bluuebunny/crossref_metadata_2025 huggingface dataset:
Anterior and Posterior Pituitary Function Testing with Simultaneous Insulin Tolerance Test and a Novel Copeptin Assay
Authors: Katan Mira , Morgenthaler Nils G. , Dixit Kashinath C. S. , Rutishauser Jonas , Brabant Georg E. , Müller Beat , Christ-Crain Mirjam
Published: April 2007

Context: Posterior pituitary function in patients with suspected diabetes insipidus is usually assessed by a water deprivation test. Alternatively, a nonosmotic stimulus such as hypoglycemia may be used to stimulate vasopressin [arginine vasopressin (AVP)] secretion. Plasma AVP measurement may aid in the diagnosis and, especially, differential diagnosis of diabetes insipidus and polydipsia. However, AVP measurement is cumbersome. Copeptin, the stable C-terminal glycopeptide of the AVP prohormone, is stoichiometrically secreted from the posterior pituitary.

Objective: The aim was to study the value of copeptin levels in the diagnosis of diabetes insipidus during insulin-induced hypoglycemia.

Patients and Methods: A total of 38 patients were studied during insulin-induced hypoglycemia as part of a combined pituitary function test for possible anterior pituitary disease. There were 29 patients who had normal posterior pituitary function, and nine had central diabetes insipidus. Blood sampling was done before and 30, 45, and 90 min after iv insulin injection. Copeptin was measured with a new sandwich immunoassay.

Results: Patients with intact posterior pituitary function had basal copeptin levels of 3.7 ± 1.5 pm, with a maximal increase to 11.1 ± 4.6 pm 45 min after insulin injection. Copeptin levels in patients with diabetes insipidus were 2.4 ± 0.5 pm before insulin injection, with a maximum increase to 3.7 ± 0.7 pm. Both basal and stimulated copeptin levels were lower in patients with diabetes insipidus as compared with patients with intact posterior pituitary function. A stimulated copeptin level 45 min after insulin injection of less than 4.75 pm had an optimal diagnostic accuracy to detect diabetes insipidus.

Conclusion: Copeptin measurement may be used to assess posterior together with anterior pituitary function during insulin-induced hypoglycemia.
Associations of Adiponectin with Body Fat Distribution and Insulin Sensitivity in Nondiabetic Hispanics and African-Americans
Authors: Hanley Anthony J. G. , Bowden Donald , Wagenknecht Lynne E. , Balasubramanyam Aarthi , Langfeld Carl , Saad Mohammed F. , Rotter Jerome I. , Guo Xiuqing , Chen Yii-Der I. , Bryer-Ash Michael , Norris Jill M. , Haffner Steven M.
Published: April 2007

Context: Hypoadiponectinemia has emerged as an independent risk factor for type 2 diabetes and cardiovascular disease. Although associations of adiponectin with central obesity and insulin resistance have been reported, very little data are available from studies using detailed measures of insulin sensitivity (SI) and/or body fat distribution in ethnic groups at high risk for metabolic disease.

Objective: The aim of the study was to identify the correlates of adiponectin in 1636 nondiabetic Hispanics and African-Americans.

Design: A cross-sectional analysis of participants in the Insulin Resistance Atherosclerosis Family Study was conducted. SI was determined from frequently sampled iv glucose tolerance tests with minimal model analysis. Subcutaneous and visceral adipose tissues (SAT, VAT, respectively) were determined with computed tomography. Triglyceride, high-density lipoprotein, C-reactive protein, and adiponectin were measured in fasting samples. Generalized estimating equation (GEE) models were used to identify factors associated with adiponectin concentration.

Setting: A multicenter study using a family-based design was conducted.

Participants: A total of 1636 nondiabetic Hispanic and African-American subjects participated.

Main Outcome Measures: Circulating adiponectin concentration was measured.

Results: Age, female gender, high-density lipoprotein, SAT, and SI were positive independent correlates of adiponectin, whereas glucose, CRP, and VAT were negative independent correlates (all P < 0.05). Ethnicity was not an independent correlate of adiponectin in this model (P = 0.27); however, an ethnicity by VAT interaction term was retained, indicating a stronger negative association of VAT with adiponectin in African-Americans compared with Hispanics.

Conclusion: Directly measured SI, VAT, and SAT were independently correlated with adiponectin in Hispanic and African-American subjects. The inverse association of VAT with adiponectin was stronger in African-Americans compared with Hispanics, a finding that suggests possible ethnic differences in the effects of visceral obesity.
Effects of Combined Recombinant Insulin-Like Growth Factor (IGF)-I and IGF Binding Protein-3 in Type 2 Diabetic Patients on Glycemic Control and Distribution of IGF-I and IGF-II among Serum Binding Protein Complexes
Authors: Clemmons D. R. , Sleevi M. , Allan G. , Sommer A.
Published: April 2007

Context: Administration of recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) to patients with type 2 diabetes improves blood glucose and enhances insulin sensitivity. The changes in various components of the IGF system that occur in response to rhIGF-I/rhIGFBP-3 as well as the minimum effective dose have not been determined.

Objectives: The aim was to determine the dose of rhIGF-I/rh-IGFBP-3 necessary to achieve a significant decrease in glucose and to determine the changes that occur in the IGF-II and acid labile subunit in response to treatment.

