bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol
Authors: Yamamoto Noboru , Tamura Tomohide , Murakami Haruyasu , Shimoyama Tatsu , Nokihara Hiroshi , Ueda Yutaka , Sekine Ikuo , Kunitoh Hideo , Ohe Yuichiro , Kodama Tetsuro , Shimizu Mikiko , Nishio Kazuto , Ishizuka Naoki , Saijo Nagahiro
Published: January 2005

Purpose

Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-β-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) –based dosing.

Patients and Methods

Fifty-nine patients with advanced non–small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m2 of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 × 10−4 × total 6-β-OHF] − [4.02 × alpha-1 acid glycoprotein] − [0.172 × AST] − [0.125 × age]) and the target AUC of 2.66 mg/L · h.

Results

In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m2 (mean, 58.1 mg/m2). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L · h) and 0.40 mg/L · h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L · h) and 0.22 mg/L · h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm.

Conclusion

The individualized dosing method based on the total amount of urinary 6-β-OHF after cortisol administration can decrease PK variability of docetaxel.
Long-Term Survival After Cisplatin-Based Induction Chemotherapy and Radiotherapy for Nasopharyngeal Carcinoma: A Pooled Data Analysis of Two Phase III Trials
Authors: Chua Daniel T.T. , Ma Jun , Sham Jonathan S.T. , Mai Hai-Qiang , Choy Damon T.K. , Hong Ming-Huang , Lu Tai-Xiang , Min Hua-Qing
Published: January 2005

Purpose

To evaluate the long-term outcome in patients with nasopharyngeal carcinoma (NPC) treated with induction chemotherapy and radiotherapy (CRT) versus radiotherapy alone (RT).

Patients and Methods

The data from two phase III studies comparing CRT with RT in NPC were updated and pooled together for analysis. A total of 784 patients were included for analysis, with an equal number of patients in both arms. Induction chemotherapy consisted of two to three cycles of cisplatin, bleomycin, and fluorouracil, or cisplatin and epirubicin. RT was given to the nasopharynx and neck using megavoltage radiation (median dose, 70 Gy). The median follow-up time for surviving patients was 67 months. Analysis was based on intention to treat.

Results

The addition of induction chemotherapy to RT was associated with a decrease in relapse by 14.3% and cancer-related deaths by 12.9% at 5 years. The 5-year relapse-free survival rate was 50.9% and 42.7% in the CRT and RT arm, respectively (P = .014), and the 5-year disease-specific survival rate was 63.5% and 58.1% in the CRT and RT arm, respectively (P = .029). The 5-year overall survival rate was 61.9% and 58.1% in CRT and RT arm, respectively (P = .092). The incidence of locoregional failure and distant metastases was reduced by 18.3% and 13.3% at 5 years, respectively, with induction chemotherapy. There was no significant difference in the treatment failure patterns between the two arms.

Conclusion

The addition of cisplatin-based induction chemotherapy to RT was associated with a modest but significant decrease in relapse and improvement in disease-specific survival in advanced-stage NPC. However, there was no improvement in overall survival.
Phase II Trial of Individualized Rituximab Dosing for Patients With CD20-Positive Lymphoproliferative Disorders
Authors: Gordan Lucio N. , Grow William B. , Pusateri Annette , Douglas Vonda , Mendenhall Nancy P. , Lynch James W.
Published: January 2005

Purpose

To determine the feasibility and efficacy of pharmacokinetic (PK) -based maintenance dosing of rituximab and possibly design a more rational maintenance schedule.

Patients and Methods

Patients with CD20-positive lymphoproliferative disorders were treated with four weekly infusions of rituximab 375 mg/m2. All patients without progressive disease were then monitored for 1 year and received a single infusion of 375 mg/m2 when the level decreased below 25 μg/mL.

Results

Twenty-nine of 31 patients were assessable with a variety of histologic subtypes. The overall response rate (ORR) for the entire group was 59% with 27% complete responses (CRs) and 32% partial responses. The median PFS for all patients was 19 months, with a median follow-up of 25 months. In 22 patients with low-grade non-Hodgkin's lymphoma (LGNHL), the ORR was 63% with 36% CR and median progression-free survival (PFS) has not been reached. Of 29 assessable patients, 22 were available for PK-based maintenance. The median time to repeat bolus was 5 months (range, 1 to 9 months) for the first, 3.5 months (range, 2 to 5 months) for the second, and 3 months (range, 2 to 4 months) for the third infusion. Ninety-five percent of patients required three or fewer infusions to be maintained in the therapeutic range.

Conclusion

Individualized PK dosing for rituximab produced efficacy comparable to other published maintenance strategies. PK data from this trial suggest that a rational maintenance strategy in patients with LGNHL would be a single dose of 375 mg/m2 of rituximab every 3 to 4 months.
Maximizing Therapeutic Benefit of Rituximab: Maintenance Therapy Versus Re-Treatment at Progression in Patients With Indolent Non-Hodgkin's Lymphoma—A Randomized Phase II Trial of the Minnie Pearl Cancer Research Network
Authors: Hainsworth John D. , Litchy Sharlene , Shaffer Don W. , Lackey Van L. , Grimaldi Manuel , Greco F. Anthony
Published: January 2005

Purpose

To compare the benefit of maintenance rituximab therapy versus rituximab re-treatment at progression in patients with previously treated indolent non-Hodgkin's lymphoma.

