bluuebunny/crossref_metadata_2025 huggingface dataset:
The tolerance to exchanges of the Watson–Crick base pair in the hammerhead ribozyme core is determined by surrounding elements
Authors: Przybilski Rita , Hammann Christian
Published: August 2007

Tertiary interacting elements are important features of functional RNA molecules, for example, in all small nucleolytic ribozymes. The recent crystal structure of a tertiary stabilized type I hammerhead ribozyme revealed a conventional Watson–Crick base pair in the catalytic core, formed between nucleotides C3 and G8. We show that any Watson–Crick base pair between these positions retains cleavage competence in two type III ribozymes. In the Arabidopsis thaliana sequence, only moderate differences in cleavage rates are observed for the different base pairs, while the peach latent mosaic viroid (PLMVd) ribozyme exhibits a preference for a pyrimidine at position 3 and a purine at position 8. To understand these differences, we created a series of chimeric ribozymes in which we swapped sequence elements that surround the catalytic core. The kinetic characterization of the resulting ribozymes revealed that the tertiary interacting loop sequences of the PLMVd ribozyme are sufficient to induce the preference for Y3–R8 base pairs in the A. thaliana hammerhead ribozyme. In contrast to this, only when the entire stem–loops I and II of the A. thaliana sequences are grafted on the PLMVd ribozyme is any Watson–Crick base pair similarly tolerated. The data provide evidence for a complex interplay of secondary and tertiary structure elements that lead, mediated by long-range effects, to an individual modulation of the local structure in the catalytic core of different hammerhead ribozymes.
Managing Osteoporosis in Patients with Fragility Fractures: Did the British Orthopaedic Association Guidelines Have Any Impact?
Authors: Nixon MF , Ibrahim T , Johari Y , Eltayef S , Hariharan D , Taylor G J
Published: August 2007

INTRODUCTION

The incidence of fragility fractures could double in the next 50 years. Effective treatments for osteoporosis exist and the British Orthopaedic Association (BOA) has guidelines governing how to manage underlying osteoporosis in patients with fragility fractures. This study assessed how well two trauma units treat underlying osteoporosis and whether the BOA guidelines made any impact.

PATIENTS AND METHODS

Case notes of patients with a fracture of their proximal femur admitted during January and February in 2003, 2004 and 2005 were reviewed. The results were analysed for differences between site and year.

RESULTS

A total of 602 case notes were reviewed. There was a significant difference in the number of patients discharged on osteoporosis medication between the two sites (27% at LRI, 8% at KGH; P < 0.001), but not between 2003 and 2005 (22% and 16%; P = 0.16). Of the patients started on treatment, 83% were started on calcium and/or vitamin D3 supplements.

CONCLUSIONS

The number of patients who had their underlying osteoporosis addressed was low and the type of treatment sub-optimal. This suggests the BOA guidelines have not made an impact and further work is required to improve the management of these patients.
Day-Case Rigid and Flexible Ureteroscopy
Authors: Bromwich EJ , Lockyer R , Keoghane SR
Published: August 2007

INTRODUCTION

The aim of this study was to evaluate the feasibility of rigid and flexible ureteroscopy as a day-surgery procedure.

PATIENTS AND METHODS

All patients requiring elective ureteroscopy from March 2004 were considered for a day-surgery procedure. The standard day-surgery exclusions existed but there were no urological criteria for exclusion. A single consultant urologist performed or supervised all procedures.

RESULTS

A total of 64 patients underwent 50 rigid and 14 flexible procedures. Six diagnostic ureteroscopies were performed. There was a 96% stone clearance rate. Five patients required an unplanned admission within the first 2 weeks' postoperatively. Three of these patients were admitted on the day of surgery, two for pain and one for social reasons. Two patients were admitted at 24 h and 48 h, respectively, for urinary retention.

CONCLUSIONS

Ureteroscopy, both rigid and flexible, is a safe procedure for the day-surgery setting. Routine use of prophylactic antibiotics, intravenous non-steroidal anti-inflammatory drugs resulted in an acceptable re-admission rate.
Mortality Following Hip Fracture Surgery in Patients with Recent Myocardial Infarction
Authors: Komarasamy Baskaran , Forster Mark C , Esler Colin N , Harper William M , Hall Andrew P
Published: August 2007

INTRODUCTION

In an elective setting, surgery is best avoided for at least 6 months following myocardial infarction. However, in the presence of a femoral neck fracture, this would most probably lead to significant complications in relation to prolonged immobilisation. There is no published mortality data for patients undergoing surgery for hip fracture following a recent myocardial infarction. The aim of this retrospective study was to assess the mortality of hip fracture patients with a recent myocardial infarction that have undergone surgery at our institution.

PATIENTS AND METHODS

Between January 2003 and October 2005, 2270 patients were admitted to our unit with a proximal femoral fracture. Of these, 11 patients were found to have a recent myocardial infarction.

RESULTS

Of these 11 patients, 8 were female. The average age was 78.2 years (range, 59–90 years). Average delay from the time of infarction to operation was 11.2 days (range, 3–23 days). Mortality at 1 and 6 months was 45.4% and 63.5%, respectively.

