bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Application of Voriconazole Concentrations in the Treatment of Invasive Aspergillosis
Authors: Howard Ashley , Hoffman Janet , Sheth Anjly
Published: November 2008

Objective:

To review the current literature to determine the clinical application of therapeutic drug monitoring of voriconazole in the treatment of invasive aspergillosis (IA).

Data Sources:

A MEDLINE search (1966–June 2008) was performed using the search terms voriconazole, aspergillosis, levels, monitoring, and serum concentration.

Study Selection and Data Extraction:

All pertinent English-language literature on voriconazole use in adults was included for evaluation.

Data Synthesis:

IA is a serious fungal infection with a mortality rate of nearly 100% without adequate treatment; current therapeutic options are limited. A clinical trial comparing amphotericin B deoxycholate with voriconazole in treatment of IA found voriconazole to be superior. The use of voriconazole, however, is complicated due to its saturable metabolism, nonlinear kinetic profile, and drug interactions, which result in considerable interpatient variability in concentrations. Therefore, therapeutic monitoring of voriconazole trough concentrations may lead to improved patient outcomes. A recent prospective study on the use of voriconazole for treatment of invasive mycoses demonstrated that 46% of the patients had a lack of response when trough plasma concentrations were less than or equal to 1 μg/mL, compared with 12% of patients with trough concentrations greater than 1 μg/mL (p = 0.02). All patients with low trough concentrations who did not respond to voriconazole improved upon dose escalation. The upper limit of a therapeutic range is based on the presence of adverse events. The most common adverse effects associated with voriconazole are visual disturbances (21%) and elevations in liver transaminase levels (12.4%). Current literature suggests that a greater incidence of adverse effects may be associated with trough concentrations greater than 6 μg/mL.

Conclusions:

A standardized therapeutic range for voriconazole has not been defined. Most available studies recommend trough concentrations of approximately 1–6 μg/mL. Prospective, randomized trials are needed to confirm the correlation between plasma voriconazole concentrations and clinical outcomes.
Probable Interaction Between Warfarin and Torsemide
Authors: Bird Jennifer , Carmona Carlos
Published: November 2008

Objective:

To report a case in which the anticoagulation effect of warfarin appeared to be potentiated by torsemide, possibly due to an interference of metabolism through competition for the CYP2C9 isoenzyme and protein-binding displacement of warfarin.

Case Summary:

A 43-year-old Hispanic female with congestive heart failure, hypothyroidism, anemia, atrial fibrillation, and a mitral mechanical valve replacement was effectively anticoagulated with a target international normalized ratio (INR) of 2.5–3.5 on a warfarin regimen of 50–52.5 mg/wk. One week following the initiation of torsemide 40 mg in the morning and 20 mg in the afternoon, a marked increase in the INR occurred (6.2), requiring a warfarin dosage reduction. Subsequent titrations over a 3-week period eventually resulted in the achievement of a therapeutic INR (from 3.3 to 2.9) with a new warfarin regimen of 47.5 mg/wk.

Discussion:

Both torsemide and warfarin are highly protein-bound to albumin and are major substrates for the CYP2C9 isoenzyme. Competition by multiple drugs for metabolism via CYP2C9 may decrease the clearance of the drugs from systemic circulation. Addition of a drug with high protein binding may result in the displacement of other drugs that circulate highly protein-bound. Therefore, it is possible that the addition of torsemide may potentiate the anticoagulant effect of warfarin by (1) competition for metabolism through CYP2C9, with a decrease in the clearance of warfarin, and (2) protein-binding displacement of warfarin from albumin, transiently potentiating anticoagulant activity. An objective causality assessment revealed that the interaction was probable. Cardiology records confirmed the absence of fluid and heart failure status changes; therefore, these were ruled out as potential etiologies. No levothyroxine dosage changes occurred over the previous 14 months; thus, this also was ruled out as a possible etiology.

Conclusions:

To our knowledge, an interaction between warfarin and torsemide has not been previously reported. While further research should be done to confirm this interaction, practitioners should be made aware of its possibility.
Recommended Nutritional Supplements for Bariatric Surgery Patients
Authors: Malone Margaret
Published: November 2008

Objective:

To review nutritional supplements commonly required after bariatric surgery to provide a practical guide and reference source for generalist healthcare providers.

Data Sources:

A PubMed literature search (1968–July 2008) was conducted, using the search term nutritional deficiency after bariatric surgery, and was limited to English-language literature on adult (aged >19 y) human subjects. Additional references from the selected literature were also included.

Study Selection and Data Extraction:

Data were extracted from large clinical series and practice guidelines whenever possible. Case reports were used only when they were the sole information source.

Data Synthesis:

Nutritional deficiencies that occur after bariatric surgery depend significantly on the type of surgery performed. Restrictive procedures such as gastric banding are the least likely to cause nutritional deficits, since none of the Intestine is bypassed. Malabsorptive procedures such as biliopancreatic diversion or mixed restrictive/malabsorpive procedures (eg, Roux-en-Y gastric bypass) can result in serious nutritional problems when patients do not take required supplements after surgery. Vitamins and minerals that are commonly deficient in this circumstance include vitamin B12, calcium, vitamin D, thiamine, folic acid, iron, zinc, and magnesium. Rare ocular complications have been reported with hypovitaminosis A.