Patients and Methods

Between June 1998 and August 2002, 114 patients who had received previous chemotherapy for indolent non-Hodgkin's lymphoma were treated with a standard 4-week course of rituximab. Patients with objective response or stable disease were randomly assigned to receive either maintenance rituximab therapy (standard 4-week courses administered at 6-month intervals) or rituximab re-treatment at the time of lymphoma progression. The duration of rituximab benefit was measured from the date of first rituximab treatment until the date other treatment was required.

Results

Ninety (79%) of 114 patients had objective response or stable disease after initial rituximab treatment, and were randomly assigned to treatment. Progression-free survival was prolonged in the maintenance group (31.3 v 7.4 months; P = .007). Final overall and complete response rates were higher in the maintenance group. Duration of rituximab benefit was similar in the maintenance and re-treatment groups (31.3 v 27.4 months, respectively). More maintenance patients remain in continuous remission, and more are currently in complete remission. Both treatment approaches were well tolerated.

Conclusion

In patients who have objective response or stable disease with single-agent rituximab therapy, duration of rituximab benefit is substantially prolonged with either scheduled maintenance treatment or rituximab re-treatment at the time of progression. At present, the magnitude of benefit with either approach appears similar. However, additional follow-up of this trial is required, and completion of phase III randomized trials is necessary to definitively answer this question.
Dynamics and interaction of caveolin-1 isoforms with BMP-receptors
Authors: Nohe Anja , Keating Eleonora , Underhill T. Michael , Knaus Petra , Petersen Nils O.
Published: January 2005

Caveolae are small invaginations of the cell membrane that are thought to play a role in important physiological functions such as cell surface signaling, endocytosis and intracellular cholesterol transport. Caveolin-1 is a key protein in these domains and contributes to the organization of cholesterol and saturated lipids within these vesicular invaginations of the plasma membrane. Caveolae are thought to be involved in the signaling of tyrosine kinase receptors and serine threonine receptors. In this article we focus on the involvement of caveolae in the signal transduction of bone morphogenetic proteins (BMPs). BMPs play important roles during embryonic development and especially in chondrogenesis, osteogenesis, neurogenesis and hematopoiesis. The initiation of the signal tranduction starts by the binding of a BMP to a corresponding set of BMP receptors.

Using image cross-correlation spectroscopy, we show that the BMP receptors BRIa and BRII colocalize with caveolin-1 isoforms α and β on the cell surface. BRIa colocalizes predominantly with the caveolin-1 α isoform. Coexpression of BRII leads to a redistribution of BRIa into domains enriched in caveolin-1 β. After stimulation with BMP-2, BRIa moves back into the region with caveolin-1 α. BRII is expressed in regions enriched in caveolin-1 α and β. Stimulation of cells with BMP-2 leads to a redistribution of BRII into domains enriched in caveolin-1 α. Immunoprecipitation studies using transfected COS-7 cells indicate that BRII binds to caveolin-1 α and β. The binding of BRII to caveolin-1 was verified using A431 cells. Stimulation of starved A431 cells with BMP-2 lead to a release of caveolin-1 from the BMP receptors. We show further that the caveolin-1 β isoform inhibits BMP signaling whereas the α isoform does not.
Phototactic activity inChlamydomonas'non-phototactic' mutants deficient in Ca2+-dependent control of flagellar dominance or in inner-arm dynein
Authors: Okita Noriko , Isogai Nahoko , Hirono Masafumi , Kamiya Ritsu , Yoshimura Kenjiro
Published: January 2005

In the mechanism underlying the phototactic behavior of Chlamydomonas, Ca2+ has been thought to control the dominance between the two flagella so as to steer the cell to correct directions. A newly isolated mutant, lsp1, that displays weak phototaxis was found to be defective in this Ca2+-dependent shift in flagellar dominance; in demembranated and reactivated cell models, the trans flagellum (the flagellum farthest from the eyespot) beat more strongly than the other (the cis flagellum) in about half of the cells regardless of the Ca2+ concentration between <10-9 M and 10-6 M, a range over which wild-type cell models display switching of flagellar dominance. This is unexpected because ptx1, another mutant that is also deficient in flagellar dominance control, has been reported to lack phototactic ability. We therefore re-examined ptx1 and another reportedly non-phototactic mutant, ida1, which lacks inner arm dynein subspecies f (also called I1). Both were found to retain reduced phototactic abilities. These results indicate that both Ca2+-dependent flagellar dominance control and inner-arm dynein subspecies f are important for phototaxis, but are not absolutely necessary. Analysis of the flagellar beat frequency in lsp1 cell models showed that both of the flagella beat at the frequency of the cis flagellum in wild type. In addition, lsp1 and ptx1 were found to be deficient in determining the sign of phototactic migration. Hence, the Ca2+-dependent flagellar dominance control detected in demembranated cells might be involved in the determination of the sign of phototaxis. The gene responsible for the lsp1 mutation was identified by phenotype rescue experiments and found to have sequences for phosphorylation.
Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation
Authors: Parrinello Simona , Coppe Jean-Philippe , Krtolica Ana , Campisi Judith
Published: January 2005

Cellular senescence suppresses cancer by arresting cells at risk of malignant tumorigenesis. However, senescent cells also secrete molecules that can stimulate premalignant cells to proliferate and form tumors, suggesting the senescence response is antagonistically pleiotropic. We show that premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice irreversibly lose differentiated properties, become invasive and undergo full malignant transformation. Moreover, using cultured mouse or human fibroblasts and non-malignant breast epithelial cells, we show that senescent fibroblasts disrupt epithelial alveolar morphogenesis, functional differentiation and branching morphogenesis. Furthermore, we identify MMP-3 as the major factor responsible for the effects of senescent fibroblasts on branching morphogenesis. Our findings support the idea that senescent cells contribute to age-related pathology, including cancer, and describe a new property of senescent fibroblasts - the ability to alter epithelial differentiation - that might also explain the loss of tissue function and organization that is a hallmark of aging.
Mechanism of early biphasic activation of poly(ADP-ribose) polymerase-1 in response to ultraviolet B radiation
Authors: Vodenicharov Momchil D. , Ghodgaonkar Medini M. , Halappanavar Sabina S. , Shah Rashmi G. , Shah Girish M.
Published: January 2005

The damage to DNA caused by ultraviolet B radiation (280-320 nm) contributes significantly to development of sunlight-induced skin cancers. The susceptibility of mice to ultraviolet B-induced skin carcinogenesis is increased by an inhibitor of the DNA damage-activated nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP), hence PARP activation is likely to be associated with cellular responses that suppress carcinogenesis. To understand the role of activated PARP in these cellular functions, we need to first clearly identify the cause of PARP activation in ultraviolet B-irradiated cells. Ultraviolet B, like ultraviolet C, causes direct DNA damage of cyclobutane pyrimidine dimer and 6, 4-photoproduct types, which are subjected to the nucleotide excision repair. Moreover, ultraviolet B also causes oxidative DNA damage, which is subjected to base excision repair. To identify which of these two types of DNA damage activates PARP, we examined mechanism of early PARP activation in mouse fibroblasts exposed to ultraviolet B and C radiations. The ultraviolet B-irradiated cells rapidly activated PARP in two distinct phases, initially within the first 5 minutes and later between 60-120 minutes, whereas ultraviolet C-irradiated cells showed only the immediate PARP activation. Using antioxidants, local irradiation, chromatin immunoprecipitation and in vitro PARP assays, we identified that ultraviolet radiation-induced direct DNA damage, such as thymine dimers, cause the initial PARP activation, whereas ultraviolet B-induced oxidative damage cause the second PARP activation. Our results suggest that cells can selectively activate PARP for participation in different cellular responses associated with different DNA lesions.
Direct transport across the plasma membrane of mammalian cells ofLeishmaniaHASPB as revealed by a CHO export mutant
Authors: Stegmayer Carolin , Kehlenbach Angelika , Tournaviti Stella , Wegehingel Sabine , Zehe Christoph , Denny Paul , Smith Deborah F. , Schwappach Blanche , Nickel Walter
Published: January 2005

Leishmania HASPB is a lipoprotein that is exported to the extracellular space from both Leishmania parasites and mammalian cells via an unconventional secretory pathway. Exported HASPB remains anchored in the outer leaflet of the plasma membrane mediated by myristate and palmitate residues covalently attached to the N-terminal SH4 domain of HASPB. HASPB targeting to the plasma membrane depends on SH4 acylation that occurs at intracellular membranes. How acylated HASPB is targeted to the plasma membrane and, in particular, the subcellular site of HASPB membrane translocation is unknown. In order to address this issue, we screened for clonal CHO mutants that are incapable of exporting HASPB. A detailed characterization of such a CHO mutant cell line revealed that the expression level of the HASPB reporter molecule is unchanged compared to CHO wild-type cells; that it is both myristoylated and palmitoylated; and that it is mainly localized to the plasma membrane as judged by confocal microscopy and subcellular fractionation. However, based on a quantitative flow cytometry assay and a biochemical biotinylation assay of surface proteins, HASPB transport to the outer leaflet of the plasma membrane is largely reduced in this mutant. From these data, we conclude that the subcellular site of HASPB membrane translocation is the plasma membrane as the reporter molecule accumulates in this location when export is blocked. Thus, these results allow us to define a two-step process of HASPB cell surface biogenesis in which SH4 acylation of HASPB firstly mediates intracellular targeting to the plasma membrane. In a second step, the plasma membrane-resident machinery, which is apparently disrupted in the CHO mutant cell line, mediates membrane translocation of HASPB. Intriguingly, the angiogenic growth factor FGF-2, another protein secreted by unconventional means, is shown to be secreted normally from the HASPB export mutant cell line. These observations demonstrate that the export machinery component defective in the export mutant cell line functions specifically in the HASPB export pathway.
Expression of junctional adhesion molecule-A prevents spontaneous and random motility
Authors: Bazzoni Gianfranco , Tonetti Paolo , Manzi Luca , Cera Maria R. , Balconi Giovanna , Dejana Elisabetta
Published: January 2005

Junctional adhesion molecule-A (JAM-A) is a cell-surface glycoprotein that localizes to intercellular junctions and associates with intracellular proteins via PSD95-Dlg-ZO1-binding residues. To define the functional consequences of JAM-A expression, we have produced endothelial cells from JAM-A-deficient mice. We report here that the absence of JAM-A enhanced spontaneous and random motility. In turn, the enhanced motility of JAM-A-negative cells was abrogated either on transfection of exogenous JAM-A or on treatment with inhibitors of glycogen synthase kinase-3β (GSK-3β). In addition, in JAM-A-positive cells, motility was enhanced on inactivation of protein kinase Cζ (PKCζ), which is an inhibitor of GSK-3β. Although these findings suggested that JAM-A might inhibit GSK-3β, we found that expression per se of JAM-A did not change the levels of inactive GSK-3β. Thus, JAM-A expression may regulate effectors of motility that are also downstream of the PKCζ/GSK-3β axis. In support of this view, we found that JAM-A absence increased the number of actin-containing protrusions, reduced the stability of microtubules and impaired the formation of focal adhesions. Notably, all the functional consequences of JAM-A absence were reversed either on treatment with GSK-3β inhibitors or on transfection of full-length JAM-A, but not on transfection of a JAM-A deletion mutant devoid of the PSD95-Dlg-ZO1-binding residues. Thus, by regulating cytoskeletal and adhesive structures, JAM-A expression prevents cell motility, probably in a PSD95-Dlg-ZO1-dependent manner.
Linkage between proton binding and folding in RNA: A thermodynamic framework and its experimental application for investigating pKa shifting
Authors: MOODY ELLEN M. , LECOMTE JULIETTE T. J. , BEVILACQUA PHILIP C.
Published: January 2005

Perturbation of pKa values can change the favored protonation states of the nucleobases at biological pH and thereby modulate the function of RNA and DNA molecules. In an effort to understand the driving forces for pKa shifting specific to nucleic acids, we developed a thermodynamic framework that relates proton binding to the nucleobases and the helix–coil transition. Key features that emerge from the treatment are a comprehensive description of all the actions of proton binding on RNA folding: acid and alkaline denaturation of the helix and pKa shifting in the folded state. Practical experimental approaches for measuring pKas from thermal denaturation experiments are developed. Microscopic pka values (where ka is the acid dissociation constant) for the unfolded state were determined directly by experiments on unstructured oligonucleotides, which led to a macroscopic pKa for the ensemble of unfolded states shifted toward neutrality. The formalism was then applied to pH-dependent UV melting data for model DNA oligonucleotides. Folded-state pka values were in good agreement with the outcome of pH titrations, and the acid and alkaline denaturation regions were well described. The formalism developed here is similar to that of Draper and coworkers for Mg2+ binding to RNA, except that the unfolded state is described explicitly owing to the presence of specific proton-binding sites on the bases. A principal conclusion is that it should be possible to attain large pKa shifts by designing RNA molecules that fold cooperatively.
Insulin Detemir—A New Basal Insulin Analog
Authors: Goldman-Levine Jennifer D , Lee Karen W
Published: January 2005

OBJECTIVE:

To review the pharmacology, pharmacokinetics, clinical trial data, adverse effects, and role in therapy of insulin detemir.

DATA SOURCES:

Articles and meeting abstracts were identified through searches of MEDLINE (1996–June 2004), EMBASE (1980–June 2004), and International Pharmaceutical Abstracts (1970–June 2004) databases, and unpublished information was provided by the manufacturer.

STUDY SELECTION AND DATA EXTRACTION:

All available studies relating to insulin detemir's pharmacology were selected. Only human studies were used for pharmacokinetic, drug interaction, efficacy, and safety data.

DATA SYNTHESIS:

Insulin detemir is a basal insulin analog that has been shown to improve glycemic control in patients with type 1 and type 2 diabetes.

CONCLUSIONS:

Insulin detemir offers some benefits over NPH for use as basal insulin in patients with type 1 and type 2 diabetes.
Mutations in PRPF31 Inhibit Pre-mRNA Splicing of Rhodopsin Gene and Cause Apoptosis of Retinal Cells
Authors: Yuan Liya , Kawada Mariko , Havlioglu Necat , Tang Hao , Wu Jane Y.
Published: January 2005

Mutations in human PRPF31 gene have been identified in patients with autosomal dominant retinitis pigmentosa (adRP). To begin to understand mechanisms by which defects in this general splicing factor cause retinal degeneration, we examined the relationship between PRPF31 and pre-mRNA splicing of photoreceptor-specific genes. We used a specific anti-PRPF31 antibody to immunoprecipitate splicing complexes from retinal cells and identified the transcript of rhodopsin gene (RHO) among RNA species associated with PRPF31-containing complexes. Mutant PRPF31 proteins significantly inhibited pre-mRNA splicing of intron 3 inRHOgene. In primary retinal cell cultures, expression of the mutant PRPF31 proteins reduced rhodopsin expression and caused apoptosis of rhodopsin-positive retinal cells. This primary retinal culture assay provides anin vitromodel to study photoreceptor cell death caused by PRPF31 mutations. Our results demonstrate that mutations in PRPF31 gene affectRHOpre-mRNA splicing and reveal a link betweenPRPF31andRHO, two major adRP genes.
Ensemble Coding of Vocal Control in Birdsong
Authors: Leonardo Anthony , Fee Michale S.
Published: January 2005

Zebra finch song is represented in the high-level motor control nucleus high vocal center (HVC) (Reiner et al., 2004) as a sparse sequence of spike bursts. In contrast, the vocal organ is driven continuously by smoothly varying muscle control signals. To investigate how the sparse HVC code is transformed into continuous vocal patterns, we recorded in the singing zebra finch from populations of neurons in the robust nucleus of arcopallium (RA), a premotor area intermediate between HVC and the motor neurons. We found that highly similar song elements are typically produced by different RA ensembles. Furthermore, although the song is modulated on a wide range of time scales (10-100 ms), patterns of neural activity in RA change only on a short time scale (5-10 ms). We suggest that song is driven by a dynamic circuit that operates on a single underlying clock, and that the large convergence of RA neurons to vocal control muscles results in a many-to-one mapping of RA activity to song structure. This permits rapidly changing RA ensembles to drive both fast and slow acoustic modulations, thereby transforming the sparse HVC code into a continuous vocal pattern.
Reorganization of Visual Processing in Macular Degeneration
Authors: Baker Chris I. , Peli Eli , Knouf Nicholas , Kanwisher Nancy G.
Published: January 2005

Macular degeneration (MD), the leading cause of visual impairment in the developed world, damages the central retina, often obliterating foveal vision and severely disrupting everyday tasks such as reading, driving, and face recognition. In such cases, the macular damage eliminates the normal retinal input to a large region of visual cortex, comprising tens of square centimeters of surface area in each hemisphere, which is normally responsive only to foveal stimuli. Using functional magnetic resonance imaging, we asked whether this deprived cortex simply becomes inactive in subjects with MD, or whether it takes on new functional properties. In two adult MD subjects with extensive bilateral central retinal lesions, we found that parts of visual cortex (including primary visual cortex) that normally respond only to central visual stimuli are strongly activated by peripheral stimuli. Such activation was not observed (1) with visual stimuli presented to the position of the former fovea and (2) in control subjects with visual stimuli presented to corresponding parts of peripheral retina. These results demonstrate large-scale reorganization of visual processing in MD and will likely prove important in any effort to develop new strategies for rehabilitation of MD subjects.
How Stress and Fluoxetine Modulate Serotonin 2C Receptor Pre-mRNA Editing
Authors: Englander Michael T. , Dulawa Stephanie C. , Bhansali Punita , Schmauss Claudia
Published: January 2005

In two inbred strains of mice, C57BL/6 and 129Sv, the majority of forebrain neocortical pre-mRNA encoding the serotonin 2C (5-HT2C) receptor is altered by adenosine-to-inosine editing. As a result, >60% of all mRNAs encode receptors with reduced constitutive and agonist-stimulated activity. However, in the BALB/c strain, a genetically distinct inbred strain with lower forebrain serotonin levels, spontaneously elevated anxiety, and increased stress reactivity, the majority of 5-HT2CmRNA is nonedited and encodes receptors with the highest constitutive activity and the highest agonist affinity and potency. Neither acute stress (the forced swim test) nor chronic treatment with the serotonin-selective reuptake inhibitor fluoxetine elicit significant changes in 5-HT2Cpre-mRNA editing in C57BL/6 mice. In contrast, exposure of BALB/c mice to acute stress and chronic treatment of nonstressed BALB/c mice with fluoxetine elicit significant, site-specific increases in 5-HT2Cpre-mRNA editing that increase the pool of mRNA encoding receptors with reduced function. These changes in 5-HT2Cpre-mRNA editing resemble those detected previously in the prefrontal cortex of subjects with major depression. However, when chronic fluoxetine treatment is combined with stress exposure of BALB/c mice, these changes in 5-HT2Cpre-mRNA editing are no longer detected. These findings illustrate that 5-HT2Cpre-mRNA editing responses to stress and chronic fluoxetine are modulated by the genetic background, as well as the behavioral state of the animal. They suggest further that the changes in 5-HT2Cpre-mRNA editing found in major depression reflect a previously unrecognized molecular response to stress that can be prevented by chronic antidepressant treatment.
Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption
Authors: He Dao-Yao , McGough Nancy N. H. , Ravindranathan Ajay , Jeanblanc Jerome , Logrip Marian L. , Phamluong Khanhky , Janak Patricia H. , Ron Dorit
Published: January 2005

Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.
A Uniquely Selective Inhibitor of the Mammalian Fetal Neuromuscular Nicotinic Acetylcholine Receptor
Authors: Teichert Russell W. , Rivier Jean , Torres Josep , Dykert John , Miller Charleen , Olivera Baldomero M.
Published: January 2005

We have purified and characterized a novel conotoxin from the venom ofConus obscurus, which has the unique property of selectively and potently inhibiting the fetal form of the mammalian neuromuscular nicotinic acetylcholine receptor (nAChR) (α1β1γδ-subunits). Although this conotoxin, αA-conotoxin OIVB (αA-OIVB), is a high-affinity antagonist (IC50of 56 nm) of the fetal muscle nAChR, it has >1800-fold lower affinity for the adult muscle nAChR (α1β1ϵδ-subunits) and virtually no inhibitory activity at a high concentration on various neuronal nAChRs (IC50> 100 μmin all cases). The peptide (amino acid sequence, CCGVONAACPOCVCNKTCG), with three disulfide bonds, has been chemically synthesized in a biologically active form. Although the neuromuscular nAChRs are perhaps the most extensively characterized of the receptors/ion channels of the nervous system, the precise physiological roles of the fetal form of the muscle nAChR are essentially unknown.αA-OIVB is a potentially important tool for delineating the functional roles ofα1β1γδ receptors in normal development, as well as in various adult tissues and in pathological states. In addition to its potential as a research tool, αA-OIVB may have some direct biomedical applications.
Responses of Human Anterior Cingulate Cortex Microdomains to Error Detection, Conflict Monitoring, Stimulus-Response Mapping, Familiarity,andOrienting
Authors: Wang Chunmao , Ulbert Istvan , Schomer Donald L. , Marinkovic Ksenija , Halgren Eric
Published: January 2005

Human anterior cingulate cortex (ACC) activity modulation has been observed in numerous tasks, consistent with a wide variety of functions. However, previous recordings have not had sufficient spatial resolution to determine whether microdomains (approximately one to two columns) are involved in multiple tasks, how activity is distributed across cortical layers, or indeed whether modulation reflected neuronal excitation, inhibition, or both. In this study, linear arrays of 24 microelectrodes were used to estimate population synaptic currents and neuronal firing in different layers of ACC during simple/choice reaction time, delayed word recognition, rhyming, auditory oddball, and cued conditional letter-discrimination tasks. Responses to all tasks, with differential responses to errors, familiarity, difficulty, and orienting, were recorded in single microdomains. The strongest responses occurred ∼300-800 ms after stimulus onset and were usually a current source with inhibited firing, strongly suggesting active inhibition in superficial layers during the behavioral response period. This was usually followed by a sink from ∼800 to 1400 ms, consistent with postresponse rebound activation. Transient phase locking of task-related theta activity in superficial cingulate layers suggested extended interactions with medial and lateral frontal and temporal sites. These data suggest that each anterior cingulate microdomain participates in a multilobar cortical network after behavioral responses in a variety of tasks.
Transient Receptor Potential Vanilloid Subtype 1 Mediates Cell Death of Mesencephalic Dopaminergic NeuronsIn VivoandIn Vitro
Authors: Kim Sang R. , Lee Da Y. , Chung Eun S. , Oh Uh T. , Kim Seung U. , Jin Byung K.
Published: January 2005

Intranigral injection of the transient receptor potential vanilloid subtype 1 (TRPV1; also known as VR1) agonist capsaicin (CAP) into the rat brain, or treatment of rat mesencephalic cultures with CAP, resulted in cell death of dopaminergic (DA) neurons, as visualized by immunocytochemistry. Thisin vivoandin vitroeffect was ameliorated by the TRPV1 antagonist capsazepine (CZP) or iodo-resiniferatoxin, suggesting the direct involvement of TRPV1 in neurotoxicity. In cultures, both CAP and anandamide (AEA), an endogenous ligand for both TRPV1 and cannabinoid type 1 (CB1) receptors, induced degeneration of DA neurons, increases in intracellular Ca2+([Ca2+]i), and mitochondrial damage, which were inhibited by CZP, the CB1 antagonistN-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) or the intracellular Ca2+chelator BAPTA/AM. We also found that CAP or AEA increased mitochondrial cytochromecrelease as well as immunoreactivity to cleaved caspase-3 and that the caspase-3 inhibitor z-Asp-Glu-Val-Asp-fmk protected DA neurons from CAP- or AEA-induced neurotoxicity. Additional studies demonstrated that treatment of mesencephalic cultures with CB1 receptor agonist (6aR)-trans3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d] pyran-9-methanol (HU210) also produced degeneration of DA neurons and increases in [Ca2+]i, which were inhibited by AM251 and BAPTA/AM. The CAP-, AEA-, or HU210-induced increases in [Ca2+]iwere dependent on extracellular Ca2+, with significantly different patterns of Ca2+influx. Surprisingly, CZP and AM251 reversed HU210- or CAP-induced neurotoxicity by inhibiting Ca2+influx, respectively, suggesting the existence of functional cross talk between TRPV1 and CB1 receptors. To our knowledge, this study is the first to demonstrate that the activation of TRPV1 and/or CB1 receptors mediates cell death of DA neurons. Our findings suggest that these two types of receptors, TRPV1 and CB1, may contribute to neurodegeneration in response to endogenous ligands such as AEA.
Dissociating Barrel Development and Lesion-Induced Plasticity in the Mouse Somatosensory Cortex
Authors: Rebsam Alexandra , Seif Isabelle , Gaspar Patricia
Published: January 2005

In the mouse somatosensory cortex, thalamocortical axons (TCAs) corresponding to individual whiskers cluster into restricted barrel domains during the first days of life. If whiskers are lesioned before that time, the cortical space devoted to the afferents from the damaged whisker shrinks and becomes occupied by thalamocortical afferents from neighboring unlesioned whiskers. This plasticity ends by postnatal day 3 (P3) to P4 when barrels emerge. To test whether TCA development and lesion-induced plasticity are linked, we used monoamine oxidase A knock-out (MAOA-KO) mice in which normal TCA development is halted by an excess of serotonin. Normal TCA development can be restored when serotonin levels are lowered by parachlorophenylalanine (PCPA). By varying the time of PCPA administration, we found that barrel development can be reinitiated until P11, although the emergence of TCA clusters becomes gradually slower and less complete. In mice in which barrels emerge 3 d later than the normal schedule, at P6 instead of P3, we examined lesion-induced plasticity. We find a progressive decline of the lesion-induced plasticity and a closure at P3, similar to normal mice, showing that this plasticity is not influenced by an excess of serotonin levels. Thus, in MAOA-KO mice, the emergence of barrel patterning can be delayed without a concomitant delay in lesion-induced plasticity, and the cortical space devoted to one whisker representation cannot be modified by the periphery once patterning is imprinted in the subcortical relays. We conclude that the closure of the lesion-induced plasticity period in the barrelfield is probably not determined at the cortical level.
Controlling Bursting in Cortical Cultures with Closed-Loop Multi-Electrode Stimulation
Authors: Wagenaar Daniel A. , Madhavan Radhika , Pine Jerome , Potter Steve M.
Published: January 2005

One of the major modes of activity of high-density cultures of dissociated neurons is globally synchronized bursting. Unlikein vivo, neuronal ensembles in culture maintain activity patterns dominated by global bursts for the lifetime of the culture (up to 2 years). We hypothesize that persistence of bursting is caused by a lack of input from other brain areas. To study this hypothesis, we grew small but dense monolayer cultures of cortical neurons and glia from rat embryos on multi-electrode arrays and used electrical stimulation to substitute for afferents. We quantified the burstiness of the firing of the cultures in spontaneous activity and during several stimulation protocols. Although slow stimulation through individual electrodes increased burstiness as a result of burst entrainment, rapid stimulation reduced burstiness. Distributing stimuli across several electrodes, as well as continuously fine-tuning stimulus strength with closed-loop feedback, greatly enhanced burst control. We conclude that externally applied electrical stimulation can substitute for natural inputs to cortical neuronal ensembles in transforming burst-dominated activity to dispersed spiking, more reminiscent of the awake cortexin vivo. This nonpharmacological method of controlling bursts will be a critical tool for exploring the information processing capacities of neuronal ensemblesin vitroand has potential applications for the treatment of epilepsy.
Neuroinflammation Alters the Hippocampal Pattern of Behaviorally InducedArcExpression
Authors: Rosi Susanna , Ramirez-Amaya Victor , Vazdarjanova Almira , Worley Paul F. , Barnes Carol A. , Wenk Gary L.
Published: January 2005

Neuroinflammation is associated with a variety of neurological and pathological diseases, such as Alzheimer's disease (AD), and is reliably detected by the presence of activated microglia. In early AD, the highest degree of activated microglia is observed in brain regions involved in learning and memory. To investigate whether neuroinflammation alters the pattern of rapidde novogene expression associated with learning and memory, we studied the expression of the activity-induced immediate early geneArcin the hippocampus of rats with experimental neuroinflammation. Rats were chronically infused with lipopolysaccharide (LPS) (0.25 μg/h) into the fourth ventricle for 28 d. On day 29, the rats explored twice a novel environment for 5 min, separated by 45 or 90 min. In the dentate gyrus and CA3 regions of LPS-infused rats, Arc and OX-6 (specific for major histocompatibility complex class II antigens) immunolabeling andArcfluorescencein situhybridization revealed both activated microglia (OX-6 immunoreactivity) and elevated exploration-inducedArcexpression compared with control-infused rats. In contrast, in the CA1 of LPS-infused rats, where there was no OX-6 immunostaining, exploration-inducedArcmRNA and protein remained similar in both LPS- and control-infused rats. LPS-induced neuroinflammation did not affect basal levels ofArcexpression. Behaviorally inducedArcexpression was altered only within the regions showing activated microglia (OX-6 immunoreactivity), suggesting that neuroinflammation may alter the coupling of neural activity with macromolecular synthesis implicated in learning and plasticity. This activity-related alteration in Arc expression induced by neuroinflammation may contribute to the cognitive deficits found in diseases associated with inflammation, such as AD.
IR Spectroscopy of Microsolvated Aromatic Cluster Ions: Ionization-Induced Switch in Aromatic Molecule–Solvent Recognition
Authors: Dopfer Otto
Published: January 2005

IR spectroscopy, mass spectrometry, and quantum chemical calculations are employed to characterize the intermolecular interaction of a variety of aromatic cations (A+) with several types of solvents. For this purpose, isolated ionic complexes of the type A+–L
n
, in which A+ is microsolvated by a controlled number (n) of ligands (L), are prepared in a supersonic plasma expansion, and their spectra are obtained by IR photodissociation (IRPD) spectroscopy in a tandem mass spectrometer. Two prototypes of aromatic ion–solvent recognition are considered: (i) microsolvation of acidic aromatic cations in a nonpolar hydrophobic solvent and (ii) microsolvation of bare aromatic hydrocarbon cations in a polar hydrophilic solvent. The analysis of the IRPD spectra of A+–L dimers provides detailed information about the intermolecular interaction between the aromatic ion and the neutral solvent, such as ion–ligand binding energies, the competition between different intermolecular binding motifs (H-bonds, π-bonds, charge–dipole bonds), and its dependence on chemical properties of both the A+ cation and the solvent type L. IRPD spectra of larger A+–L
n
clusters yield detailed insight into the cluster growth process, including the formation of structural isomers, the competition between ion–solvent and solvent–solvent interactions, and the degree of (non)cooperativity of the intermolecular interactions as a function of solvent type and degree of solvation. The systematic A+–L
n
cluster studies are shown to reveal valuable new information about fundamental chemical properties of the bare A+ cation, such as proton affinity, acidity, and reactivity. Because of the additional attraction arising from the excess charge, the interaction in the A+–L
n
cation clusters differs largely from that in the corresponding neutral A–L
n
clusters with respect to both the interaction strength and the most stable structure, implying in most cases an ionization-induced switch in the preferred aromatic molecule–solvent recognition motif. This process causes severe limitations for the spectroscopic characterization of ion–ligand complexes using popular photoionization techniques, due to the restrictions imposed by the Franck–Condon principle. The present study circumvents these limitations by employing an electron impact cluster ion source for A+–L
n
generation, which generates predominantly the most stable isomer of a given cluster ion independent of its geometry.
Anisotropic and Isotropic Light Scattering Data of Neon Gas Simultaneously Fitted by an Isotropic Ground State Interatomic Potential
Authors: El-Kader Mahamed Sayed Abdel , El-Eraky S. M.
Published: January 2005

The binary anisotropic and isotropic collision-induced light scattering spectra by gaseous room temperature neon, over an extended frequency domain have been used for deriving the empirical multi-parameter Morse–Morse–Morse–Spline van der Waals interatomic potential. These new data of scattering are accurate enough to permit for the first time a reliable determination of the isotropic potential as a function of the interatomic separation. The potential parameters describing the location and depth of the attractive well are given by ε = 41.07 K and r
m = 3.087 Å. Comparison with other potentials based on bulk properties and ab initio calculations are presented; the temperature dependence of pressure second virial coefficient, self diffusion, thermal conductivity and viscosity are also discussed for the proposed potentials. In addition, our empirical potential was used to solve the nuclear Schrödinger equation for comparison with and predication of spectroscopic properties of the dimer. The results show that it is the most accurate potential reported to date for this system.
Solar-Thermal Zinc Oxide Reduction Assisted by a Second Redox Pair
Authors: Rager Timo , Golczewski Jerzy
Published: January 2005

Thermochemical cycles have been investigated for quite some time as a means to convert heat into storable chemical energy. A particularly attractive reaction is the solar-thermal decomposition of zinc oxide into zinc and oxygen, but the efficiency of this process is impaired by the fast recombination of zinc and oxygen upon cooling of the gas phase. The combination with a second, nickel/nickel oxide redox cycle is presented as a possibility to avoid the simultaneous presence of metal and oxygen in the gas phase.
Introduction
Authors: Cassidy Suzanne B. , Allanson Judith E.
Published: January 2005

This chapter gives details on how the book is organized and informs the reader about the genetics‐related terms used. Each chapter is dedicated to the diagnosis and management of a specific syndrome that is encountered with regularity in specialty programs and occasionally in primary care experience. The authors are experts who have considerable personal experience in the management of the disorder. Each chapter contains unpublished information based on the author's experience and personal approach in addition to a review of published information. The format of each chapter is similar and provides general information on incidence and inheritance, pathogenesis, and etiology, diagnostic criteria and testing, and differential diagnosis of the specific syndrome. The myriad manifestations of each syndrome are presented system by system with emphasis on the features, evaluation, management, and prognosis. Photographs of physical findings important for diagnosis or management are provided. Each chapter concludes with a listing of family support organizations and resources available to families and professionals in print and electronic formats. Selected references stressing management issues and citations of good review articles are included.