Design: A total of 39 insulin-requiring type 2 diabetics were randomized to placebo or one of six groups that received different dosages of rhIGF-I/rhIGFBP-3. After 3 d in which insulin doses were adjusted to improve glucose control, a variable insulin dosage regimen was continued, and either placebo or one of six dosages (0.125–2.0 mg/kg·d) of rhIGF-I/rhIGFBP-3 was administered for 7 d. All subjects were hospitalized, and dietary intake as well as insulin dosage were controlled with instructions to treat to normal range targets.

Results: Fasting glucose was reduced in the groups that received either 1 (32 ± 5% reduction) or 2 mg/kg·d (40 ± 6% reduction) of the complex. Mean daily glucose (four determinations) was reduced by 26 ± 4% in the 1 mg/kg group and by 33 ± 5% in the 2 mg/kg group compared with 18 ± 4% in the placebo group. Total serum IGF-I increased between 2.0 ± 0.3- and 5.7 ± 1.3-fold by d 8. IGFBP-3 concentrations increased significantly only in the 2 mg/kg group. IGF-II concentrations declined to values that were between 27 ± 4% and 64 ± 7% below baseline. Acid labile subunit concentrations declined significantly in the three highest dose groups. The sum of the IGF-I + IGF-II concentrations was significantly increased at the two highest dosages. There were very few drug-associated adverse events reported in this study with the exception of hypoglycemia, which occurred in 15 subjects who had received rhIGF-I/rhIGFBP-3 treatment.

Conclusions: Administration of rhIGF-I/rhIGFBP-3 resulted in a redistribution of the amount of IGF-I and IGF-II that bound to IGFBP-3. Fasting and mean daily blood glucose were reduced significantly in the two highest dosage groups. The results suggest that both the total concentration of IGF-I as well as its distribution in blood may determine the extent to which insulin sensitivity is enhanced.
Effects of Testosterone Therapy on Cardiovascular Risk Markers in Androgen-Deficient Women with Hypopituitarism
Authors: Miller K. K. , Biller B. M. K. , Schaub A. , Pulaski-Liebert K. , Bradwin G. , Rifai N. , Klibanski A.
Published: April 2007

Context: Low-dose testosterone replacement therapy in women with relative androgen deficiency has been shown to have beneficial effects on body composition, bone mass, and psychosexual function. However, the safety of chronic testosterone administration on cardiovascular risk and insulin resistance is unknown.

Objective: The aim of the study was to determine the effects of physiological testosterone replacement on cardiovascular risk markers and insulin resistance in women.

Design: A 12-month, randomized, placebo-controlled study was conducted.

Setting: A General Clinical Research Center was the setting for the study.

Study Participants: A total of 51 women of reproductive age with androgen deficiency due to hypopituitarism participated.

Intervention: Study participants were randomized to physiological testosterone administration, 300 μg daily, or placebo, by patch.

Main Outcome Measures: We measured fasting glucose, fasting insulin, insulin-resistance homeostasis model of assessment (IRHOMA), quantitative insulin sensitivity check index (QUICKI), high-sensitivity C-reactive protein, vascular cell adhesion molecule (VCAM), leptin, lipoprotein (a), apolipoprotein A1, and homocysteine.

Results: At 12 months, fasting insulin and IRHOMA were significantly lower in the testosterone compared with the placebo group, and there was a trend toward a higher QUICKI level at 12 months in the testosterone compared with the placebo group. These differences were no longer significant after controlling for baseline levels. We observed no effect, either positive or negative, of testosterone administration on high-sensitivity C-reactive protein, VCAM leptin, lipoprotein (a), or apolipoprotein A1.

Conclusions: Our data suggest that physiological testosterone replacement in women with hypopituitarism for 12 months does not increase, and may improve, insulin resistance. Chronic low-dose testosterone administration does not increase markers of cardiovascular disease reflecting several different mechanistic pathways. Large, randomized, placebo-controlled, long-term prospective studies are needed to determine whether low-dose testosterone replacement affects cardiovascular risk and event rates in women.
Signal Transducer and Activator of Transcription (Stat) 5b-Mediated Inhibition of Insulin-Like Growth Factor Binding Protein-1 Gene Transcription: A Mechanism for Repression of Gene Expression by Growth Hormone
Authors: Ono Mitsuru , Chia Dennis J. , Merino-Martinez Roxana , Flores-Morales Amilcar , Unterman Terry G. , Rotwein Peter
Published: April 2007

GH plays a central role in controlling somatic growth, tissue regeneration, and intermediary metabolism in most vertebrate species through mechanisms dependent on the regulation of gene expression. Recent studies using transcript profiling have identified large cohorts of genes whose expression is induced by GH. Other results have demonstrated that signal transducer and activator of transcription (Stat) 5b, a latent transcription factor activated by the GH receptor-associated protein kinase, Jak2, is a key agent in the GH-stimulated gene activation that leads to somatic growth. By contrast, little is known about the steps through which GH-initiated signaling pathways reduce gene expression. Here we show that Stat5b plays a critical role in the GH-regulated inhibition of IGF binding protein-1 gene transcription by impairing the actions of the FoxO1 transcription factor on the IGF binding protein-1 promoter. Additional observations using transcript profiling in the liver indicate that Stat5b may be a general mediator of GH-initiated gene repression. Our results provide a model for understanding how GH may simultaneously stimulate and inhibit the expression of different cohorts of genes via the same transcription factor, potentially explaining how GH action leads to integrated biological responses in the whole organism.
Hes1 and Hes5 Control the Progenitor Pool, Intermediate Lobe Specification, and Posterior Lobe Formation in the Pituitary Development
Authors: Kita Aya , Imayoshi Itaru , Hojo Masato , Kitagawa Masashi , Kokubu Hiroshi , Ohsawa Ryosuke , Ohtsuka Toshiyuki , Kageyama Ryoichiro , Hashimoto Nobuo
Published: April 2007