Conclusions:

Healthcare professionals, especially those who practice outside large bariatric centers, must be aware of the supplements required by patients who have had bariatric surgery. Many patients fail to follow up with the surgery centers and are managed by their primary care teams and community pharmacists, especially in the selection of multivitamin and nutritional supplements.
Syndrome of Inappropriate Secretion of Antidiuretic Hormone Associated with Imatinib
Authors: Liapis Konstantinos , Apostolidis John , Charitaki Evangelia , Panitsas Fotios , Harhalakis Nikolaos , Nikiforakis Emmanuel
Published: November 2008

Objective:

Despite the high prevalence of headache and migraine in the general population, many people do not receive adequate medical attention and treatment.

Case Summary:

A 29-year-old woman was diagnosed with Bcr-abl+ acute lymphoblastic leukemia, and treatment was initiated with chemotherapy and imatinib 800 mg daily. Following imatinib initiation, a gradual decrease in serum sodium level was noticed. Prolonged aplasia and neutropenic fever prompted discontinuation of therapy for 4 weeks. Following the patient's recovery, complete remission was achieved and monotherapy with imatinib 800 mg daily was restarted; however, hyponatremia recurred a few days later. The clinical findings and laboratory workup were compatible with the diagnosis of SIADH, which was attributed to high-dose imatinib. Fluid restriction and imatinib dosage reduction (to 600 mg/day) restored sodium levels. According to the Naranjo probability scale, this adverse reaction was probably associated with imatinib.

Discussion:

Imatinib emerged as the first tyrosine kinase inhibitor to enter everyday clinical practice for the treatment of Ph+ leukemias. Due to its molecular specificity, imatinib lacks the broad cytotoxicity of conventional chemotherapy. Inhibition of kinases in normal tissues accounts for many of imatinib's adverse reactions. To our knowledge, this is the first reported case of imatinib-induced SIADH.

Conclusions:

We recommend monitoring for SIADH if a patient receiving high-dose imatinib develops hyponatremia.
Scope, Completeness, and Accuracy of Drug Information in Wikipedia
Authors: Clauson Kevin A , Polen Hyla H , Boulos Maged N Kamel , Dzenowagis Joan H
Published: November 2008

Background:

With the advent of Web 2.0 technologies, user-edited online resources such as Wikipedia are increasingly tapped for information. However, there is little research on the quality of health information found in Wikipedia.

Objective:

To compare the scope, completeness, and accuracy of drug information in Wikipedia with that of a free, online, traditionally edited database (Medscape Drug Reference [MDR]).

Methods:

Wikipedia and MDR were assessed on 8 categories of drug information. Questions were constructed and answers were verified with authoritative resources, Wikipedia and MDR were evaluated according to scope (breadth of coverage) and completeness. Accuracy was tracked by factual errors and errors of omission. Descriptive statistics were used to summarize the components. Fisher's exact test was used to compare scope and paired Student's Most was used to compare current results in Wikipedia with entries 90 days prior to the current access.

Results:

Wikipedia was able to answer significantly fewer drug information questions (40.0%) compared with MDR (82.5%; p <0.001). Wikipedia performed poorly regarding information on dosing, with a score of 0% versus the MDR score of 90.0%. Answers found in Wikipedia were 76.0% complete, white MDR provided answers that were 95.5% complete; overall, Wikipedia answers were less complete than those in Medscape (p <0.001). No factual errors were found in Wikipedia, whereas 4 answers in Medscape conflicted with the answer key; errors of omission were higher in Wikipedia (n = 48) than in MDR (n = 14). There was a marked improvement in Wikipedia over time, as current entries were superior to those 90 days prior (p = 0.024).

Conclusions:

Wikipedia has a more narrow scope, is less complete, and has more errors of omission than the comparator database. Wikipedia may be a useful point of engagement for consumers, but is not authoritative and should only be a supplemental source of drug information.
Method of Test for Determining the Splitting Tensile Strength of Rocks
Authors: Peng SS
Published: November 2008

A standard method of determining the splitting tensile strength of rock is proposed. It covers the specifications of the testing apparatus, specimen preparation, procedures, data reduction, and the report format.
Example of an Energy Calibration Report on a Standard Penetration Test (ASTM Standard D 1586–67) Drill Rig
Authors: Schmertmann JH , Smith TV , Ho R
Published: November 2008

This note provides an example of an energy calibration report on standard penetration test equipment. This calibration was designed to determine a standard hammer drop height that would produce 2100 in.·lb (237 N·m) of compression wave energy entering the drill rods as a result of the average hammer blow when using drop procedures as ordinarily used for the rig under calibration.
Excitation and Inhibition Jointly Regulate Cortical Reorganization in Adult Rats
Authors: Benali Alia , Weiler Elke , Benali Youssef , Dinse Hubert R. , Eysel Ulf T.
Published: November 2008

