either side of the node of Ranvier at a rate consistent with diffusion through an elongated helical pathway between the paranodal terminal loops of the myelin sheath. This pathway thus provides an access route for movement of water soluble nutrients and metabolites to and from the internodal axon and constitutes a pathway through which juxtaparanodal potassium channels may be activated and may in turn affect nodal excitability. This pathway may also allow access of antibodies and toxic molecules to the internodal axon in paraneoplastic syndromes and demyelinating diseases.
The Role of Presynaptic Dynamics in Processing of Natural Spike Trains in Hippocampal Synapses
Authors: Kandaswamy Umasankar , Deng Pan-Yue , Stevens Charles F. , Klyachko Vitaly A.
Published: November 2010

Short-term plasticity (STP) represents a key neuronal mechanism of information processing. In excitatory hippocampal synapses, STP serves as a high-pass filter optimized for the transmission of information-carrying place-field discharges. This STP filter enables synapses to perform a highly nonlinear, switch-like operation permitting the passage and amplification of signals with place-field–like characteristics. Because of the complexity of interactions among STP processes, the synaptic mechanisms underlying this filtering paradigm remain poorly understood. Here, we describe a simple mechanistic model of STP, derived in large part from basic principles of synaptic function, that reproduces this highly nonlinear synaptic behavior. The model, formulated in terms of release probability, considers the interactions between calcium-dependent forms of presynaptic enhancement and their impact on vesicle pool dynamics, which is described using a two-pool model of vesicle recruitment. By considering the interdependency between release probability and various forms of STP, the model attempts to provide a realistic coupling among major presynaptic processes. The model parameters are first determined using synaptic dynamics during constant-frequency stimulation. The model then accurately reproduces all major characteristics of the synaptic filtering paradigm during natural stimulus patterns without free parameters. An elimination approach is then used to identify the contribution of each STP component to synaptic dynamics. Based on this analysis, the model predicts strong calcium dependence of synaptic filtering properties, which is verified experimentally in rat hippocampal slices. This simple model may thus offer a useful framework to further investigate the role of STP in neural computations.
The Inflammasome Sensor, NLRP3, Regulates CNS Inflammation and Demyelination via Caspase-1 and Interleukin-18
Authors: Jha Sushmita , Srivastava Siddharth Y. , Brickey W. June , Iocca Heather , Toews Arrel , Morrison James P. , Chen Vivian S. , Gris Denis , Matsushima Glenn K. , Ting Jenny P.-Y.
Published: November 2010

Inflammation is increasingly recognized as an important contributor to a host of CNS disorders; however, its regulation in the brain is not well delineated. Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 (NLRP3) is a key component of the inflammasome complex, which also includes ASC (apoptotic speck-containing protein with a card) and procaspase-1. Inflammasome formation can be triggered by membrane P2X7R engagement leading to cleavage-induced maturation of caspase-1 and interleukin-1β (IL-1β)/IL-18. This work shows that expression of theNlrp3gene was increased >100-fold in a cuprizone-induced demyelination and neuroinflammation model. Mice lacking theNlrp3gene (Nlrp3−/−) exhibited delayed neuroinflammation, demyelination, and oligodendrocyte loss in this model. These mice also showed reduced demyelination in the experimental autoimmune encephalomyelitis model of neuroinflammation. This outcome is also observed forcasp1−/−andIL-18−/−mice, whereasIL-1β−/−mice were indistinguishable from wild-type controls, indicating that Nlrp3-mediated function is through caspase-1 and IL-18. Additional analyses revealed that, unlike theIL-1β−/−mice, which have been previously shown to show delayed remyelination,Nlrp3−/−mice did not exhibit delayed remyelination. Interestingly,IL-18−/−mice showed enhanced remyelination, thus providing a possible compensatory mechanism for the lack of a remyelination defect inNlrp3−/−mice. These results suggest that NLRP3 plays an important role in a model of multiple sclerosis by exacerbating CNS inflammation, and this is partly mediated by caspase-1 and IL-18. Additionally, the therapeutic inhibition of IL-18 might decrease demyelination but enhance remyelination, which has broad implications for demyelinating diseases.
Vesicular Sterols Are Essential for Synaptic Vesicle Cycling
Authors: Dason Jeffrey S. , Smith Alex J. , Marin Leo , Charlton Milton P.
Published: November 2010