DISCUSSION

This is much higher than the overall reported mortality following proximal femur fracture. This information may be useful when planning future peri-operative care and discussing overall prognosis with patients and their relatives.
Inguinal Hernia Repair: Local or General Anaesthesia?
Authors: Sanjay P , Woodward A
Published: August 2007

INTRODUCTION

Specialist hernia centres and public hospitals with a dedicated hernia service (Plymouth Hernia Service) have achieved remarkable results for inguinal hernia repair with the use of local anaesthesia and set the standards for groin hernia surgery. There is minimal data in the literature as to whether such results are reproducible in the National Health Service in the UK.

PATIENTS AND METHODS

A retrospective analysis of all inguinal hernia repairs performed in one district general hospital over a 9-year period was performed. The outcome measures were type of anaesthesia used, early and late postoperative complications and recurrence. A postal questionnaire survey was conducted to obtain satisfaction rates. In addition, a postal questionnaire survey of consultant surgeons in Wales was performed to determine the use of local anaesthesia and day-case rates for inguinal hernia repair.

RESULTS

A total of 577 hernia repairs were performed during the study period. Of these, 369 (64%) repairs were performed under local anaesthesia (LA) and 208 (36%) under general anaesthesia (GA). Day-case repair was achieved in 70% (400) of cases. The day-case rates were significantly higher under LA compared to GA (82.6% versus 42.6%; P < 0.05). Patients operated under LA had lower postoperative analgesic requirements and lower incidence of urinary retention compared with the GA group (P < 0.05). There were 7 (1.2%) recurrences at a median follow-up of 5.1 years (range, 10.3–2.5 years). Postal questionnaire revealed higher satisfaction rates with LA compared to GA repair. Only 15% of surgeons in Wales offer the majority of their patients local anaesthetic repair.

CONCLUSIONS

The use of LA results in increased day-case rates, lesser postoperative analgesic requirements and fewer micturition problems. The excellent results obtained by specialist hernia centres can be reproduced by district general hospitals by increasing the use of LA to repair inguinal hernias.
Post-Discharge Symptomatic Thromboembolic Events in Hip Fracture Patients
Authors: Anand Sanjeev , Buch Keyur
Published: August 2007

INTRODUCTION

The aim of this study was to audit referral rates for post-discharge symptomatic thromboembolic events follow-hip fracture surgery to assess the extent of the clinical problem and to initiate discussion on prolonged chemoprophylaxis.

PATIENTS AND METHODS

All patients who underwent surgery for proximal hip fractures in one year (2001–2002) were followed up. Patient case-notes were used to identify all morbidity episodes within 3 months following discharge. Patients with suspected symptomatic thromboembolic episodes were investigated to confirm the diagnoses objectively. Reasons for hospital readmission and causes of death were identified.

RESULTS

A total of 267 patients who underwent surgery for proximal hip fractures were included in the study. Forty-three patients died during initial admission episode. Of the 224 patients discharged, 46 (20.54%) patients were referred back to hospital within 3 months, for unplanned emergency management. Of these, 8 patients (3.57%) were referred back for suspected thromboembolic events. Of these, 6 (2.67%) were referred with a clinical diagnoses of deep vein thrombosis (DVT) but only 1 patient (0.45%) was confirmed to have DVT. Two patients (0.89%) were referred with features of pulmonary embolism (PE). Both were confirmed on ventilation-perfusion scans and both patients died. One patient died following PE in the community. Thus, overall, 3 deaths (1.34%) following discharge were recorded to be due to pulmonary embolism.

CONCLUSIONS

Suspected thromboembolic events constitute a major proportion of unplanned referrals back to the hospital. Three deaths due to delayed pulmonary embolism may justify prolonged universal chemoprophylaxis following hip fracture surgery.
Comment: ‘The Problem Surgical Colleague’
Authors: Taylor Irving
Published: August 2007

The review of ‘The problem surgical colleague’ by Mr John Mosley is both timely and relevant. All surgeons are naturally concerned about the mechanisms in place, both locally and through the General Medical Council (GMC) to deal with fitness-to-practise issues. It is inevitable that criticisms, often unfounded, are voiced by the profession. Most surgeons welcome a fair and transparent system to deal with such matters whilst maintaining the principle of self-regulation. We must accept that there are a small number of surgeons whose practice is impaired to such a degree that they represent a serious patient-safety risk and they must be dealt with appropriately.

As a GMC medical case examiner since 2003, and having dealt with over 600 fitness-to-practise cases, I wish to comment on some of the important issues raised by Mr Mosley, specifically in relation to the surgeon and his or her practice. In doing so, I will set out the investigative process to be followed when fitness-to-practise concerns are brought to the attention of the GMC.
Pharmaceutical Care in Community Pharmacies: Practice and Research in Brazil
Authors: Castro Mauro Silveira de , Correr Cassyano Januário
Published: August 2007

Objective:

To discuss the provision of pharmaceutical services and pharmaceutical care in Brazil.

Findings:

Professional training and pharmaceutical services are undergoing a period of restructuring in Brazil, including the adoption of incentives for pharmaceutical care. Some important national measures include the rational use of medications, evidence-based medicine, and pharmacovigilance. A new and more generalist pharmacy curriculum is being implemented and tailored for the Brazilian Public Health System; recently, the Brazilian government has provided resources for pharmaceutical care research.