The primary somatosensory cortex (SI) retains its capability for cortical reorganization after injury or differential use into adulthood. The plastic response of SI cells to peripheral stimulation is characterized by extension of cortical representations accompanied by changes of the receptive field size of neurons. We used intracortical microstimulation that is known to enforce local, intracortical synchronous activity, to induce cortical reorganization and applied immunohistochemical methods in the same individual animals to investigate how plasticity in the cortical topographic maps is linked to changes in the spatial layout of the inhibitory and excitatory neurotransmitter systems. The results reveal a differential spatiotemporal pattern of upregulation and downregulation of specific factors for an excitatory (glutamatergic) and an inhibitory (GABAergic) system, associated with changes of receptive field size and reorganization of the somatotopic map in the rat SI. Predominantly local mechanisms are the specific reduction of the calcium-binding protein parvalbumin in inhibitory neurons and the low expression of the activity marker c-Fos. Reorganization in the hindpaw representation and in the adjacent SI cortical areas (motor cortex and parietal cortex) is accompanied by a major increase of the excitatory transmitter glutamate and c-Fos. The spatial extent of the reorganization appears to be limited by an increase of glutamic acid decarboxylase and the inhibitory transmitter GABA. The local and medium-range net effects are excitatory and can facilitate receptive field enlargements and cortical map expansion. The longer-range increase of inhibition appears suited to limit these effects and to prevent neurons from pathological hyperexcitability.
Distinct Regions of Prefrontal Cortex Mediate Resistance and Vulnerability to Depression
Authors: Koenigs Michael , Huey Edward D. , Calamia Matthew , Raymont Vanessa , Tranel Daniel , Grafman Jordan
Published: November 2008

The neuroanatomical correlates of depression remain unclear. Functional imaging data have associated depression with abnormal patterns of activity in prefrontal cortex (PFC), including the ventromedial (vmPFC) and dorsolateral (dlPFC) sectors. If vmPFC and dlPFC are critical neural substrates for the pathogenesis of depression, then damage to either area should affect the expression of depressive symptoms. Using patients with brain lesions we show that, relative to nonfrontal lesions, bilateral vmPFC lesions are associated with markedly low levels of depression, whereas bilateral dorsal PFC lesions (involving dorsomedial and dorsolateral areas in both hemispheres) are associated with substantially higher levels of depression. These findings demonstrate that vmPFC and dorsal PFC are critically and causally involved in depression, although with very different roles: vmPFC damage confers resistance to depression, whereas dorsal PFC damage confers vulnerability.
A Novel Gβγ-Subunit Inhibitor Selectively Modulates μ-Opioid-Dependent Antinociception and Attenuates Acute Morphine-Induced Antinociceptive Tolerance and Dependence
Authors: Mathews Jennifer L. , Smrcka Alan V. , Bidlack Jean M.
Published: November 2008

The Gβγ subunit has been implicated in many downstream signaling events associated with opioids. We previously demonstrated that a small molecule inhibitor of Gβγ-subunit-dependent phospholipase (PLC) activation potentiated morphine-induced analgesia (Bonacci et al., 2006). Here, we demonstrate that this inhibitor, M119 (cyclohexanecarboxylic acid [2-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)-(9Cl)]), is selective for μ-opioid receptor-dependent analgesia and has additional efficacy in mouse models of acute tolerance and dependence. When administered by an intracerebroventricular injection in mice, M119 caused 10-fold and sevenfold increases in the potencies of morphine and the μ-selective peptide, DAMGO, respectively. M119 had little or no effect on analgesia induced by the κ agonist U50,488 or δ agonists DPDPE or Deltorphin II. Similar results were obtainedin vitro, as only activation of the μ-opioid receptor stimulated PLC activation, whereas no effect was seen with the κ- and δ-opioid receptors. M119 inhibited μ-receptor-dependent PLC activation. In studies to further explore thein vivoefficacy of M119, systemic administration M119 also resulted in a fourfold shift increase in potency of systemically administered morphine. Of particular interest, M119 was also able to attenuate acute, antinociceptive tolerance and dependence in mice treated concomitantly with both M119 and morphine. These studies suggest that small organic molecules, such as M119, that specifically regulate Gβγ subunit signaling may have important therapeutic applications in enhancing opioid analgesia, while attenuating the development of tolerance and dependence.
Inhibition Shapes Sex Selectivity in the Mouse Accessory Olfactory Bulb
Authors: Hendrickson Rebecca C. , Krauthamer Sandra , Essenberg James M. , Holy Timothy E.
Published: November 2008

Laterally connected inhibitory circuitry is found throughout the nervous system, including many early sensory processing systems. The extent to which it plays a role in shaping neuronal stimulus selectivity in systems like olfaction, however, which lack a simple two-dimensional representation of their stimulus space, has remained controversial. We examined this issue using an experimental preparation that allowed electrophysiological recording from the accessory olfactory bulb of an anesthetized mouse during the controlled delivery of pheromonal stimuli, in this case derived from the urine of male and female mice. We found that individual neurons were often highly selective for the sex of the urine donor. Examination of both explicitly inhibitory responses, as well as responses to mixtures of male and female urine, revealed that laterally connected inhibition was both prevalent and of large magnitude, particularly for male-selective neurons. Pharmacological manipulation of this inhibition resulted in a shift in many neurons' stimulus selectivities. Finally, we found that a behavioral response (pregnancy block) evoked by the presence of unfamiliar male urine could be suppressed by the addition of female urine to the stimulus, demonstrating that this system displays a behavioral opponency consistent with neural inhibition. Together, these results indicate that laterally connected inhibitory circuitry in the accessory olfactory bulb plays an important role in shaping neural selectivity for natural stimuli.
Rescue of Neurons from Ischemic Injury by Peroxisome Proliferator-Activated Receptor-γ Requires a Novel Essential Cofactor LMO4
Authors: Schock Sarah C. , Xu Jin , Duquette Philippe M. , Qin Zhaohong , Lewandowski Adam J. , Rai Punarpreet S. , Thompson Charlie S. , Seifert Erin L. , Harper Mary-Ellen , Chen Hsiao-Huei
Published: November 2008