Synaptic vesicles have a high sterol content, but the importance of vesicular sterols during vesicle recycling is unclear. We used theDrosophilatemperature-sensitive dynamin mutant,shibire-ts1, to block endocytosis of recycling synaptic vesicles and to trap them reversibly at the plasma membrane where they were accessible to sterol extraction. Depletion of sterols from trapped vesicles prevented recovery of synaptic transmission after removal of the endocytic block. Measurement of vesicle recycling with synaptopHluorin, FM1-43, and FM4-64 demonstrated impaired membrane retrieval after vesicular sterol depletion. When plasma membrane sterols were extracted before vesicle trapping, no vesicle recycling defects were observed. Ultrastructural analysis indicated accumulation of endosomes and a defect in the formation of synaptic vesicles in synaptic terminals subjected to vesicular sterol depletion. Our results demonstrate the importance of a high vesicular sterol concentration for endocytosis and suggest that vesicular and membrane sterol pools do not readily intermingle during vesicle recycling.
Synaptic Acidification Enhances GABAASignaling
Authors: Dietrich Craig J. , Morad Martin
Published: November 2010

To determine the role of cellularly generated protons in synaptic signaling, we recorded GABA miniature IPSCs (mIPSCs) from cultured rat cerebellar granule cells (CGCs) while varying the extracellular pH buffering capacity. Consistent with previous reports, we found that increasing pH from 7.4 to 8.0 sped mIPSC rise time and suppressed both amplitude of the current and total charge transferred. Conversely, acidification (from pH 7.4 to 6.8) slowed the rise time and increased current amplitude and total charge transferred. In a manner consistent with alkalinization, increasing the buffering capacity from 3 to 24 mmHEPES at pH 7.4 resulted in faster mIPSC rise time, a 37% reduction in amplitude, and a 48% reduction in charge transferred. Supplementing the normal physiological buffers (24 mmHCO3−/5%CO2) with 10 mmHEPES similarly diminished mIPSCs in a manner consistent with alkalinization, resulting in faster rise time, a 39% reduction in amplitude, and a 51% reduction in charge transferred. These findings suggest the existence of an acidifying synaptic force that is overcome by commonly used concentrations (10 mm) of HEPES buffer. Here we show that Na+/H+exchanger (NHE) activity appears to, in part, contribute to this synaptic acidification because inhibition of NHE by amiloride or lithium under physiological or weak buffering conditions alters mIPSCs in a manner consistent with alkalinization. These results suggest that acidification of the synaptic cleft occurs physiologically during GABAergic transmission and that NHE plays a critical role in generating the acidic nano-environment at the synapse.
Appetite-regulating hormones cortisol and peptide YY are associated with disordered eating psychopathology, independent of body mass index
Authors: Lawson Elizabeth A , Eddy Kamryn T , Donoho Daniel , Misra Madhusmita , Miller Karen K , Meenaghan Erinne , Lydecker Janet , Herzog David , Klibanski Anne
Published: November 2010

Objective

Disordered eating occurs in women at both weight extremes of anorexia nervosa (AN) and obesity. Cortisol, peptide YY (PYY), leptin, and ghrelin are hormones involved in appetite and feeding behavior that vary with weight and body fat. Abnormal levels of these hormones have been reported in women with AN, functional hypothalamic amenorrhea (HA), and obesity. The relationship between appetite-regulating hormones and disordered eating psychopathology is unknown. We therefore studied the relationship between orexigenic and anorexigenic hormones and disordered eating psychopathology in women across a range of weights.

Design

A cross-sectional study of 65 women, 18–45 years: 16 with AN, 12 normal-weight with HA, 17 overweight or obese, and 20 normal-weight in good health.