Discussion:

A proposal for national consensus in Brazilian pharmaceutical care was published in 2002. The components of this proposal include drug dispensing, counseling, health education, symptoms advice, and pharmacotherapy follow-up. Pharmacy practice is currently focused on drug dispensing and logistic aspects of drug distribution. Professionals are satisfied with patients' confidence in being counseled by pharmacists and reveal interest in extending their role in patient care. Most pharmacy customers were originally unaware of the term “pharmaceutical care”; however, following an explanation, they showed an interest in this service. Furthermore, over 50% stated that they would pay for this service. Despite these initiatives, numerous barriers to the development of pharmaceutical care remain, the main ones being the commercial objective of most pharmacies that sell medications and the insufficient training of professionals. Although government-owned pharmacies also distribute medications, they do not meet all of the needs of the population and lack sufficient pharmacists.

Conclusions:

Several actions are required to stimulate the implementation and development of pharmaceutical care and services in Brazil. Recent research incentives in pharmaceutical care and reorientation of pharmacy education will contribute to this development.
Pegfilgrastim-Induced Hyperleukocytosis
Authors: Snyder Ronald L , Stringham Delevan J
Published: August 2007

Objective:

To report a pediatric case of pegfilgrastim-induced hyperleukocytosis.

Case Summary:

A 3-year-old boy with medulloblastoma therapy presented with white blood cell (WBC) count 0.1 × 103/μL and absolute neutrophil count (ANC) 0.014 × 103/μL on day 27 following a course of induction chemotherapy. The patient received pegfilgrastim 200 μg/kg the following day. On his return 6 days later for the next planned course of chemotherapy, hyperleukocytosis was determined, with WBC 149 × 103/μL and ANC 110 × 103/μL (“neutrophil overshoot”). No sources of the elevated WBC count other than administration of pegfilgrastim (eg, steroids, antiepileptics, infection) were present. Chemotherapy was delayed until the WBC count had fallen to 35.2 × 103/μL (ANC 28.9 × 103/μL). No sequelae from this adverse effect occurred.

Discussion:

Pegfilgrastim has unique saturable neutrophil receptor-mediated clearance, the ability for self-regulation. Due to this clearance mechanism, hyperleukocytosis associated with pegfilgrastim use is uncommon in adults and has not been previously reported in pediatrics. The pegfilgrastim dose in children is under investigation; however, 100–110 μg/kg has been effective and safe in this population. Use of the Naranjo probability scale suggested that pegfilgrastim was the probable cause of hyperleukocytosis in our patient.

Conclusions:

Pegfilgrastim 200 μg/kg, in excess of the 100 μg/kg dose used in limited pediatric clinical trials, appeared to exceed saturable neutrophil receptor-mediated clearance. The inability of this mechanism to self-regulate neutrophil counts in the normal range led to neutrophil overshoot. Routine pediatric use of the pegylated dosage form of G-CSF should await further published clinical trials to validate a safe and effective dose.
Limited Efficacy of Gastrointestinal Decontamination in Severe Slow-Release Carbamazepine Overdose
Authors: Lurie Yael , Bentur Yedidia , Levy Yishai , Baum Elena , Krivoy Norberto
Published: August 2007

Objective:

To report the limited efficacy of both multiple doses of activated charcoal (MDAC) and whole bowel irrigation (WBI) in a patient with severe overdose of slow-release carbamazepine.

Case Summary:

A 25-year-old man was admitted in a comatose state with seizures after a suicide attempt with slow-release carbamazepine. Serum carbamazepine concentration on admission (16 h postingestion) was 52.08 μg/mL. The patient was mechanically ventilated and treated with MDAC and a 4 hour charcoal hemoperfusion. Carbamazepine concentration at the end of hemoperfusion was 27.16 μg/mL. Despite continuous treatment with MDAC, a rebound in carbamazepine concentration to 36 μg/mL was observed 32 hours after hemoperfusion (58 h postingestion). WBI was performed over a 10 hour period. The carbamazepine concentration continued to increase to 38.55 μg/mL and seizures recurred. After WBI was performed, MDAC was reinstituted; 33 hours later (102 h postingestion), the carbamazepine concentration began to decline. The hospitalization course was complicated by pneumonia, which necessitated continuation of mechanical ventilation and administration of antibiotics. The patient recovered completely and was discharged without sequelae 15 days after admission.

Discussion:

Serum carbamazepine concentration and toxicity were effectively reduced by hemoperfusion. The role of MDAC coadministered during hemoperfusion cannot be ruled out. However, a rebound in carbamazepine concentration with recurrent seizures was observed despite MDAC and WBI. The most likely explanation for this rebound (65 h postingestion, 39 h posthemoperfusion) is prolonged absorption, possibly from a pharmacobezoar. Redistribution cannot be excluded, but this is not supported by the concentration–time course and previous reports.