Activation of peroxisome proliferator-activated receptor-γ (PPARγ) signaling after stroke may reduce brain injury, but this effect will depend on the levels of receptor and cofactors. Here, we showed that the direct effect of PPARγ signaling to protect neurons from ischemic injury requires a novel cofactor LMO4, because this effect was lost in LMO4-null cortical neurons. PPARγ agonist also failed to reduce cerebral infarction after transient focal ischemia in CaMKIIαCre/LMO4loxP mice with LMO4 ablated in neurons of the forebrain. Expressing LMO4 in LMO4-null cortical neurons rescued the PPARγ-protective effect. PPARγ signaling activates the promoter of the antioxidant gene SOD2 and this process requires LMO4. Addition of a superoxide dismutase mimetic MnTBAP [manganese(III)tetrakis(4-benzoic acid)porphyrin] bypassed the deficiency in PPARγ signaling and was able to directly rescue LMO4-null cortical neurons from ischemic injury. Like LMO4, PPARγ and PGC1α (PPARγ coactivator 1α) levels in neurons are elevated by hypoxic stress, and absence of LMO4 impairs their upregulation. Coimmunoprecipitation and mammalian two-hybrid assays revealed that LMO4 interacts in a ligand-dependent manner with PPARγ. LMO4 augments PPARγ-dependent gene activation, in part, by promoting RXRα (retinoid X receptor-α) binding to PPARγ and by increasing PPARγ binding to its target DNA sequence. Together, our results identify LMO4 as an essential hypoxia-inducible cofactor required for PPARγ signaling in neurons. Thus, upregulation of LMO4 expression after stroke is likely to be an important determinant of neuron survival.
Trial-by-Trial Fluctuations in the Event-Related Electroencephalogram Reflect Dynamic Changes in the Degree of Surprise
Authors: Mars Rogier B. , Debener Stefan , Gladwin Thomas E. , Harrison Lee M. , Haggard Patrick , Rothwell John C. , Bestmann Sven
Published: November 2008

The P300 component of the human event-related brain potential has often been linked to the processing of rare, surprising events. However, the formal computational processes underlying the generation of the P300 are not well known. Here, we formulate a simple model of trial-by-trial learning of stimulus probabilities based on Information Theory. Specifically, we modeled the surprise associated with the occurrence of a visual stimulus to provide a formal quantification of the “subjective probability” associated with an event. Subjects performed a choice reaction time task, while we recorded their brain responses using electroencephalography (EEG). In each of 12 blocks, the probabilities of stimulus occurrence were changed, thereby creating sequences of trials with low, medium, and high predictability. Trial-by-trial variations in the P300 component were best explained by a model of stimulus-bound surprise. This model accounted for the data better than a categorical model that parametrically encoded the stimulus identity, or an alternative model of surprise based on the Kullback–Leibler divergence. The present data demonstrate that trial-by-trial changes in P300 can be explained by predictions made by an ideal observer keeping track of the probabilities of possible events. This provides evidence for theories proposing a direct link between the P300 component and the processing of surprising events. Furthermore, this study demonstrates how model-based analyses can be used to explain significant proportions of the trial-by-trial changes in human event-related EEG responses.
NMDA Receptor Activation by HIV-Tat Protein Is Clade Dependent
Authors: Li Wenxue , Huang Yan , Reid Rollie , Steiner Joseph , Malpica-Llanos Tanya , Darden Thomas A. , Shankar Susarla K. , Mahadevan Anita , Satishchandra Parthasarthy , Nath Avindra
Published: November 2008

In countries infected with HIV clade B, some patients develop a rapidly progressive dementia that if untreated results in death. In regions of the world infected with HIV clade C, only milder forms of cognitive impairment have been recognized. HIV-infected macrophages are the principal mediators of dementia. HIV clade C, however, efficiently infects macrophages and HIV-infected macrophages are found in the brains of clade C-infected patients. HIV-infected macrophages release Tat protein, which may act directly on neurons to cause toxicity. We found that Tat released from Tat-expressing cells was at least 1000-fold more toxic than recombinant Tat protein. We determined whether Tat could interact with NMDA receptors and whether these interactions are clade dependent. It is demonstrated that Tat binds directly to the NMDA receptor leading to excitotoxicity. The Cys 30-Cys 31 motif in Tat is critical for exciting the NMDA receptor and the Cys31Ser mutation found in clade C Tat has a significantly attenuated neurotoxic response. Through molecular modeling and site-directed mutagenesis, we predict that Cys 31 disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor by directly interacting with Cys 744 leading to a free thiol group on Cys 798 and subsequent persistent activation of the NMDA receptor.
A Role for Dopamine in Temporal Decision Making and Reward Maximization in Parkinsonism
Authors: Moustafa Ahmed A. , Cohen Michael X. , Sherman Scott J. , Frank Michael J.
Published: November 2008