The pituitary gland is composed of two distinct entities: the adenohypophysis, including the anterior and intermediate lobes, and the neurohypophysis, known as the posterior lobe. This critical endocrine organ is essential for homeostasis, metabolism, reproduction, and growth. The pituitary development requires the control of proliferation and differentiation of progenitor cells. Although multiple signaling molecules and transcription factors are required for the proper pituitary development, the mechanisms that regulate the fate of progenitor cells remain to be elucidated. Hes genes, known as Notch effectors, play a crucial role in specifying cellular fates during the development of various tissues and organs. Here, we report that mice deficient for Hes1 and Hes5 display severe pituitary hypoplasia caused by accelerated differentiation of progenitor cells. In addition, this hypoplastic pituitary gland (adenohypophysis) lacks the intermediate lobe and exhibits the features of the anterior lobe only. Hes1 and Hes5 double-mutant mice also lack the neurohypophysis (the posterior lobe), probably due to incomplete evagination of the diencephalon. Thus, Hes genes control not only maintenance of progenitor cells but also intermediate vs. anterior lobe specification during the adenohypophysis development. Hes genes are also essential for the formation of the neurohypophysis.
Terbinafine-Induced Acute Autoimmune Hepatitis in the Setting of Hepatitis B Virus Infection
Authors: Paredes Angelo H , Lewis James H
Published: April 2007

Objective:

To report a case of terbinafine-induced autoimmune hepatitis in a patient with chronic hepatitis B infection.

Case Summary:

A 57-year-old Taiwanese male with chronic hepatitis 8 virus (HBV) began an oral regimen of terbinafine 250 mg once daily for dermatophyte toenail onychomycosis, despite the manufacturer's recommendation not to use the drug in patients with liver dysfunction. The patient's liver enzyme levels were within normal limits at initiation of therapy. Immediately prior to concluding the 12 week treatment course, he became anorexic with malaise and subsequently developed ascites and jaundice. After a visit to an outside emergency department and positively trending liver function test levels, he was referred to our liver clinic. The patient was taking no other medications or herbal supplements, did not drink alcohol, and did not appear to suffer a flare of HBV infection. The diagnosis was supported by the presence of transient autoantibodies and a liver biopsy consistent with acute autoimmune drug injury. Three weeks after terbinafine was discontinued, peak levels of aspartate aminotransferase (1282 IU/L), alanine aminotransferase (1044 IU/L), and bilirubin (5.9 mg/dL) were noted; his platelet level had decreased to 77 × 103/mm3. He was treated with supportive care that included vitamin K for coagulopathy, diuretics for ascites, and adefovir to prevent hepatitis B exacerbation. The patient's liver function studies began to normalize 6 weeks after terbinafine was discontinued.

Discussion:

Terbinafine-induced hepatobiliary dysfunction, due to hepatocellular injury, cholestasis, or mixed form, has been reported, but this is the first case of autoimmune hepatitis supported by serologic, biochemical, and biopsy results. Use of the Naranjo probability scale revealed a probable relationship between the patient's hepatitis and terbinafine. Furthermore, the Roussel Uclaf Causality Assessment Method, a scoring system that specifically assesses the likelihood of drug-induced elevated levels of liver-associated enzymes, also supported a probable relationship. The pathogenesis of most drug-induced autoimmune hepatitis remains speculative, likely involving hapten-carrier complex and the cytochrome P450 isoenzymes. In this patient, his chronic HBV carrier state may have predisposed him to this autoimmune reaction.

Conclusions:

Healthcare practitioners should heed the manufacturer's warning that terbinafine not be used in patients with underlying hepatic disease.
Bazedoxifene: A Third-Generation Selective Estrogen Receptor Modulator for Treatment of Postmenopausal Osteoporosis
Authors: Stump Amy L , Kelley Kristi W , Wensel Terri M
Published: April 2007

Objective:

To review clinical studies and other available literature regarding the development, pharmacology, toxicology, pharmacokinetics/pharmacodynamics, adverse effects, and place in therapy of bazedoxifene, a selective estrogen receptor modulator (SERM), currently in Phase III clinical trials for the treatment and prevention of postmenopausal osteoporosis.

Data Sources:

A literature search was performed of PubMed (1966–February 2007). International Pharmaceutical Abstracts (1970–February 2007), Web of Science (1975–February 2007), Biological Abstracts (1926–2007), and Google Scholar (2001–February 2007) databases, using the search terms bazedoxifene, TSE-424, Indole-33, WAY-140424, selective estrogen receptor modulator, and SERM. In addition, product information was requested from the manufacturer, and www.clinicaltrials.gov was searched for unpublished Phase III clinical trials in progress.

Study Selection and Data Extraction:

Articles on Phase I and II trials were selected for review, as well as articles discussing preclinical development of bazedoxifene. At the time of writing, no articles on Phase III trials were available for review. Abstracts of unpublished data were reviewed, as was information provided by the manufacturer.

Data Synthesis:

Bazedoxifene is a third-generation SERM currently in Phase III clinical trials. It has been found to act as an agonist on skeletal tissue, with bone turnover reduced by 20–25% with doses of 20 or 40 mg daily. In addition, bazedoxifene has been found to be an antagonist on breast tissue and uterine tissue, demonstrating inhibition of breast tissue proliferation and decreased endometrial stimulation as the dose is increased.

Conclusions:

Current literature suggests that bazedoxifene will likely be safe and effective when used in the treatment of postmenopausal osteoporosis. Completion of Phase III clinical trials will more fully elucidate the safety and efficacy profile of bazedoxifene, as well as more clearly define its place in therapy.
Drug-Induced Sweet's Syndrome
Authors: Thompson Dennis F , Montarella Kristin E
Published: April 2007

Objective:

To systematically review the pertinent literature on drug-induced Sweet's syndrome (SS).

Data Sources:

MEDLINE (1966–December 2006), International Pharmaceutical Abstracts (1970–December 2006), Science Citation Index (1945–December 2006), and EMBASE (1980–December 2006) were searched using the key terms Sweet's syndrome, drug-induced, and acute neutrophilic dermatitis.

Study Selection and Data Extraction:

All case reports of drug-induced SS located using the above databases were collected for causality assessment. In addition, relevant articles regarding the various causes and presentations of SS were selected to provide background information. Bibliographies of all relevant articles were reviewed for additional citations.

Data Synthesis:

All case reports of drug-induced SS were evaluated against an expanded Naranjo scale with specific criteria for SS. Tables were developed listing key criteria for evaluating the case reports for causality. Data were evaluated by quantity and quality of evidence, and an assessment was made as to whether there was a feasible pharmacologic mechanism to explain causality.

Conclusions:

Granulocyte colony-stimulating factor (G-CSF), all-trans retinoic acid (ATRA), and vaccines met 2 of 3 criteria for an association with SS. There are sufficient data and a plausible pharmacologic mechanism for G-CSF and ATRA. Vaccines meet the qualitative criteria and also have a plausible pharmacologic mechanism. The evidence regarding minocycline is of high quality; however, the quantity of evidence and a reasonable pharmacologic mechanism are lacking. A host of miscellaneous drugs have also been implicated in causing the disorder, all without sufficient evidence.
Glycopeptide-Induced Neutropenia: Cross-Reactivity Between Vancomycin and Teicoplanin
Authors: Hsiao Shu-Hwa , Chang Chia-Ming , Tsai Jui-Chen , Lin Chia-Yin , Liao Li-Hsiang , Lin Wen-Liang , Wu Ta-Jen
Published: April 2007

Objective:

To report teicoplanin-related neutropenia that developed after an episode of neutropenia induced by vancomycin therapy.

Case Summary:

A 57-year-old female suffered from osteomyelitis of the left humerus, with a white blood cell (WBC) count of 2.8 × 103/mm3 and absolute neutrophil count (ANC) of 0.28 × 103/mm3, occurring after 24 days of vancomycin therapy. Vancomycin was changed to teicoplanin and the agranulocytosis resolved 4 days later. However, a new episode of neutropenia, with a WBC count of 2.8 × 103/mm3 and ANC of 0.448 × 103/mm3, occurred 11 days after teicoplanin initiation. Agranulocytosis resolved 4 days following withdrawal of teicoplanin.

Discussion:

Because of the close time relationship between drug administration and the development of symptoms and signs, as well as between drug withdrawal and changes in WBC count and ANC, the episodes of neutropenia were suspected to be drug related. Teicoplanin-induced agranulocytosis that followed vancomycin-induced agranulocytosis suggests a possible cross-reactivity between the 2 drugs. Both reactions were categorized as probable according to the Naranjo probability scale.

Conclusions:

For all patients with vancomycin-induced neutropenia, possible cross-reactivity of teicoplanin should be monitored.
Temporal Dissociation between Hand Shaping and Grip Force Scaling in the Anterior Intraparietal Area
Authors: Davare Marco , Andres Michael , Clerget Emeline , Thonnard Jean-Louis , Olivier Etienne
Published: April 2007

In humans, both clinical and functional imaging studies have evidenced the critical role played by the posterior parietal cortex, and particularly by the anterior intraparietal area (AIP), in skilled hand movements. However, the exact contribution of AIP to precision grasping remains debated. Here we used transcranial magnetic stimulation (TMS) to induce virtual lesions of the left and/or right AIP in subjects performing a grip-lift task with either hand.

We found that, during movement preparation, a virtual lesion of AIP had distinct consequences on precision grasping of either hand depending on its time of occurrence: TMS applied 270–220 ms before the fingers contacted the manipulandum altered specifically the hand shaping, whereas lesions induced 170–120 ms before contact time only affected the grip force scaling. The lateralization of these two processes in AIP is also strikingly different: whereas a bilateral lesion of AIP was necessary to impair hand shaping, only a unilateral lesion of the left AIP altered the grip force scaling in either hand.