Conclusions:

Both MDAC and WBI may be ineffective in reducing absorption and enhancing elimination in overdose of slow-release carbamazepine. Repeated hemoperfusion or other elimination enhancement techniques should be considered when the clinical and toxicokinetic course suggests the presence of a refractory pharmacobezoar.
Alzheimer's Disease: Will Advances Made in the Past Turn the Tide?
Authors: Semla Todd P
Published: August 2007

2006 marked the 40th year of publication for The Annals. Throughout its history, The Annals has provided important contributions to the development of clinical pharmacy. In 2007, we are continuing to publish articles reflecting on the history of clinical pharmacy through the eyes of practitioners, including those pioneering clinical pharmacy, as well as those who have more recently entered the profession and a well-established specialty. In addition, we are presenting articles and editorials from the early history of The Annals that have given direction and shape to the practice of clinical pharmacy (see page 1499).
Effect of Clonazepam on Raynaud's Phenomenon and Fingertip Ulcers in Scleroderma
Authors: Colakoğlu Murat , Cobankara Veli , Akpolat Tekin
Published: August 2007

Objective:

To report the novel finding of a significant improvement in Raynaud's phenomenon symptoms with clonazepam in a patient with systemic sclerosis.

Case Summary:

A 45-year-old female with limited scleroderma and chronic renal failure was admitted to our hospital due to hyponatremia (sodium 103 mEq/L). Her hyponatremia was treated by intravenous infusion of NaCI 3%. Clonazepam, which had been prescribed previously for anxiety and insomnia, was discontinued. Three weeks after she was discharged from the hospital, the patient presented with the complaint of increased severity of Raynaud's phenomenon and digital ulcers. She told us that her fingertip ulcers had been healed while she was taking clonazepam and that episodes of Raynaud's phenomenon had increased after discontinuation of the drug. Clonazepam 1 mg twice daily was restarted, and Raynaud's phenomenon and fingertip ulcers resolved within a month. On 2 occasions after that time, we discontinued clonazepam and replaced it with alprazolam, as the patient believed alprazolam was more beneficial in alleviating anxiety. Episodes of Raynaud's phenomenon and new digital ulcers recurred on both of these occasions, and clonazepam was restarted. At the time of writing, no severe episodes of Raynaud's phenomenon or fingertip ulcers have occurred with clonazepam treatment.

Discussion:

Raynaud's phenomenon and recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis and lead to pain, impaired function, and tissue loss. Few drugs have previously been shown to affect digital ulcers in the setting of scleroderma. Our patient experienced a significant and sustained improvement in Raynaud's phenomenon and digital ulcers following the initiation of clonazepam. To our knowledge, as of March 2007, this is the first reported use of clonazepam in Raynaud's phenomenon and digital ulcer. While its therapeutic mechanism remains unclear, clonazepam may offer some advantages compared with current agents.

Conclusions:

We report a case of Raynaud's phenomenon and digital ulcers responding to clonazepam. Further research is warranted to test the robustness of this preliminary finding.
Optical Restriction of Plasma Emission Light for Nanometric Sampling Depth and Depth Profiling of Multilayered Metal Samples
Authors: Čtvrtníčková T. , Fortes F. J. , Cabalín L. M. , Laserna J. J.
Published: July 2007

Improvement in depth profiling capabilities of laser-induced breakdown spectrometry (LIBS) for multilayered samples has been attempted. For this purpose, in a typical LIBS experiment, an optical restriction consisting of a pinhole placed between the dichroic mirror and the collecting lenses has been used. This new optical approach allows observing only the light emission coming from the central region of the plume. The microplasma was created on the sample by a pulsed Nd:YAG laser operating at 1064 nm with a homogeneous distribution of energy across the beam. Light emitted by the microplasma was detected with an intensified charge-coupled device (iCCD) multichannel detector. The effect of pinhole diameter and the delay time influence on depth analysis have been assessed. An ablation range of only a few nanometers per pulse has been achieved. Depth profiles of various metals (Cr, Ni, Cu) from multilayered samples have been generated by LIBS and depth resolution at different delay times using various pinhole diameters have been calculated and compared.
Feasibility of a Wide Area Illumination Scheme for Reliable Raman Measurement of Petroleum Products
Authors: Kim Jaejin , Han Jintae , Noh Jaegeun , Chung Hoeil
Published: July 2007

A newly developed Raman collection scheme, a wide area illumination (WAI) scheme, was employed to demonstrate its utility for the analysis of petroleum products. For this purpose, the compositional analysis of simulated naphtha samples was attempted. The WAI scheme utilized a laser beam that illuminated a sample in a circular fashion with a diameter of 6 mm and a focal length of 250 mm. The reproducibility of the Raman measurement can be improved due to decreased sensitivity of the sample position as well as orientation with regard to the focal plane, as shown in a previous study.1 Near-infrared (NIR) spectroscopy, widely adopted in the field of petroleum refining, was also employed to compare with the prediction results obtained using the WAI scheme. Since the Raman spectral feature is more distinct and selective, the resulting calibration accuracy could be improved as long as reproducible Raman spectra could be collected. Overall prediction results using Raman spectroscopy were superior to those from NIR spectroscopy. The feasibility of the WAI scheme for reliable Raman analysis of petroleum products such as naphtha was demonstrated in this paper.
Applied Spectroscopy News
Authors: Hellgeth John W.
Published: July 2007

Applied Spectroscopy News is a monthly feature in the journal. It includes information from the Society for Applied Spectroscopy, news from other societies and institutions, announcements of meetings, schools, or other activities, and reports of symposia from recent conferences. If you have news items, a meeting announcement, or a report from a symposium that would be of interest to readers of Applied Spectroscopy, contact Deborah K. Bradshaw, Applied Spectroscopy News Editor, P.O. Box 536307, Orlando, Florida 32853-6307, e-mail: 70454.151@compuserve.com , Ph: (407) 898-3823.
Book Review: Ion Mobility Spectrometry, Biophotonics—Visions for Better Health Care
Authors: Hill Herbert H. , Schultz Zachary D.
Published: July 2007

Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL 61801
A Sensitive Chemiluminescence Procedure for the Determination of Carbon Monoxide with Myoglobin—Luminol Chemiluminescence System
Authors: Xie Xiaofeng , He Xili , Song Zhenghua
Published: July 2007

A novel chemiluminescence method combined with the flow injection technique for the determination of carbon monoxide is presented in this paper. The chemiluminescence signal based on the reaction between myoglobin and luminol in an alkaline medium was remarkably enhanced by carbon monoxide. The enhanced chemiluminescence intensity was linear with carbon monoxide concentration in the range from 0.01 to 10.0 pmol·L−1, and the detection limit was 3 × 10−3 pmol·L−1 (3σ). The whole process, including sampling and washing, could be completed in 0.5 min with a relative standard deviation of less than 4.0%. The proposed method was applied successfully in the assay of carbon monoxide in human serum and artificial water samples without any pretreatment procedure.
Use of a solid-phase extraction with radioimmunoassay to identify the proportional bias of clinical B-type natriuretic peptide immunoassay: the impact of plasma matrix and antibody multispecificity
Authors: Naik George O.A. , Moe Gordon W.
Published: July 2007

Clin Chem Lab Med 2007;45:1353–9.
Differentiating transudative from exudative pleural effusion: should we measure effusion cholesterol dehydrogenase?
Authors: Leers Mathie P.G. , Kleinveld Henne A. , Scharnhorst Volkher
Published: July 2007

Clin Chem Lab Med 2007;45:1332–8.
Neutralization of Nerve Growth Factor Induces Plasticity of ATP-Sensitive P2X3Receptors of Nociceptive Trigeminal Ganglion Neurons
Authors: D'Arco Marianna , Giniatullin Rashid , Simonetti Manuela , Fabbro Alessandra , Nair Asha , Nistri Andrea , Fabbretti Elsa
Published: August 2007

The molecular mechanisms of migraine pain are incompletely understood, although migraine mediators such as NGF and calcitonin gene-related peptide (CGRP) are believed to play an algogenic role. Although NGF block is proposed as a novel analgesic approach, its consequences on nociceptive purinergic P2X receptors of trigeminal ganglion neurons remain unknown. We investigated whether neutralizing NGF might change the function of P2X3receptors natively coexpressed with NGF receptors on cultured mouse trigeminal neurons. Treatment with an NGF antibody (24 h) decreased P2X3receptor-mediated currents and Ca2+transients, an effect opposite to exogenously applied NGF. Recovery from receptor desensitization was delayed by anti-NGF treatment without changing desensitization onset. NGF neutralization was associated with decreased threonine phosphorylation of P2X3subunits, presumably accounting for their reduced responses and slower recovery. Anti-NGF treatment could also increase the residual current typical of heteromeric P2X2/3receptors, consistent with enhanced membrane location of P2X2subunits. This possibility was confirmed with cross-linking and immunoprecipitation studies. NGF neutralization also led to increased P2X2esplicing variant at mRNA and membrane protein levels. These data suggest that NGF controlled plasticity of P2X3subunits and their membrane assembly with P2X2subunits. Despite anti-NGF treatment, CGRP could still enhance P2X3receptor activity, indicating separate NGF- or CGRP-mediated mechanisms to upregulate P2X3receptors. In anin vivomodel of mouse trigeminal pain, anti-NGF pretreatment suppressed responses evoked by P2X3receptor activation. Our findings outline the important contribution by NGF signaling to nociception of trigeminal sensory neurons, which could be counteracted by anti-NGF pretreatment.
RhoA Regulates Dendrite Branching in Hippocampal Neurons by Decreasing Cypin Protein Levels
Authors: Chen Hongxin , Firestein Bonnie L.
Published: August 2007

The way a dendrite is patterned determines how a neuron will receive information. The Rho GTPases have been reported to play increasingly well defined roles in determining dendritic branch and spine development and morphology. Much is known about how these small GTPases regulate the actin cytoskeleton; however, very little is known about how they alter the microtubule cytoskeleton. Our laboratory previously cloned and characterized cypin, a guanine deaminase that increases dendrite number by binding to tubulin heterodimers and promoting microtubule assembly. In the present study, we show that cypin and RhoA are part of a common pathway that regulates dendrite number. Inhibition of Rho kinase activity does not affect cypin-mediated dendrite branching. Furthermore, cypin does not affect the activity of RhoA, as measured by GTP binding to RhoA. In fact, activated RhoA acts to inhibit cypin protein expression and, by doing so, decreases dendrite number. In addition, this decrease in cypin protein occurs via a translation-dependent mechanism. Together, our data suggest that cypin acts downstream of the small GTPase RhoA to regulate dendrite branching in hippocampal neurons, providing a novel mechanism for RhoA action on microtubule dynamics.
Spontaneous Activity of Auditory-Nerve Fibers: Insights into Stochastic Processes at Ribbon Synapses
Authors: Heil Peter , Neubauer Heinrich , Irvine Dexter R. F. , Brown Mel
Published: August 2007