Converging evidence implicates striatal dopamine (DA) in reinforcement learning, such that DA increases enhance “Go learning” to pursue actions with rewarding outcomes, whereas DA decreases enhance “NoGo learning” to avoid non-rewarding actions. Here we test whether these effects apply to the response time domain. We employ a novel paradigm which requires the adjustment of response times to a single response. Reward probability varies as a function of response time, whereas reward magnitude changes in the opposite direction. In the control condition, these factors exactly cancel, such that the expected value across time is constant (CEV). In two other conditions, expected value increases (IEV) or decreases (DEV), such that reward maximization requires either speeding up (Go learning) or slowing down (NoGo learning) relative to the CEV condition. We tested patients with Parkinson's disease (depleted striatal DA levels) on and off dopaminergic medication, compared with age-matched controls. While medicated, patients were better at speeding up in the DEV relative to CEV conditions. Conversely, nonmedicated patients were better at slowing down to maximize reward in the IEV condition. These effects of DA manipulation on cumulative Go/NoGo response time adaptation were captured with our a priori computational model of the basal ganglia, previously applied only to forced-choice tasks. There were also robust trial-to-trial changes in response time, but these single trial adaptations were not affected by disease or medication and are posited to rely on extrastriatal, possibly prefrontal, structures.
RANTES Modulates the Release of Glutamate in Human Neocortex
Authors: Musante Veronica , Longordo Fabio , Neri Elisa , Pedrazzi Marco , Kalfas Fotios , Severi Paolo , Raiteri Maurizio , Pittaluga Anna
Published: November 2008

The effects of the recombinant chemokine human RANTES (hRANTES) on the release of glutamate from human neocortex glutamatergic nerve endings were investigated. hRANTES facilitated the spontaneous release of d [3H]d-aspartate ([3H]dASP-) by binding Pertussis toxin-sensitive G-protein-coupled receptors (GPCRs), whose activation caused Ca2+mobilization from inositol trisphosphate-sensitive stores and cytosolic tyrosine kinase-mediated phosphorylations. Facilitation of release switched to inhibition when the effects of hRANTES on the 12 mmK+-evoked [3H]d-ASP exocytosis were studied. Inhibition of exocytosis relied on activation of Pertussis toxin-sensitive GPCRs negatively coupled to adenylyl cyclase. Both hRANTES effects were prevented by met-RANTES, an antagonist at the chemokine receptors (CCRs) of the CCR1, CCR3, and CCR5 subtypes. Interestingly, human neocortex glutamatergic nerve endings seem to possess all three receptor subtypes. Blockade of CCR1 and CCR5 by antibodies against the extracellular domain of CCRs prevented both the hRANTES effect on [3H]d-ASP release, whereas blockade of CCR3 prevented inhibition, but not facilitation, of release. The effects of RANTES on the spontaneous and the evoked release of [3H]d-ASP were also observed in experiments with mouse cortical synaptosomes, which may therefore represent an appropriate animal model to study RANTES-induced effects on neurotransmission. It is concluded that glutamate transmission can be modulated in opposite directions by RANTES acting at distinct CCR receptor subtypes coupled to different transduction pathways, consistent with the multiple and sometimes contrasting effects of the chemokine.
Inflammation Regulates Functional Integration of Neurons Born in Adult Brain
Authors: Jakubs Katherine , Bonde Sara , Iosif Robert E. , Ekdahl Christine T. , Kokaia Zaal , Kokaia Merab , Lindvall Olle
Published: November 2008

Inflammation influences several steps of adult neurogenesis, but whether it regulates the functional integration of the new neurons is unknown. Here, we explored, using confocal microscopy and whole-cell patch-clamp recordings, whether a chronic inflammatory environment affects the morphological and electrophysiological properties of new dentate gyrus granule cells, labeled with a retroviral vector encoding green fluorescent protein. Rats were exposed to intrahippocampal injection of lipopolysaccharide, which gave rise to long-lasting microglia activation. Inflammation caused no changes in intrinsic membrane properties, location, dendritic arborization, or spine density and morphology of the new cells. Excitatory synaptic drive increased to the same extent in new and mature cells in the inflammatory environment, suggesting increased network activity in hippocampal neural circuitries of lipopolysaccharide-treated animals. In contrast, inhibitory synaptic drive was more enhanced by inflammation in the new cells. Also, larger clusters of the postsynaptic GABAAreceptor scaffolding protein gephyrin were found on dendrites of new cells born in the inflammatory environment. We demonstrate for the first time that inflammation influences the functional integration of adult-born hippocampal neurons. Our data indicate a high degree of synaptic plasticity of the new neurons in the inflammatory environment, which enables them to respond to the increase in excitatory input with a compensatory upregulation of activity and efficacy at their afferent inhibitory synapses.
Novel Leptin-Regulated Genes Revealed by Transcriptional Profiling of the Hypothalamic Paraventricular Nucleus
Authors: Tung Yi-Chun Loraine , Ma Marcella , Piper Sarah , Coll Anthony , O'Rahilly Stephen , Yeo Giles S. H.
Published: November 2008