Methods

Two validated measures of disordered eating psychopathology, the Eating Disorders Examination-Questionnaire (EDE-Q) and Eating Disorders Inventory-2 (EDI-2), were administered. Fasting PYY, leptin, and ghrelin levels were measured; cortisol levels were pooled from serum samples obtained every 20 min from 2000 to 0800 h.

Results

Cortisol and PYY levels were positively associated with disordered eating psychopathology including restraint, eating concerns, and body image disturbance, independent of body mass index (BMI). Although leptin levels were negatively associated with disordered eating psychopathology, these relationships were not significant after controlling for BMI. Ghrelin levels were generally not associated with EDE-Q or EDI-2 scores.

Conclusions

Higher levels of cortisol and PYY are associated with disordered eating psychopathology independent of BMI in women across the weight spectrum, suggesting that abnormalities in appetite regulation may be associated with specific eating disorder pathologies.
Pregnancy in women heterozygous for MCT8 mutations: risk of maternal hypothyroxinemia and fetal care
Authors: Ramos Helton Estrela , Morandini Melina , Carré Aurore , Tron Elodie , Floch Corinne , Mandelbrot Laurent , Neri Nathalie , De Sarcus Benoit , Simon Albane , Bonnefont Jean Paul , Amiel Jeanne , Desguerre Isabelle , Valayannopoulos Vassili , Castanet Mireille , Polak Michel
Published: November 2010

Context

Monocarboxylate transporter 8 (MCT8 or SLC16A2) mutations cause X-linked Allan–Herndon–Dudley syndrome. Heterozygous females are usually asymptomatic, but pregnancy may modify thyroid function and MCT8 is expressed in the placenta, suggesting that maternal and fetal abnormalities might develop even in the absence of MCT8 fetal mutation. Genetic counseling is so far based on X-linked transmission, and prenatal diagnosis is rarely performed.

Objective

To describe thyroid function and the prenatal diagnosis in pregnant mothers harboring heterozygous MCT8 mutations and management of the persistent maternal hypothyroxinemia.

Patients

Two women heterozygous for MCT8 mutations (c.1690G>A and c.1393-1G>C) were monitored throughout pregnancy.

Methods

Prenatal diagnosis included sex determination, direct MCT8 sequencing, and familial linkage analysis. Ultrasonography and hormonal assays for maternal thyroid function evaluation were performed serially during pregnancy. Neonatal thyroid hormonal status was assessed.

Results

None of the three fetuses (two males and one female) carried MCT8 mutations. One of the two heterozygous mothers revealed gestational hypothyroxinemia, prompting early levothyroxine (l-T4) therapy until delivery. The second heterozygous mother showed normal thyroid function but was preventively traited by l-T4 and all of the three neonates had normal thyroid hormone levels and thyroid gland at birth, suggesting advantages of prenatal care and/or compensatory mechanisms.

Conclusion

Heterozygous MCT8 women should be monitored for requirement of l-T4 therapy to prevent fetal and neonatal hypothyroidism and to avoid risk of potential cognitive delay due to gestational hypothyroxinemia. Moreover, when the disease-causing mutation is known and/or the first child is affected, prenatal diagnosis for male fetuses should be assessed early for MCT8 mutations by direct sequencing.
The Putative Lipid Transporter, Arv1, Is Required for Activating Pheromone-Induced MAP Kinase Signaling in Saccharomyces cerevisiae
Authors: Villasmil Michelle L , Ansbach Alison , Nickels Joseph T
Published: November 2010

Saccharomyces cerevisiae haploid cells respond to extrinsic mating signals by forming polarized projections (shmoos), which are necessary for conjugation. We have examined the role of the putative lipid transporter, Arv1, in yeast mating, particularly the conserved Arv1 homology domain (AHD) within Arv1 and its role in this process. Previously it was shown that arv1 cells harbor defects in sphingolipid and glycosylphosphatidylinositol (GPI) biosyntheses and may harbor sterol trafficking defects. Here we demonstrate that arv1 cells are mating defective and cannot form shmoos. They lack the ability to initiate pheromone-induced G1 cell cycle arrest, due to failure to polarize PI(4,5)P2 and the Ste5 scaffold, which results in weakened MAP kinase signaling activity. A mutant Ste5, Ste5Q59L, which binds more tightly to the plasma membrane, suppresses the MAP kinase signaling defects of arv1 cells. Filipin staining shows arv1 cells contain altered levels of various sterol microdomains that persist throughout the mating process. Data suggest that the sterol trafficking defects of arv1 affect PI(4,5)P2 polarization, which causes a mislocalization of Ste5, resulting in defective MAP kinase signaling and the inability to mate. Importantly, our studies show that the AHD of Arv1 is required for mating, pheromone-induced G1 cell cycle arrest, and for sterol trafficking.
Genetic Evidence for Antagonism Between Pak Protein Kinase and Rho1 Small GTPase Signaling in Regulation of the Actin Cytoskeleton During Drosophila Oogenesis
Authors: Vlachos Stephanie , Harden Nicholas
Published: November 2010

During Drosophila oogenesis, basally localized F-actin bundles in the follicle cells covering the egg chamber drive its elongation along the anterior–posterior axis. The basal F-actin of the follicle cell is an attractive system for the genetic analysis of the regulation of the actin cytoskeleton, and results obtained in this system are likely to be broadly applicable in understanding tissue remodeling. Mutations in a number of genes, including that encoding the p21-activated kinase Pak, have been shown to disrupt organization of the basal F-actin and in turn affect egg chamber elongation. pak mutant egg chambers have disorganized F-actin distribution and remain spherical due to a failure to elongate. In a genetic screen to identify modifiers of the pak rounded egg chamber phenotype several second chromosome deficiencies were identified as suppressors. One suppressing deficiency removes the rho1 locus, and we determined using several rho1 alleles that removal of a single copy of rho1 can suppress the pak phenotype. Reduction of any component of the Rho1-activated actomyosin contractility pathway suppresses pak oogenesis defects, suggesting that Pak counteracts Rho1 signaling. There is ectopic myosin light chain phosphorylation in pak mutant follicle cell clones in elongating egg chambers, probably due at least in part to mislocalization of RhoGEF2, an activator of the Rho1 pathway. In early egg chambers, pak mutant follicle cells have reduced levels of myosin phosphorylation and we conclude that Pak both promotes and restricts myosin light chain phosphorylation in a temporally distinct manner during oogenesis.
Validation of the Dutch Registry of Common Oral Clefts: Quality of Recording Specific Oral Cleft Features
Authors: Rozendaal Anna M. , Luijsterburg Antonius J.M. , Mohangoo Ashna D. , Ongkosuwito Edwin M. , De Vries Esther , Vermeij-Keers Christl
Published: November 2010

Objective

Since 1997, common oral clefts in the Netherlands have been recorded in the national oral cleft registry using a unique descriptive recording system. This study validates data on the topographic-anatomical structure, morphology, and side of individual anomalies of the primary palate and secondary palate that form the oral cleft.

Design

Validation study.

Setting

All 15 Dutch cleft palate teams reporting presurgery oral cleft patients to the national registry.

Patients

A random sample of 250 cases registered in the national database with oral clefts from 1997 through 2003; of these, 13 cases were excluded.

Main Outcome Measures

By linking registry data with clinical data, we identified differential recording rates by comparing the prevalence, and we measured the degree of agreement by computing validity and reliability statistics.

Results

The topographic-anatomical structures (lip, alveolus, and hard and soft palates) of the anomalies had near-perfect interdatabase agreement with a sensitivity of 88% to 99%. However, when analyzing the individual anomalies in detail (morphology and side), validity decreased and depended on morphological severity. This association was most evident for anomalies of the secondary palate. For example, sensitivity was higher for “complete cleft hard palate” (92%) than for “submucous cleft hard/soft palate” (69%).

Conclusions

Overall, the validity of Dutch registry data on oral clefts is good, supporting the feasibility of this unique recording system. However, when analyzing oral cleft data in detail, the quality appears to be related to anatomical location and morphological severity. This might have implications for etiologic research based on registry data and for guidelines on neonatal examination.