In several sensory systems, the conversion of the representation of stimuli from graded membrane potentials into stochastic spike trains is performed by ribbon synapses. In the mammalian auditory system, the spiking characteristics of the vast majority of primary afferent auditory-nerve (AN) fibers are determined primarily by a single ribbon synapse in a single inner hair cell (IHC), and thus provide a unique window into the operation of the synapse. Here, we examine the distributions of interspike intervals (ISIs) of cat AN fibers under conditions when the IHC membrane potential can be considered constant and the processes generating AN fiber activity can be considered stationary, namely in the absence of auditory stimulation. Such spontaneous activity is commonly thought to result from an excitatory Poisson point process modified by the refractory properties of the fiber, but here we show that this cannot be the case. Rather, the ISI distributions are one to two orders of magnitude better and very accurately described as a result of a homogeneous stochastic process of excitation (transmitter release events) in which the distribution of interevent times is a mixture of an exponential and a gamma distribution with shape factor 2, both with the same scale parameter. Whereas the scale parameter varies across fibers, the proportions of exponentially and gamma distributed intervals in the mixture, and the refractory properties, can be considered constant. This suggests that all of the ribbon synapses operate in a similar manner, possibly just at different rates. Our findings also constitute an essential step toward a better understanding of the spike-train representation of time-varying stimuli initiated at this synapse, and thus of the fundamentals of temporal coding in the auditory pathway.
Dopaminergic Mechanisms in Actions and Habits: Figure 1.
Authors: Wickens Jeffery R. , Horvitz Jon C. , Costa Rui M. , Killcross Simon
Published: August 2007

Recent studies suggest new ways to interpret dopaminergic actions in goal-directed performance and habitual responding. In the early stages of learning dopamine plays an essential role, but with extended training dopamine appears to play a decreasing role in response expression. Experimental manipulation of dopamine levels alters the correlation of cortical and striatal neural activity in behaving animals, and these dopamine-dependent changes in corticostriatal correlations may be reflected in changes in action selection in the basal ganglia. Consistent with this hypothesis, changes in dopamine signaling brought about by sensitization with amphetamine mimic the transition from goal-directed to habit-based instrumental performance. At the cellular level, dopamine-dependent synaptic plasticity may be important initially, and subsequently lead to more persistent changes that no longer require dopamine. The locus of these actions within the cortical and corticostriatal circuitry is a focus on ongoing research.
Homeostatic Regulation of Intrinsic Excitability and Synaptic Transmission in a Developing Visual Circuit
Authors: Pratt Kara G. , Aizenman Carlos D.
Published: August 2007

One of the major challenges faced by the developing visual system is how to stably process visual information, yet at the same time remain flexible enough to accommodate growth and plasticity induced by visual experience. We find that in theXenopusretinotectal circuit, during a period in development when the retinotectal map undergoes activity-dependent refinement and visual inputs strengthen, tectal neurons adapt their intrinsic excitability such that a stable relationship between the total level of synaptic input and tectal neuron spike output is conserved. This homeostatic balance between synaptic and intrinsic properties is maintained, in part, via regulation of voltage-gated Na+currents, resulting in a stable neuronal input–output function. We experimentally manipulated intrinsic excitability or synapse strengthening in developing tectal neuronsin vivoby electroporation of a leak K+channel gene or a peptide that interferes with normal AMPA receptor trafficking. Both manipulations resulted in a compensatory increase in voltage-gated Na+currents. This suggests that intrinsic neuronal properties are actively regulated as a function of the total level of neuronal activity experienced during development. We conclude that the coordinated changes between synaptic and intrinsic properties allow developing optic tectal neurons to remain within a stable dynamic range, even as the pattern and strength of visual inputs changes over development, suggesting that homeostatic regulation of intrinsic properties plays a central role in the functional development of neural circuits.
Mitochondrial and Plasma Membrane Potential of Cultured Cerebellar Neurons during Glutamate-Induced Necrosis, Apoptosis, and Tolerance
Authors: Ward Manus W. , Huber Heinrich J. , Weisová Petronela , Düssmann Heiko , Nicholls David G. , Prehn Jochen H. M.
Published: August 2007

A failure of mitochondrial bioenergetics has been shown to be closely associated with the onset of apoptotic and necrotic neuronal injury. Here, we developed an automated computational model that interprets the single-cell fluorescence for tetramethylrhodamine methyl ester (TMRM) as a consequence of changes in either ΔΨmor ΔΨp, thus allowing for the characterization of responses for populations of single cells and subsequent statistical analysis. Necrotic injury triggered by prolonged glutamate excitation resulted in a rapid monophasic or biphasic loss of ΔΨmthat was closely associated with a loss of ΔΨpand a rapid decrease in neuronal NADPH and ATP levels. Delayed apoptotic injury, induced by transient glutamate excitation, resulted in a small, reversible decrease in TMRM fluorescence, followed by a sustained hyperpolarization of ΔΨmas confirmed using the ΔΨp-sensitive anionic probe DiBAC2(3). This hyperpolarization of ΔΨmwas closely associated with a significant increase in neuronal glucose uptake, NADPH availability, and ATP levels. Statistical analysis of the changes in ΔΨmor ΔΨpat a single-cell level revealed two major correlations; those neurons displaying a more pronounced depolarization of ΔΨpduring the initial phase of glutamate excitation entered apoptosis more rapidly, and neurons that displayed a more pronounced hyperpolarization of ΔΨmafter glutamate excitation survived longer. Indeed, those neurons that were tolerant to transient glutamate excitation (18%) showed the most significant increases in ΔΨm. Our results indicate that a hyperpolarization of ΔΨmis associated with increased glucose uptake, NADPH availability, and survival responses during excitotoxic injury.
Chronic Glucocorticoids Increase Hippocampal Vulnerability to Neurotoxicity under Conditions That Produce CA3 Dendritic Retraction But Fail to Impair Spatial Recognition Memory
Authors: Conrad Cheryl D. , McLaughlin Katie J. , Harman James S. , Foltz Cainan , Wieczorek Lindsay , Lightner Elizabeth , Wright Ryan L.
Published: August 2007

We previously found that chronic stress conditions producing CA3 dendritic retraction and spatial memory deficits make the hippocampus vulnerable to the neurotoxin ibotenic acid (IBO). The purpose of this study was to determine whether exposure to chronic corticosterone (CORT) under conditions that produce CA3 dendritic retraction would enhance CA3 susceptibility to IBO. Male Sprague Dawley rats were chronically treated for 21 d with CORT in drinking water (400 μg/ml), and half were given daily injections of phenytoin (40 mg/kg), an antiepileptic drug that prevents CA3 dendritic retraction. Three days after treatments stopped, IBO was infused into the CA3 region. Conditions producing CA3 dendritic retraction (CORT and vehicle) exacerbated IBO-induced CA3 damage compared with conditions in which CA3 dendritic retraction was not observed (vehicle and vehicle, vehicle and phenytoin, CORT and phenytoin). Additionally, spatial recognition memory was assessed using the Y-maze, revealing that conditions producing CA3 dendritic retraction failed to impair spatial recognition memory. Furthermore, CORT levels in response to a potentially mild stressor (injection and Y-maze exposure) stayed at basal levels and failed to differ among key groups (vehicle and vehicle, CORT and vehicle, CORT and phenytoin), supporting the interpretations that CORT levels were unlikely to have been elevated during IBO infusion and that the neuroprotective actions of phenytoin were not through CORT alterations. These data are the first to show that conditions with prolonged glucocorticoid elevations leading to structural changes in hippocampal dendritic arbors can make the hippocampus vulnerable to neurotoxic challenges. These findings have significance for many disorders with elevated glucocorticoids that include depression, schizophrenia, Alzheimer's disease, and Cushing's disease.
Chronic Nicotine Cell Specifically Upregulates Functional α4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path
Authors: Nashmi Raad , Xiao Cheng , Deshpande Purnima , McKinney Sheri , Grady Sharon R. , Whiteaker Paul , Huang Qi , McClure-Begley Tristan , Lindstrom Jon M. , Labarca Cesar , Collins Allan C. , Marks Michael J. , Lester Henry A.
Published: August 2007

Understanding effects of chronic nicotine requires identifying the neurons and synapses whose responses to nicotine itself, and to endogenous acetylcholine, are altered by continued exposure to the drug. To address this problem, we developed mice whose α4 nicotinic receptor subunits are replaced by normally functioning fluorescently tagged subunits, providing quantitative studies of receptor regulation at micrometer resolution. Chronic nicotine increased α4 fluorescence in several regions; among these, midbrain and hippocampus were assessed functionally. Although the midbrain dopaminergic system dominates reward pathways, chronic nicotine does not change α4* receptor levels in dopaminergic neurons of ventral tegmental area (VTA) or substantia nigra pars compacta. Instead, upregulated, functional α4* receptors localize to the GABAergic neurons of the VTA and substantia nigra pars reticulata. In consequence, GABAergic neurons from chronically nicotine-treated mice have a higher basal firing rate and respond more strongly to nicotine; because of the resulting increased inhibition, dopaminergic neurons have lower basal firing and decreased response to nicotine. In hippocampus, chronic exposure to nicotine also increases α4* fluorescence on glutamatergic axons of the medial perforant path. In hippocampal slices from chronically treated animals, acute exposure to nicotine during tetanic stimuli enhances induction of long-term potentiation in the medial perforant path, showing that the upregulated α4* receptors in this pathway are also functional. The pattern of cell-specific upregulation of functional α4* receptors therefore provides a possible explanation for two effects of chronic nicotine: sensitization of synaptic transmission in forebrain and tolerance of dopaminergic neuron firing in midbrain.
Control of Chronic Pain by the Ubiquitin–Proteasome System in the Spinal Cord
Authors: Ossipov Michael H. , Bazov Igor , Gardell Luis R. , Kowal Justin , Yakovleva Tatiana , Usynin Ivan , Ekström Tomas J. , Porreca Frank , Bakalkin Georgy
Published: August 2007

Chronic pain is maintained in part by long-lasting neuroplastic changes in synapses and several proteins critical for synaptic plasticity are degraded by the ubiquitin–proteasome system (UPS). Here, we show that proteasome inhibitors administered intrathecally or subcutaneously prevented the development and reversed nerve injury-induced pain behavior. They also blocked pathological pain induced by sustained administration of morphine or spinal injection of dynorphin A, an endogenous mediator of chronic pain. Proteasome inhibitors blocked mechanical allodynia and thermal hyperalgesia in all three pain models although they did not modify responses to mechanical stimuli, but partially inhibited responses to thermal stimuli in control rats. In the spinal cord, these compounds abolished the enhanced capsaicin-evoked calcitonin gene-related peptide (CGRP) release and dynorphin A upregulation, both elicited by nerve injury. Model experiments demonstrated that the inhibitors may act directly on dynorphin-producing cells, blocking dynorphin secretion. Thus, the effects of proteasome inhibitors on chronic pain were apparently mediated through several cellular mechanisms indispensable for chronic pain, including those of dynorphin A release and postsynaptic actions, and of CGRP secretion. Levels of several UPS proteins were reduced in animals with neuropathic pain, suggesting that UPS downregulation, like effects of proteasome inhibitors, counteracts the development of chronic pain. The inhibitors did not produce marked or disabling motor disturbances at doses that were used to modify chronic pain. These results suggest that the UPS is a critical intracellular regulator of pathological pain, and that UPS-mediated protein degradation is required for maintenance of chronic pain and nociceptive, but not non-nociceptive responses in normal animals.
Intentionality and Expertise: Learning from Observations of Children at Play in Multilingual, Multicultural Contexts
Authors: Long Susi
Published: August 2007

This article draws from three ethnographic studies of children playing sociodramatically in multilingual, multicultural contexts. Countering a deficit perspective that focuses on what children from nondominant cultures do not know, we use the concept of syncretism to illuminate children's expertise and intentionality as they blend knowledge from multiple worlds to reinvent cultural practices and create new spaces for learning. Findings encourage educators to learn from the syncretic nature of children's teaching and learning through play.
Male Development Time Influences the Strength of Wolbachia-Induced Cytoplasmic Incompatibility Expression inDrosophila melanogaster
Authors: Yamada Ryuichi , Floate Kevin D , Riegler Markus , O'Neill Scott L
Published: July 2007

Cytoplasmic incompatibility (CI) is the most widespread reproductive modification induced in insects by the maternally inherited intracellular bacteria, Wolbachia. Expression of CI in Drosophila melanogaster is quite variable. Published papers typically show that CI expression is weak and often varies between different Drosophila lines and different labs reporting the results. The basis for this variability is not well understood but is often considered to be due to unspecified host genotype interactions with Wolbachia. Here, we show that male development time can greatly influence CI expression in D. melanogaster. In a given family, males that develop fastest express very strong CI. The “younger brothers” of these males (males that take longer to undergo larval development) quickly lose their ability to express the CI phenotype as a function of development time. This effect is independent of male age effects and is enhanced when flies are reared under crowded conditions. No correlation is seen between this effect and Wolbachia densities in testes, suggesting that a more subtle interaction between host and symbiont is responsible. The observed younger brother effect may explain much of the reported variability in CI expression in this species. When male development time is controlled, it is possible to obtain consistently high levels of CI expression, which will benefit future studies that wish to use D. melanogaster as a model host to unravel CI mechanisms.
Age Specificity of Inbreeding Load inDrosophila melanogasterand Implications For the Evolution of Late-Life Mortality Plateaus
Authors: Reynolds Rose M , Temiyasathit Sara , Reedy Melissa M , Ruedi Elizabeth A , Drnevich Jenny M , Leips Jeff , Hughes Kimberly A
Published: July 2007

Current evolutionary theories explain the origin of aging as a byproduct of the decline in the force of natural selection with age. These theories seem inconsistent with the well-documented occurrence of late-life mortality plateaus, since under traditional evolutionary models mortality rates should increase monotonically after sexual maturity. However, the equilibrium frequencies of deleterious alleles affecting late life are lower than predicted under traditional models, and thus evolutionary models can accommodate mortality plateaus if deleterious alleles are allowed to have effects spanning a range of neighboring age classes. Here we test the degree of age specificity of segregating alleles affecting fitness in Drosophila melanogaster. We assessed age specificity by measuring the homozygous fitness effects of segregating alleles across the adult life span and calculated genetic correlations of these effects across age classes. For both males and females, we found that allelic effects are age specific with effects extending over 1–2 weeks across all age classes, consistent with modified mutation-accumulation theory. These results indicate that a modified mutation-accumulation theory can both explain the origin of senescence and predict late-life mortality plateaus.
A Selective Sweep in the Chloroplast DNA of Dioecious Silene (SectionElisanthe)
Authors: Muir Graham , Filatov Dmitry
Published: July 2007

Gene flow occurs predominantly via pollen in angiosperms, leading to stronger population subdivision for maternally inherited markers, relative to paternally or biparentally inherited genes. In contrast to this trend, population subdivision within Silene latifolia and S. dioica, as well as subdivision between the two species, is substantially lower in maternally inherited chloroplast genes compared to paternally inherited Y-linked genes. A significant frequency spectrum bias toward rare polymorphisms and a significant loss of polymorphism in chloroplast genes compared to Y-linked and autosomal genes suggest that intra- and inter-specific subdivision in the chloroplast DNA may have been eroded by a selective sweep that has crossed the S. latifolia and S. dioica species boundary.