Leptin plays a major role in coordinating the integrated response of the CNS to changes in nutritional state. Neurons within the paraventricular nucleus (PVN) of the hypothalamus express leptin receptors and receive dense innervation from leptin receptor-expressing neurons in the arcuate nucleus. To obtain new insights into the effects of circulating leptin on PVN function, we compared global transcriptional profiles of laser-captured PVN fromad libitumfed mice versus 48 h fasted mice receiving either sham or leptin treatment intraperitoneally. Five hundred twenty-seven PVN-expressed genes were altered by fasting in a manner that was at least partially reversible by leptin. Consistent with previous reports, thyrotrophin releasing hormone mRNA levels were decreased by fasting but restored to fed levels with leptin treatment. mRNA levels of oxytocin, vasopressin, and somatostatin were also reduced by fasting and restored by leptin. Given the known effects of leptin on synaptic remodeling, it is notable that, among the top 15 genes that were positively regulated by leptin, five have been implicated in synaptic function and/or plasticity (basigin,apolipoprotein E,Gap43,GABAAreceptor-associated protein, andsynuclein-γ). Pathway analysis identified oxidative phosphorylation, in particular, genes encoding complex 1 proteins that play a role in ubiquinone biosynthesis, to be the predominant gene set that was significantly regulated in a leptin-dependent manner. Thus, in addition to its effects on the expression of a broad range of neuropeptides, leptin may also exert more general influences on synaptic function in, and the bioenergetic state of, the PVN.
Sec24- and ARFGAP1-Dependent Trafficking of GABA Transporter-1 Is a Prerequisite for Correct Axonal Targeting
Authors: Reiterer Veronika , Maier Susanne , Sitte Harald H. , Kriz Alexander , Rüegg Markus A. , Hauri Hans-Peter , Freissmuth Michael , Farhan Hesso
Published: November 2008

The GABA transporter-1 (GAT1) is a prototypical protein of the synaptic specialization. Export of GAT1 from the endoplasmic reticulum (ER) is contingent on its interaction with the COPII (coatomer protein-II) coat subunit Sec24D. Here we show that silencing all four Sec24 isoforms strongly inhibits transport of GAT1 to the cell surface. In contrast, transport of GAT1-RL/AS, a mutant that is deficient in Sec24D recruitment, was not inhibited, suggesting a nonconventional, COPII-independent pathway. However, ARFGAP1 bound directly to the C terminus of both GAT1-RL/AS and wild-type GAT1. Surface expression of GAT1-RL/AS involved ARFGAP1. GAT1-RL/AS appeared to bypass the ER-Golgi-intermediate compartment, but its pathway to the plasma membrane still involved passage through the Golgi. Thus, the GAT1-RL/AS mutant allowed to test whether COPII-dependent ER-export is required for correct sorting of GAT1 to the axon terminal in neuronal cells. In contrast to wild-type GAT1, GAT1-RL/AS failed to be specifically enriched at the tip of neurite extensions of CAD.a cells (a neuroblastoma cell line that can be differentiated into a neuron-like phenotype) and in the axon terminals of hippocampal neurons. These findings indicate that correct sorting to the axon is contingent on ER export via the COPII machinery and passage through the ER-Golgi-intermediate compartment.
The Semaphorin Receptor PlexinA3 Mediates Neuronal Apoptosis during Dorsal Root Ganglia Development
Authors: Ben-Zvi Ayal , Manor Osnat , Schachner Melitta , Yaron Avraham , Tessier-Lavigne Marc , Behar Oded
Published: November 2008

Extensive neuronal cell death during development is believed to be due to a limiting supply of neurotrophic factors.In vitrostudies suggest that axon guidance molecules directly regulate neuronal survival, raising the possibility that they play a direct role in neuronal cell deathin vivo. However, guidance errors may also influence survival indirectly due to loss of target-derived neurotrophic support. The role of guidance molecules in neuronal deathin vivohas thus been difficult to decipher. Semaphorin3A, a repulsive guidance cue for sensory neurons, can induce sensory neuron deathin vitro. Null mice studies of the Semaphorin3A coreceptors showed that guidance activity is mediated by PlexinA4, but PlexinA3 partially compensates in PlexinA4−/−mice. Here we demonstrate that both Plexins contribute to Sema3A-induced cell deathin vitro, albeit in a different hierarchy. PlexinA3 is absolutely required, while PlexinA4 makes a smaller contribution to cell death. We found that PlexinA3−/−mice, which, unlike PlexinA4−/−mice, do not exhibit sensory axon patterning defects, show reduced neuronal apoptosis and an increased number of DRG neurons. Semaphorin3A involvement in neuronal deathin vivowas demonstrated by a sensitization experiment using the proapoptotic effectorBax. Our results identify Plexins as mediators of Semaphorin-induced cell deathin vitro, and provide the first evidence implicating Semaphorin/Plexin signaling in neuronal survival independent of its role in axon guidance. The results also support the idea that naturally occurring neuronal cell death reflects not only competition for target-derived trophic factors, but also the action of proapoptotic signaling via a Semaphorin/Plexin pathway.
The Sound of Concepts: Four Markers for a Link between Auditory and Conceptual Brain Systems
Authors: Kiefer Markus , Sim Eun-Jin , Herrnberger Bärbel , Grothe Jo , Hoenig Klaus
Published: November 2008

Traditionally, concepts are conceived as abstract mental entities distinct from perceptual or motor brain systems. However, recent results let assume modality-specific representations of concepts. The ultimate test for grounding concepts in perception requires the fulfillment of the following four markers: conceptual processing during (1) an implicit task should activate (2) a perceptual region (3) rapidly and (4) selectively. Here, we show using functional magnetic resonance imaging and recordings of event-related potentials, that acoustic conceptual features recruit auditory brain areas even when implicitly presented through visual words. Fulfilling the four markers, the findings of our study unequivocally link the auditory and conceptual brain systems: recognition of words denoting objects, for which acoustic features are highly relevant (e.g.,“telephone”), ignited cell assemblies in posterior superior and middle temporal gyri (pSTG/MTG) within 150 ms that were also activated by sound perception. Importantly, activity within a cluster of pSTG/MTG increased selectively as a function of acoustic, but not of visual and action-related feature relevance. The implicitness of the conceptual task, the selective modulation of left pSTG/MTG activity by acoustic feature relevance, the early onset of this activity at 150 ms and its anatomical overlap with perceptual sound processing are four markers for a modality-specific representation of auditory conceptual features in left pSTG/MTG. Our results therefore provide the first direct evidence for a link between perceptual and conceptual acoustic processing. They demonstrate that access to concepts involves a partial reinstatement of brain activity during the perception of objects.
Nonrandom Local Circuits in the Dentate Gyrus
Authors: Larimer Phillip , Strowbridge Ben W.
Published: November 2008