The present study shows that, during movement preparation, AIP is responsible for processing two distinct, temporally dissociated, precision grasping parameters, regardless of the hand in use. This indicates that the contribution of AIP to hand movements is “effector- independent,” a finding that may explain the invariance of grasping movements performed with either hand.
Determining the Neural Substrates of Goal-Directed Learning in the Human Brain
Authors: Valentin Vivian V. , Dickinson Anthony , O'Doherty John P.
Published: April 2007

Instrumental conditioning is considered to involve at least two distinct learning systems: a goal-directed system that learns associations between responses and the incentive value of outcomes, and a habit system that learns associations between stimuli and responses without any link to the outcome that that response engendered. Lesion studies in rodents suggest that these two distinct components of instrumental conditioning may be mediated by anatomically distinct neural systems. The aim of the present study was to determine the neural substrates of the goal-directed component of instrumental learning in humans. Nineteen human subjects were scanned with functional magnetic resonance imaging while they learned to choose instrumental actions that were associated with the subsequent delivery of different food rewards (tomato juice, chocolate milk, and orange juice). After training, one of these foods was devalued by feeding the subject to satiety on that food. The subjects were then scanned again, while being re-exposed to the instrumental choice procedure (in extinction). We hypothesized that regions of the brain involved in goal-directed learning would show changes in their activity as a function of outcome devaluation. Our results indicate that neural activity in one brain region in particular, the orbitofrontal cortex, showed a strong modulation in its activity during selection of a devalued compared with a nondevalued action. These results suggest an important contribution of orbitofrontal cortex in guiding goal-directed instrumental choices in humans.
High-ResolutionIn VivoImaging of the Neurovascular Unit during Spreading Depression
Authors: Chuquet Julien , Hollender Liad , Nimchinsky Esther A.
Published: April 2007

Spreading depression (SD) is a propagating wave of neuronal depolarization and ionic shifts, seen in stroke and migraine.In vitro, SD is associated with astrocytic [Ca2+] waves, but it is unclear what role they play and whether they influence cerebral blood flow, which is altered in SD. Here we show that SDin vivois associated with [Ca2+] waves in astrocytes and neurons and with constriction of intracortical arterioles severe enough to result in arrest of capillary perfusion. The vasoconstriction is correlated with fast astrocytic [Ca2+] waves and is inhibited when they are reduced. [Ca2+] waves appear in neurons before astrocytes, and inhibition of astrocytic [Ca2+] waves does not depress SD propagation. This suggests that astrocytes do not drive SD propagation but are responsible for the hemodynamic failure seen deep in the cortex. Similar waves occur in anoxic depolarizations (AD), supporting the notion that SD and AD are related processes.
Actin Filaments Mediate Mechanical Gating during Osmosensory Transduction in Rat Supraoptic Nucleus Neurons
Authors: Zhang Zizhen , Kindrat Alexandra N. , Sharif-Naeini Reza , Bourque Charles W.
Published: April 2007

Osmosensory transduction is a bidirectional process displayed by neurons involved in the control of thirst and antidiuretic hormone release, and is therefore crucial for body fluid homeostasis. Although this mechanism is known to involve the activation of nonselective cation channels during hypertonicity-evoked shrinking, and the inhibition of these channels during hypotonicity-evoked swelling, the basis for this regulation is unknown. Here, we investigated this process using whole-cell patch-clamp recordings from neurons acutely isolated from the supraoptic nucleus of adult rats. The mechanosensitivity index, defined as the ratio of conductance change to normalized volume change, was quantitatively equivalent whether cell volume was increased or decreased by changes in extracellular fluid osmolality, or by changes in pipette pressure. Moreover, responses induced by hyperosmotic or hypo-osmotic media could be reversed by increasing or decreasing pipette pressure, respectively. The mechanosensitivity index was significantly reduced in neurons treated with cytochalasin-D, a compound that promotes the depolymerization of actin filaments. Conversely, cells treated with jasplakinolide, a compound that promotes actin polymerization, showed a significant increase in mechanosensitivity index. Finally, the depolarizing and excitatory effects of hypertonic stimuli were significantly enhanced by jasplakinolide and reduced by cytochalasin-D. We conclude that osmosensory transduction in these neurons is a reversible mechanical process that depends on an intact actin cytoskeleton, and the sensitivity of the transducer appears to vary in proportion with the density of actin filaments.
Wnt Signaling Promotes Regeneration in the Retina of Adult Mammals
Authors: Osakada Fumitaka , Ooto Sotaro , Akagi Tadamichi , Mandai Michiko , Akaike Akinori , Takahashi Masayo
Published: April 2007

Regeneration in the mammalian CNS is severely limited. Unlike in the chick, current models hold that retinal neurons are never regenerated. Previously we demonstrated that, in the adult mammalian retina, Müller glia dedifferentiate and produce retinal cells, including photoreceptors, after acute neurotoxic injuryin vivo. However, the number of newly generated retinal neurons is very limited. Here we demonstrate that Wnt (wingless-type MMTV integration site family)/β-catenin signaling promotes proliferation of Müller glia-derived retinal progenitors and neural regeneration after damage or during degeneration. Wnt3a treatment increases proliferation of dedifferentiated Müller glia >20-fold in the photoreceptor-damaged retina. Supplementation with retinoic acid or valproic acid induces differentiation of these cells primarily into Crx (cone rod homeobox)-positive and rhodopsin-positive photoreceptors. Notably, injury induces nuclear accumulation of β-catenin, cyclin D1 upregulation, and Wnt/β-catenin reporter activity. Activation of Wnt signaling by glycogen synthase kinase-3β inhibitors promotes retinal regeneration, and, conversely, inhibition of the signaling attenuates regeneration. This Wnt3a-mediated regeneration of retinal cells also occurs inrdmice, a model of retinal degeneration. These results provide evidence that Wnt/β-catenin signaling contributes to CNS regeneration in the adult mammal.
Anti-GM1 Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers
Authors: Susuki Keiichiro , Rasband Matthew N. , Tohyama Koujiro , Koibuchi Katsura , Okamoto Saori , Funakoshi Kei , Hirata Koichi , Baba Hiroko , Yuki Nobuhiro
Published: April 2007

Voltage-gated Na+(Nav) channels are highly concentrated at nodes of Ranvier in myelinated axons and facilitate rapid action potential conduction. Autoantibodies to gangliosides such as GM1 have been proposed to disrupt nodal Nav channels and lead to Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To test this hypothesis, we examined the molecular organization of nodes in a disease model caused by immunization with gangliosides. At the acute phase with progressing limb weakness, Navchannel clusters were disrupted or disappeared at abnormally lengthened nodes concomitant with deposition of IgG and complement products. Paranodal axoglial junctions, the nodal cytoskeleton, and Schwann cell microvilli, all of which stabilize Navchannel clusters, were also disrupted. The nodal molecules disappeared in lesions with complement deposition but no localization of macrophages. During recovery, complement deposition at nodes decreased, and Navchannels redistributed on both sides of affected nodes. These results suggest that Navchannel alterations occur as a consequence of complement-mediated disruption of interactions between axons and Schwann cells. Our findings support the idea that acute motor axonal neuropathy is a disease that specifically disrupts the nodes of Ranvier.
β-Catenin Regulates Acetylcholine Receptor Clustering in Muscle Cells through Interaction with Rapsyn
Authors: Zhang Bin , Luo Shiwen , Dong Xian-Ping , Zhang Xian , Liu Chunming , Luo Zhenge , Xiong Wen-Cheng , Mei Lin
Published: April 2007

Agrin is believed to be a factor used by motoneurons to direct acetylcholine receptor (AChR) clustering at the neuromuscular junction. However, exactly how agrin mediates this effect remains unclear. Here we demonstrate that the β-catenin interacts with rapsyn, a molecule key for AChR clustering. Agrin stimulation increases the association of β-catenin with surface AChRs. Suppression of β-catenin expression inhibited agrin-induced AChR clustering, suggesting a necessary role of β-catenin in this event. The β-catenin action did not appear to require the function of T-cell factors (TCFs), suggesting a mechanism independent of TCF-mediated transcription. In contrast, prevention of β-catenin from interacting with α-catenin attenuated agrin-induced AChR clustering. These results suggest that β-catenin may serve as a link between AChRs and α-catenin-associated cytoskeleton, revealing a novel function of β-catenin in synaptogenesis.
2-Aminoethoxydiphenylborane Is an Acute Inhibitor of Directly Photosensitive Retinal Ganglion Cell ActivityIn VitroandIn Vivo
Authors: Sekaran Sumathi , Lall Gurprit S. , Ralphs Katherine L. , Wolstenholme Adrian J. , Lucas Robert J. , Foster Russell G. , Hankins Mark W.
Published: April 2007

The mammalian retina contains directly photosensitive retinal ganglion cells (RGCs), which use the photopigment melanopsin. The generation of mice lacking melanopsin has been invaluable in elucidating the function of these cells. These animals display deficiencies in circadian photoentrainment, the pupil light reflex, and the circadian regulation of the cone pathway. Interpreting the results from such gene knock-out models is always complicated by neuronal plasticity and the potential for restructuring of neuronal networks. Until now, the study of photosensitive RGCs has lacked an acute inhibitor. 2-Aminoethoxydiphenylborane (2-APB) is an antagonist at IP3receptors and an inhibitor of canonical transient receptor potential ion channels (TRPCs). Here, we show that 2-APB is an extremely potentin vitroinhibitor of the photosensitive RGCs and that its effect is independent of store-dependent Ca2+release. The identification of canonical TRPC6 and TRPC7 ion channels in melanopsin-expressing ganglion cells suggests that 2-APB may act directly on a TRPC ion channel. Importantly, using the pupil light reflex as a functional assay, we show that 2-APB inhibits photosensitive RGC activityin vivo. Collectively, our data further elucidate the phototransduction pathway in the photosensitive RGCs and demonstrate that 2-APB can be used to silence activity in these cells bothin vitroandin vivo.
PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome
Authors: Hanson Jesse E. , Madison Daniel V.
Published: April 2007

Almost all female and some male fragile X syndrome (FXS) patients are mosaic for expression of theFMR1gene, yet all research in models of FXS has been in animals uniformly lackingFmr1expression. Therefore, we developed a system allowing neuronal genotype to be visualizedin vitroin mouse brain slices mosaic forFmr1expression. Whole-cell recordings from individual pairs of presynaptic and postsynaptic neurons in organotypic hippocampal slices were used to probe the cell-autonomous effects ofFmr1genotype in mosaic networks. These recordings revealed that wild-type presynaptic neurons formed synaptic connections at a greater rate than presynaptic neurons lacking normalFmr1function in mosaic networks. At the same time, the postsynapticFmr1genotype did not influence the probability that a neuron received synaptic connections. Asymmetric presynaptic function during development of the brain could result in a decreased participation in network function by the portion of neurons lackingFMR1expression.
Early Cross-Modal Interactions in Auditory and Visual Cortex Underlie a Sound-Induced Visual Illusion
Authors: Mishra Jyoti , Martinez Antigona , Sejnowski Terrence J. , Hillyard Steven A.
Published: April 2007

When a single flash of light is presented interposed between two brief auditory stimuli separated by 60–100 ms, subjects typically report perceiving two flashes (Shams et al., 2000, 2002). We investigated the timing and localization of the cortical processes that underlie this illusory flash effect in 34 subjects by means of 64-channel recordings of event-related potentials (ERPs). A difference ERP calculated to isolate neural activity associated with the illusory second flash revealed an early modulation of visual cortex activity at 30–60 ms after the second sound, which was larger in amplitude in subjects who saw the illusory flash more frequently. These subjects also showed this early modulation in response to other combinations of auditory and visual stimuli, thus pointing to consistent individual differences in the neural connectivity that underlies cross-modal integration. The overall pattern of cortical activity associated with the cross-modally induced illusory flash, however, differed markedly from that evoked by a real second flash. A trial-by-trial analysis showed that short-latency ERP activity localized to auditory cortex and polymodal cortex of the temporal lobe, concurrent with gamma bursts in visual cortex, were associated with perception of the double-flash illusion. These results provide evidence that perception of the illusory second flash is based on a very rapid dynamic interplay between auditory and visual cortical areas that is triggered by the second sound.
Short-Term Plasticity of Kainate Receptor-Mediated EPSCs Induced by NMDA Receptors at Hippocampal Mossy Fiber Synapses
Authors: Rebola Nelson , Sachidhanandam Shankar , Perrais David , Cunha Rodrigo A. , Mulle Christophe
Published: April 2007

Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors that play a variety of functions in the regulation of the activity of synaptic networks. Little is known about the regulation of the function of synaptic KARs in the brain. In the present study, we found that a conditioning activation of synaptic NMDA receptors (NMDARs) induces short-term depression of KAR–EPSCs but not of AMPA receptor–EPSCs at synapses between mossy fibers and CA3 pyramidal cells. Short-term depression of KAR–EPSCs by synaptic NMDARs peaked at 1 s and reversed within 20 s, was likely induced and expressed postsynaptically, and was homosynaptic. It depended on a rise of Ca2+in the postsynaptic cell and on the activation of the phosphatase calcineurin that likely binds to the GluR6b (glutamate receptor subunit 6b) subunit splice variant allowing the dephosphorylation of KARs and inhibition of activity. Finally, we show in the current-clamp mode that short-term depression of KAR–EPSPs is induced by the coincident discharge of action potentials in the postsynaptic cell together with synaptic stimulation. Hence, this study describes a form of short-term synaptic plasticity that is postsynaptic, depends on the temporal order of presynaptic and postsynaptic spiking, and likely affects the summation properties of mossy fiber EPSPs.
Distribution of Interaural Time Difference in the Barn Owl's Inferior Colliculus in the Low- and High-Frequency Ranges
Authors: Wagner Hermann , Asadollahi Ali , Bremen Peter , Endler Frank , Vonderschen Katrin , von Campenhausen Mark
Published: April 2007

Interaural time differences are an important cue for azimuthal sound localization. It is still unclear whether the same neuronal mechanisms underlie the representation in the brain of interaural time difference in different vertebrates and whether these mechanisms are driven by common constraints, such as optimal coding. Current sound localization models may be discriminated by studying the spectral distribution of response peaks in tuning curves that measure the sensitivity to interaural time difference. The sound localization system of the barn owl has been studied intensively, but data that would allow discrimination between currently discussed models are missing from this animal. We have therefore obtained extracellular recordings from the time-sensitive subnuclei of the barn owl's inferior colliculus. Response peaks were broadly scattered over the physiological range of interaural time differences. A change in the representation of the interaural phase differences with frequency was not observed. In some neurons, response peaks fell outside the physiological range of interaural time differences. For a considerable number of neurons, the peak closest to zero interaural time difference was not the behaviorally relevant peak. The data are in best accordance with models suggesting that a place code underlies the representation of interaural time difference. The data from the high-frequency range, but not from the low-frequency range, are consistent with predictions of optimal coding. We speculate that the deviation of the representation of interaural time difference from optimal-coding models in the low-frequency range is attributable to the diminished importance of low frequencies for catching prey in this species.
Amygdala Neurons Differentially Encode Motivation and Reinforcement
Authors: Tye Kay M. , Janak Patricia H.
Published: April 2007

Lesion studies demonstrate that the basolateral amygdala complex (BLA) is important for assigning motivational significance to sensory stimuli, but little is known about how this information is encoded. We usedin vivoelectrophysiology procedures to investigate how the amygdala encodes motivating and reinforcing properties of cues that induce reinstatement of reward-seeking behavior. Two groups of rats were trained to respond to a sucrose reward. The “paired” group was trained with a reward-predictive cue, whereas the “unpaired” group was trained with a randomly presented cue. Both groups underwent identical extinction and reinstatement procedures during which the reward was withheld. The proportion of neurons that were phasically cue responsive during reinstatement was significantly higher in the paired group (46 of 100) than in the unpaired group (8 of 112). Cues that induce reward-seeking behavior can do so by acting as incentives or reinforcers. Distinct populations of neurons responded to the cue in trials in which the cue acted as an incentive, triggering a motivated reward-seeking state, or as a reinforcer, supporting continued instrumental responding. The incentive motivation-encoding population of neurons (34 of 46 cue-responsive neurons; 74%) extinguished in temporal agreement with a decrease in the rate of instrumental responding. The conditioned reinforcement-encoding population of neurons (12 of 46 cue-responsive neurons; 26%) maintained their response for the duration of cue-reinforced instrumental responding. These data demonstrate that separate populations of cue-responsive neurons in the BLA encode the motivating or reinforcing properties of a cue previously associated with a reward.
M1and M3Muscarinic Receptors Control Physiological Processing of Cellular Prion by Modulating ADAM17 Phosphorylation and Activity
Authors: Alfa Cissé Moustapha , Sunyach Claire , Slack Barbara E. , Fisher Abraham , Vincent Bruno , Checler Frédéric
Published: April 2007

The cellular prion protein (PrPc) undergoes a physiological processing yielding the N-terminal fragment referred to as N1, the production of which can be constitutive or protein kinase C regulated. We show that activation of endogenous muscarinic receptors by carbachol and by the M1-selective agonist AF267B increases N1 recovery in an atropine-sensitive manner, in mouse embryonic primary neurons. To identify the muscarinic receptor subtype involved, we used human embryonic kidney HEK293 (HEK) cells stably overexpressing M1, M2, M3, or M4receptor subtype. Carbachol and the selective M1agonist AF267B dose dependently increased N1 release by HEK-M3and HEK-M1cells, respectively, whereas carbachol did not modify N1 production by HEK-M2or HEK-M4cells. We demonstrate that the increase of N1 was not attributable to modified trafficking to the membrane of either PrPcor the disintegrin metalloproteases ADAM10 or ADAM17. Furthermore, we establish that carbachol affects the overall phosphorylation of ADAM17 on its threonine and tyrosine but not serine residues, whereas levels of phosphorylated ADAM9 were not affected. Interestingly, carbachol also increases the hydrolysis of the fluorimetric substrate JMV2770, which mimicked the sequence encompassing the N1 site cleavage and was shown previously to behave as an ADAM protease substrate. Mutations of threonine 735 but not of tyrosine 702 of the ADAM17 cytoplasmic tail abolishes the carbachol-induced increase of N1, ADAM17 phosphorylation, and JMV2770-hydrolyzing activity in M1- and M3-expressing HEK293 cells. Thus, our data provide strong evidence that muscarinic receptor activation increases the physiological processing of PrPcby upregulating the phosphorylation state and activity of ADAM17 protease.
Visual Phosphene Perception Modulated by Subthreshold Crossmodal Sensory Stimulation
Authors: Ramos-Estebanez Ciro , Merabet Lotfi B. , Machii Katsuyuki , Fregni Felipe , Thut Gregor , Wagner Timothy A. , Romei Vicenzo , Amedi Amir , Pascual-Leone Alvaro
Published: April 2007

Crossmodal sensory interactions serve to integrate behaviorally relevant sensory stimuli. In this study, we investigated the effect of modulating crossmodal interactions between visual and somatosensory stimuli that in isolation do not reach perceptual awareness. When a subthreshold somatosensory stimulus was delivered within close spatiotemporal congruency to the expected site of perception of a phosphene, a subthreshold transcranial magnetic stimulation pulse delivered to the occipital cortex evoked a visual percept. The results suggest that under subthreshold conditions of visual and somatosensory stimulation, crossmodal interactions presented in a spatially and temporally specific manner can sum up to become behaviorally significant. These interactions may reflect an underlying anatomical connectivity and become further enhanced by attention modulation mechanisms.
White Matter Axon Vulnerability to AMPA/Kainate Receptor-Mediated Ischemic Injury Is Developmentally Regulated
Authors: McCarran William J. , Goldberg Mark P.
Published: April 2007

Periventricular white matter injury (PWMI) is the leading cause of neurodevelopmental morbidity in survivors of premature birth. Cerebral ischemia is considered a major etiologic factor in the generation of PWMI. In adult white matter (WM), ischemic axonal damage is mediated by AMPA/kainate receptors. Mechanisms of ischemic axonal injury during development are not well defined. We used a murine brain slice model to characterize mechanisms of ischemic axonal injury in developing WM. Acute coronal brain slices were prepared fromthy1–yellow fluorescent protein (YFP) mice at postnatal day 3 (P3), P7, P10, and P21. Ischemia was simulated by oxygen-glucose deprivation (OGD). YFP-positive axon morphology in the corpus callosum was preserved for at least 15 h under normoxic conditions. OGD resulted in delayed degeneration of YFP-positive axons, characterized by axonal beading, fragmentation, and loss of YFP. AMPA and cyclothiazide damaged WM axons at P7, P10, and P21 but not at P3. The AMPA/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) decreased OGD-induced axonal degeneration and oligodendrocyte loss at P10 and P21. At P3 and P7, NBQX protected oligodendrocytes but did not prevent axonal degeneration after OGD. The NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] provided no protection at any age. These results indicate that developing WM axons are susceptible to ischemic injury. However, mechanisms of axonal degeneration are developmentally regulated. At P3 and P7, corresponding developmentally to the window of peak vulnerability to PWMI in humans, ischemic axonal injury is not mediated by AMPA/kainate receptors. Strategies to protect WM during this period may be substantially different from those used at later developmental stages.