The dentate hilus has been extensively studied in relation to its potential role in memory and in temporal lobe epilepsy. Little is known, however, about the synapses formed between the two major cell types in this region, glutamatergic mossy cells and hilar interneurons, or the organization of local circuits involving these cells. Using triple and quadruple simultaneous intracellular recordings in rat hippocampal slices, we find that mossy cells evoke EPSPs with high failure rates onto hilar neurons. Mossy cells show profound synapse specificity; 87.5% of their intralamellar connections are onto hilar interneurons. Hilar interneurons also show synapse specificity and preferentially inhibit mossy cells; 81% of inhibitory hilar synapses are onto mossy cells. Hilar IPSPs have low failure rates, are blocked by the GABAAreceptor antagonist gabazine, and exhibit short-term depression when tested at 17 Hz. Surprisingly, more than half (57%) of the mossy cell synapses we found onto interneurons were part of reciprocal excitatory/inhibitory local circuit motifs. Neither the high degree of target cell specificity, nor the significant enrichment of structured polysynaptic local circuit motifs, could be explained by nonrandom sampling or somatic proximity. Intralamellar hilar synapses appear to function primarily by integrating synchronous inputs and presynaptic burst discharges, allowing hilar cells to respond over a large dynamic range of input strengths. The reciprocal mossy cell/interneuron local circuit motifs we find enriched in the hilus may generate sparse neural representations involved in hippocampal memory operations.
Crucial Role of α4 and α6 Nicotinic Acetylcholine Receptor Subunits from Ventral Tegmental Area in Systemic Nicotine Self-Administration
Authors: Pons S. , Fattore L. , Cossu G. , Tolu S. , Porcu E. , McIntosh J. M. , Changeux J. P. , Maskos U. , Fratta W.
Published: November 2008

The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novelin vivoparadigms were developed to match this aim. Although the β2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different α subunit partners of β2 (i.e., α4 and α6), the homo-pentameric α7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7–52.6 μg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the β2, α4, α6 and α7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VECmice). We show that WT mice, β2-VECmice with the β2 subunit re-expressed exclusively in the VTA, α4-VECmice with selective α4 re-expression in the VTA, α6-VECmice with selective α6 re-expression in the VTA, and α7-KO mice promptly self-administer nicotine intravenously, whereas β2-KO, β2-VECin the substantia nigra, α4-KO and α6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of α4β2- and α6β2-subunit containing nicotinic receptors (α4β2*- and α6β2*-nAChRs), but not α7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice.
Marked Calpastatin (CAST) Depletion in Alzheimer's Disease Accelerates Cytoskeleton Disruption and Neurodegeneration: Neuroprotection by CAST Overexpression
Authors: Rao Mala V. , Mohan Panaiyur S. , Peterhoff Corrinne M. , Yang Dun-Sheng , Schmidt Stephen D. , Stavrides Philip H. , Campbell Jabbar , Chen Yuanxin , Jiang Ying , Paskevich Peter A. , Cataldo Anne M. , Haroutunian Vahram , Nixon Ralph A.
Published: November 2008

Increased activity of calpains is implicated in synaptic dysfunction and neurodegeneration in Alzheimer's disease (AD). The molecular mechanisms responsible for increased calpain activity in AD are not known. Here, we demonstrate that disease progression is propelled by a marked depletion of the endogenous calpain inhibitor, calpastatin (CAST), from AD neurons, which is mediated by caspase-1, caspase-3, and calpains. Initial CAST depletion focally along dendrites coincides topographically with calpain II and ERK 1/2 activation, tau cleavage by caspase-3, and tau and neurofilament hyperphosphorylation. These same changes, together with cytoskeletal proteolysis and neuronal cell death, accompany CAST depletion after intrahippocampal kainic acid administration to mice, and are substantially reduced in mice overexpressing human CAST. Moreover, CAST reduction by shRNA in neuronal cells causes calpain-mediated death at levels of calcium-induced injury that are sublethal to cells normally expressing CAST. Our results strongly support a novel hypothesis that CAST depletion by multiple abnormally activated proteases accelerates calpain dysregulation in AD leading to cytoskeleton disruption and neurodegeneration. CAST mimetics may, therefore, be neuroprotective in AD.
The Midbrain Periaqueductal Gray Control of Respiration
Authors: Subramanian Hari H. , Balnave Ron J. , Holstege Gert
Published: November 2008

The midbrain periaqueductal gray (PAG) organizes basic survival behavior, which includes respiration. How the PAG controls respiration is not known. We studied the PAG control of respiration by injectingd,l-homocysteic acid in the PAG in unanesthetized precollicularly decerebrated cats. Injections in different parts of the PAG caused different respiratory effects. Stimulation in the dorsomedial PAG induced slow and deep breathing and dyspnea. Stimulation in the dorsolateral PAG resulted in active breathing and tachypnea consistent with the respiratory changes during fright and flight. Stimulation in the medial part of lateral PAG caused inspiratory apneusis. Stimulation in lateral parts of the lateral and ventrolateral PAG produced respiratory changes associated with vocalization (mews, alternating mews and hisses, or hisses).d,l-Homocysteic acid injections in the caudal ventrolateral PAG induced irregular breathing. These results demonstrate that the PAG exerts a strong influence on respiration, suggesting that it serves as the behavioral modulator of breathing.
scn1bb, a Zebrafish Ortholog ofSCN1BExpressed in Excitable and Nonexcitable Cells, Affects Motor Neuron Axon Morphology and Touch Sensitivity
Authors: Fein Amanda J. , Wright Melissa A. , Slat Emily A. , Ribera Angeles B. , Isom Lori L.
Published: November 2008

Voltage-gated Na+channels initiate and propagate action potentials in excitable cells. Mammalian Na+channels are composed of one pore-forming α-subunit and two β-subunits.SCN1Bencodes the Na+channel β1-subunit that modulates channel gating and voltage dependence, regulates channel cell surface expression, and functions as a cell adhesion molecule (CAM). We recently identifiedscn1ba, a zebrafish ortholog ofSCN1B. Here we report that zebrafish express a second β1-like paralog,scn1bb. In contrast to the restricted expression ofscn1bamRNA in excitable cells, we detectedscn1bbtranscripts and protein in several ectodermal derivatives including neurons, glia, the lateral line, peripheral sensory structures, and tissues derived from other germ layers such as the pronephros. As expected for β1-subunits, elimination of Scn1bb proteinin vivoby morpholino knock-down reduced Na+current amplitudes in Rohon-Beard neurons of zebrafish embryos, consistent with effects observed in heterologous systems. Further, after Scn1bb knock-down, zebrafish embryos displayed defects in Rohon-Beard mediated touch sensitivity, demonstrating the significance of Scn1bb modulation of Na+current to organismal behavior. In addition to effects associated with Na+current modulation, Scn1bb knockdown produced phenotypes consistent with CAM functions. In particular, morpholino knock-down led to abnormal development of ventrally projecting spinal neuron axons, defasciculation of the olfactory nerve, and increased hair cell number in the inner ear. We propose that, in addition to modulation of electrical excitability, Scn1bb plays critical developmental roles by functioning as a CAM in the zebrafish embryonic nervous system.
Cryo-Immunogold Electron Microscopy for Prions: Toward Identification of a Conversion Site
Authors: Godsave Susan F. , Wille Holger , Kujala Pekka , Latawiec Diane , DeArmond Stephen J. , Serban Ana , Prusiner Stanley B. , Peters Peter J.
Published: November 2008

Prion diseases are caused by accumulation of an abnormally folded isoform (PrPSc) of the cellular prion protein (PrPC). The subcellular distribution of PrPScand the site of its formation in brain are still unclear. We performed quantitative cryo-immunogold electron microscopy on hippocampal sections from mice infected with the Rocky Mountain Laboratory strain of prions. Two antibodies were used: R2, which recognizes both PrPCand PrPSc; and F4–31, which only detects PrPCin undenatured sections. At a late subclinical stage of prion infection, both PrPCand PrPScwere detected principally on neuronal plasma membranes and on vesicles resembling early endocytic or recycling vesicles in the neuropil. The R2 labeling was approximately six times higher in the infected than the uninfected hippocampus and gold clusters were only evident in infected tissue. The biggest increase in labeling density (24-fold) was found on the early/recycling endosome-like vesicles of small-diameter neurites, suggesting these as possible sites of conversion. Trypsin digestion of infected hippocampal sections resulted in a reduction in R2 labeling of >85%, which suggests that a high proportion of PrPScmay be oligomeric, protease-sensitive PrPSc.
Selective Activation of p38 Mitogen-Activated Protein Kinase in Dopaminergic Neurons of Substantia Nigra Leads to Nuclear Translocation of p53 in 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Mice
Authors: Karunakaran Smitha , Saeed Uzma , Mishra Mamata , Valli R. Khader , Datt Joshi Shanker , Meka Durga Praveen , Seth Pankaj , Ravindranath Vijayalakshmi
Published: November 2008

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Activation of the mixed lineage kinase and c-Jun N-terminal kinase (JNK) has been reported in models of PD. Our focus was to discern whether distinct pathways were activated in cell-specific manner within the SNpc. We now demonstrate the selective phosphorylation of p38 MAP kinase within the dopaminergic neurons, whereas JNK activation occurs predominantly in the microglia. p38 activation results in downstream phosphorylation of p53 and increased p53 mediated transcription of Bax and Puma in the ventral midbrain. Treatment with p38 inhibitor, SB239063 protected primary dopaminergic neurons derived from human progenitor cells from MPP+mediated cell death and prevented the downstream phosphorylation of p53 and its translocation to the nucleusin vivo, in the ventral midbrain. The increased staining of phosphorylated p38 in the surviving neurons of SNpc in human brain sections from patients with PD and in MPTP treated mice but not in the ventral tegmental area provides further evidence suggesting a role for p38 in the degeneration of dopaminergic neurons of SNpc. We thus demonstrate the cell specific activation of MAP kinase pathways within the SNpc after MPTP treatment emphasizing the role of multiple signaling cascades in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression.