bluuebunny/crossref_metadata_2025 huggingface dataset:
Lidocaine reduces the transition to slow inactivation in Nav1.7 voltage‐gated sodium channels
Authors: Sheets Patrick L , Jarecki Brian W , Cummins Theodore R
Published: January 2011

BACKGROUND AND PURPOSEThe primary use of local anaesthetics is to prevent or relieve pain by reversibly preventing action potential propagation through the inhibition of voltage‐gated sodium channels. The tetrodotoxin‐sensitive voltage‐gated sodium channel subtype Nav1.7, abundantly expressed in pain‐sensing neurons, plays a crucial role in perception and transmission of painful stimuli and in inherited chronic pain syndromes. Understanding the interaction of lidocaine with Nav1.7 channels could provide valuable insight into the drug's action in alleviating pain in distinct patient populations. The aim of this study was to determine how lidocaine interacts with multiple inactivated conformations of Nav1.7 channels.

EXPERIMENTAL APPROACHWe investigated the interactions of lidocaine with wild‐type Nav1.7 channels and a paroxysmal extreme pain disorder mutation (I1461T) that destabilizes fast inactivation. Whole cell patch clamp recordings were used to examine the activity of channels expressed in human embryonic kidney 293 cells.

KEY RESULTSDepolarizing pulses that increased slow inactivation of Nav1.7 channels also reduced lidocaine inhibition. Lidocaine enhanced recovery of Nav1.7 channels from prolonged depolarizing pulses by decreasing slow inactivation. A paroxysmal extreme pain disorder mutation that destabilizes fast inactivation of Nav1.7 channels decreased lidocaine inhibition.

CONCLUSIONS AND IMPLICATIONSLidocaine decreased the transition of Nav1.7 channels to the slow inactivated state. The fast inactivation gate (domain III–IV linker) is important for potentiating the interaction of lidocaine with the Nav1.7 channel.
Stable expression and functional characterization of a human nicotinic acetylcholine receptor with α6β2 properties: discovery of selective antagonists
Authors: Capelli Anna Maria , Castelletti Laura , Chen Yu Hua , Van der Keyl Harjeet , Pucci Luca , Oliosi Beatrice , Salvagno Cristian , Bertani Barbara , Gotti Cecilia , Powell Andrew , Mugnaini Manolo
Published: January 2011

BACKGROUND AND PURPOSE

Despite growing evidence that inhibition of α6β2‐containing (α6β2*) nicotinic acetylcholine receptors (nAChRs) may be beneficial for the therapy of tobacco addiction, the lack of good sources of α6β2*‐nAChRs has delayed the discovery of α6β2‐selective antagonists. Our aim was to generate a cell line stably expressing functional nAChRs with α6β2 properties, to enable pharmacological characterization and the identification of novel α6β2‐selective antagonists.

EXPERIMENTAL APPROACH

Different combinations of the α6, β2, β3, chimeric α6/3 and mutant β3V273Ssubunits were transfected in human embryonic kidney cells and tested for activity in a fluorescent imaging plate reader assay. The pharmacology of rat immune‐immobilized α6β2*‐nAChRs was determined with125I‐epibatidine binding.

KEY RESULTS

Functional channels were detected after co‐transfection of α6/3, β2 and β3V273Ssubunits, while all other subunit combinations failed to produce agonist‐induced responses. Stably expressed α6/3β2β3V273S‐nAChR pharmacology was unique, and clearly distinct from α4β2‐, α3β4‐, α7‐ and α1β1δε‐nAChRs. Antagonist potencies in inhibiting α6/3β2β3V273S‐nAChRs was similar to their binding affinity for rat native α6β2*‐nAChRs. Agonist affinities for α6β2*‐nAChRs was higher than their potency in activating α6/3β2β3V273S‐nAChRs, but their relative activities were equivalent. Focussed set screening at α6/3β2β3V273S‐nAChRs, followed by cross‐screening with the other nAChRs, led to the identification of novel α6β2‐selective antagonists.

CONCLUSIONS AND IMPLICATIONS

We generated a mammalian cell line stably expressing nAChRs, with pharmacological properties similar to native α6β2*‐nAChRs, and used it to identify novel non‐peptide, low molecular weight, α6β2‐selective antagonists. We also propose a pharmacophore model of α6β2 antagonists, which offers a starting point for the development of new smoking cessation agents.
β2‐adrenoceptor agonists: current and future direction
Authors: Cazzola Mario , Calzetta Luigino , Matera Maria Gabriella
Published: January 2011

Despite the passionate debate over the use of β2‐adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of β2‐adrenoceptor agonists with long half‐lives, also called ultra long‐acting β2‐adrenoceptor agonists (ultra‐LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF‐610355) are currently under development with the hopes of achieving once‐daily dosing. It is likely that the once‐daily dosing of a bronchodilator would be a significant convenience and probably a compliance‐enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long‐acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a β2‐adrenoceptor agonist, some novel once‐daily combinations of LABAs and ICSs or LAMAs are under development.

LINKED ARTICLESThis article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visithttp://dx.doi.org/10.1111/bph.2011.163.issue‐1
Alzheimer's disease & metals: therapeutic opportunities
Authors: Kenche Vijaya B , Barnham Kevin J
Published: January 2011

Alzheimer's disease (AD) is the most common age related neurodegenerative disease. Currently, there are no disease modifying drugs, existing therapies only offer short‐term symptomatic relief. Two of the pathognomonic indicators of AD are the presence of extracellular protein aggregates consisting primarily of the Aβ peptide and oxidative stress. Both of these phenomena can potentially be explained by the interactions of Aβ with metal ions. In addition, metal ions play a pivotal role in synaptic function and their homeostasis is tightly regulated. A breakdown in this metal homeostasis and the generation of toxic Aβ oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Therefore, approaches that are designed to prevent Aβ metal interactions, inhibiting the formation of toxic Aβ species as well as restoring metal homeostasis may have potential as disease modifying strategies for treating AD. This review summarizes the physiological and pathological interactions that metal ions play in synaptic function with particular emphasis placed on interactions with Aβ. A variety of therapeutic strategies designed to address these pathological processes are also described. The most advanced of these strategies is the so‐called ‘metal protein attenuating compound’ approach, with the lead molecule PBT2 having successfully completed early phase clinical trials. The success of these various strategies suggests that manipulating metal ion interactions offers multiple opportunities to develop disease modifying therapies for AD.
Use of cryopreserved autologous cells for extracorporeal photochemotherapy: clinical applications
Authors: Merlin Etienne , Jacomet Florence , D'Incan Michel , Halle Pascale , Berger Marc , Gandemer Virginie , Piguet Chirstophe , Souteyrand Pierre , Deméocq François , Kanold Justyna
Published: January 2011

BACKGROUND: Using autologous cryopreserved mononuclear cells (MNCs) for extracorporeal photochemotherapy (ECP) offers several advantages, such as treating patients from geographically distant care centers or maintaining ECP schedule while dramatically reducing number of apheresis sessions. We previously reported that cryopreserved cells retain their immunomodulatory properties when exposed to UVA and psoralen. To date, there are no clinical data on the use of cryopreserved MNCs for ECP (“cryo‐ECP”).

CASE REPORTS: Three patients were treated by cryo‐ECP for refractory dermatomyositis, juvenile localized scleroderma, and acute graft‐versus‐host disease. For the first two patients, cryo‐ECP aimed to reduce the number of apheresis sessions. Each cell product was split into three equal fractions: one was infused, and the other two were frozen for later infusion. The third patient was referred to our center from a hospital 700 km away. Fifteen apheresis procedures were performed during his stay: 12 were immediately treated and infused while three were cryopreserved. After discharge, the three cryopreserved bags were thawed, ECP‐treated, and then sent back to the patient.

CONCLUSION: In all three patients, cryo‐ECP was safe and feasible. These cases illustrate promising clinical applications of the technique, opening perspectives for making ECP much more acceptable to patients while extending its indications.
Assessment of the Regional Economic Impacts of Catastrophic Events: CGE Analysis of Resource Loss and Behavioral Effects of an RDD Attack Scenario
Authors: Giesecke J. A. , Burns W. J. , Barrett A. , Bayrak E. , Rose A. , Slovic P. , Suher M.
Published: January 2011

We investigate the regional economic consequences of a hypothetical catastrophic event—attack via radiological dispersal device (RDD)—centered on the downtown Los Angeles area. We distinguish two routes via which such an event might affect regional economic activity: (i) reduction in effective resource supply (the resource loss effect) and (ii) shifts in the perceptions of economic agents (the behavioral effect). The resource loss effect relates to the physical destructiveness of the event, while the behavioral effect relates to changes in fear and risk perception. Both affect the size of the regional economy. RDD detonation causes little capital damage and few casualties, but generates substantial short‐run resource loss via business interruption. Changes in fear and risk perception increase the supply cost of resources to the affected region, while simultaneously reducing demand for goods produced in the region. We use results from a nationwide survey, tailored to our RDD scenario, to inform our model values for behavioral effects. Survey results, supplemented by findings from previous research on stigmatized asset values, suggest that in the region affected by the RDD, households may require higher wages, investors may require higher returns, and customers may require price discounts. We show that because behavioral effects may have lingering long‐term deleterious impacts on both the supply‐cost of resources to a region and willingness to pay for regional output, they can generate changes in regional gross domestic product (GDP) much greater than those generated by resource loss effects. Implications for policies that have the potential to mitigate these effects are discussed.
Estimating the Probability of Rare Events: Addressing Zero Failure Data
Authors: Quigley John , Revie Matthew
Published: January 2011

Traditional statistical procedures for estimating the probability of an event result in an estimate of zero when no events are realized. Alternative inferential procedures have been proposed for the situation where zero events have been realized but often these are ad hoc, relying on selecting methods dependent on the data that have been realized. Such data‐dependent inference decisions violate fundamental statistical principles, resulting in estimation procedures whose benefits are difficult to assess. In this article, we propose estimating the probability of an event occurring through minimax inference on the probability that future samples of equal size realize no more events than that in the data on which the inference is based. Although motivated by inference on rare events, the method is not restricted to zero event data and closely approximates the maximum likelihood estimate (MLE) for nonzero data. The use of the minimax procedure provides a risk adverse inferential procedure where there are no events realized. A comparison is made with the MLE and regions of the underlying probability are identified where this approach is superior. Moreover, a comparison is made with three standard approaches to supporting inference where no event data are realized, which we argue are unduly pessimistic. We show that for situations of zero events the estimator can be simply approximated with , where n is the number of trials.
International quotidian dialysis registry: Annual report 2010
Authors: LINDSAY Robert M. , SURI Rita S. , MOIST Louise M. , GARG Amit X. , CUERDEN Meaghan , LANGFORD Sarah , HAKIM Raymond , OFSTHUN Norma J. , MCDONALD Stephen P. , HAWLEY Carmel , CASKEY Ferqus J. , COUCHOUD Cecile , AWARAJI Christian , NESRALLAH Gihad E.
Published: January 2011

The International Quotidian Dialysis Registry (IQDR) is a global initiative designed to study practices and outcomes associated with the use of hemodialysis (HD) regimens of increased frequency and/or duration. The IQDR grew out of the initiative that lead to the randomized prospective studies of nocturnal HD and short hours daily dialysis vs. conventional thrice weekly HD that are conducted by the Frequent Hemodialysis Network sponsored by the National Institutes of Health. These 2 separate studies are drawing to a close and the first results are expected to be reported later this year. These studies use surrogate outcomes for their primary endpoints as they are not powered to look at outcomes of mortality and hospitalization. The IQDR attempts to aggregate long‐term follow‐up data from centers utilizing alternative HD regimens worldwide and will have adequate statistical power to examine those important outcomes. To date, the IQDR has enrolled patients from Canada, the United States, Australia, New Zealand, and France and has linked with commercial databases and national registries. This sixth annual report of the IQDR describes: (1) An update on the governance structure; (2) The recommendations made at the first general meetings of the IQDR Scientific Committee and Advisory Board; (3) The status of those recommendations; (4) A summary of current data sources and participating registries; (5) The status of recruitment to date; (6) The creation of a specific Canadian IQDR data set and; (7) The current research agenda.
The carbon footprints of home and in‐center maintenance hemodialysis in the United Kingdom
Authors: CONNOR Andrew , LILLYWHITE Robert , COOKE Matthew W.
Published: January 2011

Climate change presents a global health threat. However, the provision of healthcare, including dialysis, is associated with greenhouse gas emissions. The aim of this study was to determine the carbon footprints of the differing modalities and treatment regimes used to deliver maintenance hemodialysis (HD), in order to inform carbon reduction strategies at the level of both individual treatments and HD programs. This was a component analysis study adhering to PAS2050. Emissions factors were applied to data that were collected for building energy use, travel and procurement. Thrice weekly in‐center HD has a carbon footprint of 3.8 ton CO2 Eq per patient per year. The majority of emissions arise within the medical equipment (37%), energy use (21%), and patient travel (20%) sectors. The carbon footprint of providing home HD varies with the regime. For standard machines: 4 times weekly (4 days, 4.5 hours), 4.3 ton CO2 Eq; 5 times weekly (5 days, 4 hours), 5.1 ton CO2 Eq; short daily (6 days, 2 hours), 5.2 ton CO2 Eq; nocturnal (3 nightly, 7 hours), 3.9 ton CO2 Eq; and nocturnal (6 nightly, 7 hours), 7.2 ton CO2 Eq. For NxStage equipment: short daily (5.5 days, 3 hours), 1.8 t CO2 Eq; 6 nightly nocturnal (2.1 ton CO2 Eq). The carbon footprint of HD is influenced more by the frequency of treatments than by their duration. The anticipated rise in the prevalence of home HD patients, dialyzing more frequently and for longer than in‐center patients, will increase the emissions associated with HD programs (despite reductions in patient travel emissions). Emerging technologies, such as NxStage, might offer a solution to this problem.
Early Indicators and Risk Factors for Ethical Issues in Clinical Practice
Authors: Pavlish Carol , Brown‐Saltzman Katherine , Hersh Mary , Shirk Marilyn , Nudelman Olga
Published: January 2011

Purpose: Nurses in all clinical settings encounter ethical issues that frequently lead to moral distress. This critical incident study explored nurses’ descriptions of ethically difficult situations to identify risk factors and early indicators of ethical conflicts.

Methods: Employing the critical incident technique, researchers developed a questionnaire that collected information on ethically difficult situations, their risk factors and early indicators, nurse actions, and situational outcomes. Two nurse researchers independently analyzed and categorized data using a constant comparison technique.

Findings: Most of the ethically difficult situations pertained to end‐of‐life care for children and adults. Conflicts in interpersonal relationships were prevalent. Nurses were especially moved by patient and family suffering and concerned about patient vulnerability, harm‐benefit ratio, and patient autonomy. Researchers discovered risk factor categories for patients, families, healthcare providers, and health systems. Additionally, researchers found subcategories in six major categories of early indicators: signs of conflict, patient suffering, nurse distress, ethics violation, unrealistic expectations, and poor communication.

Conclusions: Nurses are keenly aware of pertinent risk factors and early indicators of unfolding ethical conflicts. Many nurses reported feeling powerless in the face of ethical conflict. Research that develops interventions to strengthen nurses’ voices in ethically difficult situation is warranted.

Clinical Relevance: Nurses are in a key position to identify patient situations with a high risk for ethical conflict. Initiating early ethics consultation and interventions can alter the course of pending conflicts and diminish the potential for patient and family suffering and nurses’ moral distress.
An enzymatic mechanism for generating the precursor of endogenous 13‐cisretinoic acid in the brain
Authors: Takahashi Yusuke , Moiseyev Gennadiy , Chen Ying , Farjo Krysten , Nikolaeva Olga , Ma Jian‐Xing
Published: January 2011

13‐cisRetinoic acid (13cRA), a stereoisomeric form of retinoic acid, is naturally generated in the body and is also used clinically to treat acute promyelocytic leukemia, some skin diseases and cancer. Furthermore, it has been suggested that 13cRA modulates brain neurochemical systems because increased 13cRA levels are correlated with depression and increased suicidal tendencies. However, the mechanism for the generation of endogenous 13cRA is not well understood. The present study identified and characterized a novel enzyme in zebrafish brain, 13‐cisisomerohydrolase (13cIMH) (EC 5.2.1.7), which exclusively generated 13‐cisretinol and can be oxidized to 13cRA. 13cIMH shares 74% amino acid sequence identity with human retinal pigment epithelium specific 65 kDa protein (RPE65), an 11‐cisisomerohydrolase in the visual cycle, and retains the key residues essential for the isomerohydrolase activity of RPE65. Similar to RPE65, 13cIMH is a membrane‐associated protein, requires all‐transretinyl ester as its intrinsic substrate, and its enzymatic activity is dependent on iron. The purified 13cIMH converted all‐transretinyl ester exclusively to 13‐cisretinol withKm = 2.6 μmandkcat = 4.4 × 10−4·s−1. RT‐PCR, western blot analysis and immunohistochemistry detected 13cIMH expression in the brain. These results suggest that 13cIMH may play a key role in the generation of 13cRA, as well as in the modulation of neuronal functions in the brain.
Intermittent Androgen Suppression in Prostate Cancer: Testosterone Levels and its Implication
Authors: Mearini Luigi , Zucchi Alessandro , Costantini Elisabetta , Bini Vittorio , Porena Massimo
Published: January 2011

Introduction

Intermittent androgen suppression (IAS) in patients affected by prostate cancer seems to lessen the severity of the side effects that are associated with continuous androgen ablation.

Aim

This report monitors the effect of IAS on testosterone values, quality of life, and sexual function during phases of therapy.

Methods

A total of 100 patients entered a prospective study of IAS. Androgen blockade was prolonged until a serum prostate specific antigen (PSA) nadir was reached and then resumed for a PSA threshold of 10 ng/mL, in repeated cycles. During I phase, we assessed testosterone levels, well-being with quality-of-life score, and sexual function.

Main Outcome Measures

All patients were followed up every 3 months with PSA and total testosterone determinations, and with quality-of-life score using a 10-point questionnaire. Side effects were assessed using yes/no questions. Sexual function was assessed using yes/no questions and in the sexually active patients with International Index of Erectile Function-5 (IIEF).

Results

All patients completed I cycle of treatment (I ON plus I OFF phase). During the OFF phase, 46% of patients showed low testosterone levels, while the others recovered normal testosterone concentrations at a mean of 6.2 months after therapy. There is a negative correlation between baseline PSA values and length of OFF phase and testosterone recovery, and a negative correlation between length of OFF phase and testosterone value during OFF phase. Worsening in Quality of Life (QOL) was significant during active treatment with respect to baseline, but therapy withdrawal showed a positive impact with respect to treatment period. Improvement in quality of life correlated to testosterone recovery and time to testosterone recovery. Fifty-four percent of subjects had normal sexual intercourse at therapy withdrawal, with a correspondence to time to testosterone recovery.

Conclusions

Quality of life and sexual function seem to follow testosterone normalization. These results could have implications in the analysis of IAS.
Development and Validation of Chinese Version of Female Sexual Function Index in a Chinese Population—A Pilot Study
Authors: Sun Xiaoguang , Li Chunying , Jin Lina , Fan Yangjun , Wang Dongmei
Published: January 2011

Introduction

Female sexual dysfunction (FSD) is a prevalent problem that has been continuously overlooked in mainland China. An assessment instrument for FSD is urgently needed.

Aim

To develop and validate the Chinese version of the Female Sexual Function Index (CVFSFI) to assess FSD in China.

Methods

A total of 328 women (20–65 years old) participated in this study. The CVFSFI was developed through the procedures of translation, back translation, revision by research team, and pilot study. After an interview for clinical diagnosis of FSD based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria, all participants completed the CVFSFI for a validation study. Eighty-three women completed CVFSFI again 3–4 weeks after the first visit. Test–retest reliability was determined by Pearson product–moment correlations. Internal consistency reliability was estimated with Cronbach’s alpha coefficient. Construct validity was evaluated by principal component analysis using varimax rotation. Discriminant validity was assessed with between-groups analysis of variance.

Main Outcome Measures

Including the reliability and the validity of the CVFSFI and its domains.

Results

A total of 172 women (52.4%) met the DSM-IV-TR criteria for diagnosis of sexual dysfunction and were included in the FSD group, while 156 (47.6%) women without FSD were included in the control group. We showed that the overall test–retest reliability coefficients were high for total CVFSFI and each domain (r at least 0.69) and the internal consistency reliability of CVFSFI was within the acceptable range (Cronbach’s alpha values: from 0.69 to 0.94). Moreover, the principal component analysis with varimax rotation produced six-factor structure similar to the original FSFI. We found significant differences in both total and domain scores between FSD and control groups, demonstrating a good discriminant validity of CVFSFI.

Conclusion

The CVFSFI is a reliable and valid questionnaire, which can be used in the assessment of FSD among Chinese women.
Relationship between Premature Ejaculation and Depression in Korean Males
Authors: Son Hwancheol , Song Sang Hoon , Lee Jun-Young , Paick Jae-Seung
Published: January 2011

Introduction

The psychological impacts of premature ejaculation (PE), which include guilt, anxiety, and distress, have been well established in Western countries. However, in Asia, although a substantial number of epidemiological studies have surveyed the prevalence of PE, researchers have not thoroughly investigated the relationship between PE and depression, or have defined PE properly.

Aim

We studied the association between PE and depression and other psychological disturbances, in a Korean cohort by applying an appropriate definition for PE and validated outcome measures of depression.

Methods

A total of 956 males (≥20 years) were initially approached via an Internet survey company. Participants were asked to complete a questionnaire requesting detailed medical and sexual histories, which included questions from the Erectile Function Domain score in the International Index of Erectile Function (IIEF-EF) and the Beck Depression Inventory (BDI). The prevalence of PE was evaluated using two different definitions—self-assessed PE and presumed PE. Presumed PE was defined as a short ejaculation time (an estimated intravaginal ejaculatory latency time ≤5 minutes), an inability to control ejaculation, and the presence of distress resulting from PE.

Main Outcome Measures

Ejaculation-related questionnaire, the IIEF-EF, and BDI.

Results

A total of 334 men were evaluated. The prevalence of PE was 10.5% according to the Presumed PE definition, whereas by self-assessment, it was 25.4%. Self-assessed PE patients suffered from various psychological problems, such as depression, low self-esteem, bother, and low sexual satisfaction. Even after excluding erectile dysfunction (ED) subjects, a significant relationship was found between self-assessed PE and depression. Moreover, after further classification of the Self-assessed PE group, we found that subjects included in this group, but not in the Presumed PE group, suffered more from psychological burden than any other members of the cohort.

Conclusion

Korean men with subjective perceptions of PE are prone to various psychological problems, which include depression.
Three Phases of Corporal Tracing Elicited by Electrical Field Stimulation on Rabbit Corpus Cavernosum Smooth Muscle in Penile Perfusion Model
Authors: Zhao Chen , Cho Kyung Woo , Park Jong Kwan
Published: January 2011

Introduction

Nitric oxide (NO) has been shown to mediate electrical field stimulation (EFS)-caused smooth muscle relaxation. It is known that the neural control of penile erection involves adrenergic, cholinergic, and non-adrenergic-non-cholinergic (NANC) neuro-effector systems; however, the effects of EFS on adrenergic and cholinergic nerves are not clear.

Aims

To elucidate EFS-induced signal transductions involved in adrenergic, cholinergic, and NANC neuro-effector systems by using an in vitro penile perfusion model.

Methods

EFS was performed on penile corpus cavernosum smooth muscle from male New Zealand White rabbits, which was pre-contracted with L-phenylephrine (10 µM). We investigated the penile tracing elicited by EFS on tissues pre-incubated with guanethidine (Guan, 50 µM), tetrodotoxin (TTX, 10 µM), Nω nitro-L-arginine-methyl ester (L-NAME, 1 mM), atropine (50 µM), or eserine (10 µM).

Main Outcome Measures

The time-to-peak of each phase, the percentage of relaxation, and the area under the curve (AUC).

Results

We discovered an extraordinary phenomenon: three distinct phases elicited by EFS. Phase I was abolished by L-NAME. Phase II was decreased by eserine and Guan, but increased by L-NAME. Phase III was abolished by atropine, but enhanced by eserine and Guan. TTX diminished all three phases. The time to reach the top of phase I was delayed by TTX. The time to attain the peak of phase II was shortened by L-NAME, but delayed by TTX and atropine. The time to reach the top of phase III was shortened by L-NAME, eserine, and Guan. AUC was significantly decreased by L-NAME and TTX.

Conclusions

EFS stimulated adrenergic, cholinergic, and NANC neuro-effector systems simultaneously. Phase I was related to the NO pathway. Phase II was multiply affected by self-recovery properties, and adrenergic and cholinergic nerves. Phase III was related to cholinergic nerves. The corporal tracing elicited by EFS was the balanced result of multiple factors.
Preparation and Characterization of PLLA/CaSiO3/Apatite Composite Films
Authors: Yu Huixian , Ning Congqin , Lin Kaili , Chen Lei
Published: January 2011

CaSiO3/apatite composites prepared by a biomimetic method were used to fabricate Poly‐l‐lactic acid (PLLA)/CaSiO3/apatite composite films via a solvent evaporation technique. The in vitro bioactivity and mechanical properties of the films were investigated. The results suggested that the composition and particle size of the CaSiO3/apatite composites were dominated by the powder/solution ratio used during the immersion. The ability of the films to form apatite in vitro was dependent on the β‐CaSiO3 content. The introduction of inorganic components into the PLLA matrix resulted in a significant drop in tensile strength, while better dispersion and more apatite content enhanced the tensile strength.
New Uses for Old Drugs: Pharmacophore‐Based Screening for the Discovery of P‐Glycoprotein Inhibitors
Authors: Palmeira Andreia , Rodrigues Freddy , Sousa Emília , Pinto Madalena , Vasconcelos M. Helena , Fernandes Miguel X.
Published: January 2011

P‐glycoprotein (P‐gp) is one of the best characterized transporters responsible for the multidrug resistance phenotype exhibited by cancer cells. Therefore, there is widespread interest in elucidating whether existing drugs are candidate P‐gp substrates or inhibitors. With this aim, a pharmacophore model was created based on known P‐gp inhibitors and it was used to screen a database of existing drugs. The P‐gp modulatory activity of the best hits was evaluated by several methods such as the rhodamine‐123 accumulation assay using K562Dox cell line, and a P‐gp ATPase activity assay. The ability of these compounds to enhance the cytotoxicity of doxorubicin was assessed with the sulphorhodamine‐B assay. Of the 21 hit compounds selectedin silico, 12 were found to significantly increase the intracellular accumulation of Rhodamine‐123, a P‐gp substrate. In addition, amoxapine and loxapine, two tetracyclic antidepressant drugs, were discovered to be potent non‐competitive inhibitors of P‐gp, causing a 3.5‐fold decrease in the doxorubicin GI50in K562Dox cell line. The overall results provide important clues for the non‐label use of known drugs as inhibitors of P‐gp. Potent inhibitors with a dibenzoxazepine scaffold emerged from this study and they will be further investigated in order to develop new P‐gp inhibitors.
The descent of memory T cells
Authors: Gerlach Carmen , van Heijst Jeroen W.J. , Schumacher Ton N.M.
Published: January 2011

Our T cell repertoire is shaped by antigen encounter. From a naive T cell pool that contains millions of different T cells with unknown specificities, pathogen infection leads to selection of those T cells that can detect pathogen‐derived antigens. Following clearance of infection, a population of memory T cells remains and protects the individual from severe reinfection. A central question in the field has been how the generation of long‐lived memory T cells, versus short‐lived (“terminally differentiated”) T cells, is controlled. In this review we discuss the models that have been put forward to explain the generation of memory T cells after infection and the experimental evidence supporting these hypotheses. Based on the available data we propose a new model that stipulates that during immune responses T cells do not acquire different fates that determine their subsequent long‐term survival but rather T cells assume different states that simply reflect the likelihood of future survival, states that can still be modulated by external signals.
GGR Biennial Review: Advances in Laser Ablation and Solution ICP‐MS from 2008 to 2009 with Particular Emphasis on Sensitivity Enhancements, Mitigation of Fractionation Effects and Exploration of New Applications
Authors: Arevalo Ricardo , Bellucci Jeremy , McDonough William F.
Published: January 2011

Recent developments from 2008 to 2009 in ICP‐MS engineering, methods and applications are reviewed here. Of particular emphasis are advances in: (a) maximising sensitivity and reducing elemental/isotopic fractionation during laser ablation processing; (b) developing new analytical techniques to measure major, minor and trace element abundances without depending on matrix‐matched calibrating materials, pre‐determined internal standard concentrations and/or multiple analytical methods; (c) applying in situ and solution‐based ICP‐MS techniques to the analysis of forensic materials for criminal and/or nuclear investigations; and (d) improving precision and limits of detection of laser ablation multi‐collector ICP‐MS measurements of (ultra) trace elemental and isotopic abundances.
Telomeres as age markers in vertebrate molecular ecology
Authors: DUNSHEA GLENN , DUFFIELD DEBORAH , GALES NICK , HINDELL MARK , WELLS RANDALL S. , JARMAN SIMON N.
Published: January 2011

Chronological age is a fundamental and yet elusive variable in studies of many wild animals. Telomeres are nucleoprotein structures on the ends of chromosomes that change size throughout the life of many animals and because of this property have been advocated as a means to estimate age. In this review, we assess the existing and potential application of using telomeres for age estimation. We argue that there are conceptual and statistical inconsistencies in previous studies and that the basis for telomere change over time is not well understood and affected by several intrinsic and extrinsic process unrelated to chronological time. Furthermore, these processes are likely to vary spatially and temporally for animal populations. We conclude that the current data suggest telomeres should not be used for age estimation. If telomere‐based age estimation is to be used, more work in understanding variability in key processes affecting telomere dynamics and rigorous substantiation via blind testing is needed.
Treatment of diffuse diabetic macular oedema using steroid eye drops
Authors: Nakano Goto Sakiko , Yamamoto Teiko , Kirii Eriko , Abe Sachi , Yamashita Hidetoshi
Published: January 2011

Purpose:  To evaluate the efficacy of treatment of diffuse diabetic macular oedema (DME) with difluprednate ophthalmic emulsion 0.05% (Durezol™) in eyes before vitrectomy.

Methods:  This study enrolled patients with diffuse DME for whom more than 3 months had passed since prior treatment. Nineteen eyes in 15 subjects were treated with difluprednate ophthalmic emulsion 0.05% four times daily for the first month and then twice daily for 2 months (treatment group). As a control group, 22 eyes in 11 subjects with DME were selected from subjects who underwent the steroid responder test.

Results:  In the treatment group, the mean visual acuity (VA) (±SD) was 0.38 ± 0.25 logMAR and mean retinal thickness was 461.1 ± 109.9 μm at baseline. After 1 month of treatment, the mean VA had improved to 0.29 ± 0.25 (Wilcoxon rank‐sum test, p = 0.30), while mean retinal thickness had decreased to 372.1 ± 70.0 μm (p = 0.006). The rate of effective improvement in retinal thickness was 42% and that of VA was 26%. In the control group, changes in neither VA nor retinal thickness were significant.

Conclusions:  Eye drop therapy using difluprednate ophthalmic emulsion 0.05% is a useful and effective treatment modality without surgical intervention or severe side‐effects.
Response of corneal hysteresis and central corneal thickness following clear corneal cataract surgery
Authors: Kandarakis Artemios , Soumplis Vasileios , Karampelas Michalis , Koutroumanos Ioannis , Panos Christos , Kandarakis Stylianos , Karagiannis Dimitrios
Published: January 2011

Purpose:  To evaluate the effect of routine phacoemulsification in corneal viscoelastic properties determined by corneal hysteresis (CH) and central corneal thickness (CCT) and to explore the impact of phaco energy on the above parameters.

Methods:  Forty‐one eyes of 41 patients undergoing cataract surgery were enrolled in this prospective study. CH and CCT were measured preoperatively, 1 day and 1 week postoperatively. CCT measurement was performed using a non‐contact optical pachymeter followed by ocular response analyzer (ORA) examination. Intraoperatively ultrasound time, average phaco power and effective phaco time (EPT) were recorded.

Results:  Mean CH was 10.05 ± 1.86 mmHg preoperatively, 8.25 ± 1.85 mmHg 1 day and 9.12 ± 1.37 mmHg 1 week postoperatively (p < 0.001). The mean CCT was 534 ± 37.33 μm preoperatively, 592.22 ± 46.34 μm 1 day and 563.21 ± 49.84 μm 1 week postoperatively (p < 0.001). CCT and CH were statistically significantly correlated preoperatively (p = 0.01, r = 0.396). This correlation was not sustained on the first postoperative day (p = 0.094, r = 0.265) and was re‐established 1 week postoperatively (p = 0.002, r = 0.568). On the first postoperative day, the CCT increase was positively correlated with EPT (p = 0.009, r = 0.404), which was not found between CH change and EPT.

Conclusion:  Structural corneal alterations following cataract surgery resulted in a statistical change in CH and CCT. These two parameters responded in a different manner that clearly demarcates their different nature. On the first postoperative day, CCT increase was correlated at a statistically significant level with intraoperative EPT. This correlation was not found with CH reduction. Other factors, besides cornea oedema or phacoemulsification energy, could be responsible for this CH modification.
Complement factor H Y402H gene polymorphism and response to intravitreal bevacizumab in exudative age‐related macular degeneration
Authors: Nischler Christian , Oberkofler Hannes , Ortner Christoph , Paikl Doris , Riha Wolfgang , Lang Nora , Patsch Wolfgang , Egger Stefan F.
Published: January 2011

Purpose:  To determine whether different complement factor H (CFH) genotypes play a role in treatment of age‐related macular degeneration (AMD) with intravitreal bevacizumab.

Methods:  In this prospective study, we included 197 patients with exudative AMD and treated with 1.25 mg intravitreal bevacizumab at 6‐week intervals until choroidal neovascularization (CNV) was no longer active. In all patients, ophthalmological examinations, visual acuity, optical coherence tomography (OCT), fundus photography and fluorescein angiography were performed. Single nucleotide polymorphism (SNP) genotyping was performed using restriction fragment length polymorphism (RFLP) analysis of polymerase chain reaction (PCR) products.

Results:  Age, gender and baseline mean visual acuity were similar among the three CFH genotypes. There was no significant difference in underlying lesion type of CNV, lesion size, number of injections or macula thickness. When examining the effect of genotype on post‐treatment visual acuities, we observed a significant worse outcome for distance and reading visual acuity in the CFH 402HH genotype group. The number of patients who lost 3 or more lines in distance and reading visual acuity testing was significantly higher in the CFH 402HH (41%, 46%) genotype group than in patients with the CFH 402YY (28%, 26%) and CFH 402YH (26%, 24%) genotype.

Conclusions:  In addition to the higher risk for exudative AMD in patients with the CFH 402HH genotype that was found in previous studies, our results show that the CFH 402HH genotype also correlates with lower visual acuity outcome after treatment with bevacizumab, suggesting that pharmacogenetics of CFH plays a role in response to treatment of wet AMD.
Comparative study of taurine and tauropyrone: GABA receptor binding, mitochondrial processes and behaviour
Authors: Dzirkale Zane , Pupure Jolanta , Rumaks Juris , Svirskis Simons , Vanina Marija , Mezhapuke Rudolfs , Sile Velga , Fernandes Maria Augusta , Duburs Gunars , Klusa Vija
Published: January 2011

Objectives

Taurine, a sulfur-containing amino acid, has high hydrophilicity and is poorly absorbed. Tauropyrone, a taurine-containing 1,4-dihydropyridine derivative, is suggested to have greater activity than taurine owing to improved physicochemical properties that facilitate delivery of the compound to target cells. The aim of this study was to determine whether the 1,4-dihydropyridine moiety in tauropyrone improves the pharmacological efficacy of taurine in vitro and in vivo.

Methods

The effects of taurine and tauropyrone, as well as of the 1,4-dihydropyridine moiety were compared in in-vitro experiments to determine the binding to GABA receptors and influence on mitochondrial processes (isolated rat liver mitochondria), and in in-vivo tests to assess the influence on behavioural effects caused by the GABA-A receptor ligands, bicuculline, diazepam and ethanol.

Key findings

Unlike taurine, tauropyrone did not display binding activity for the GABA-A receptor, and only taurine (but not tauropyrone) at low doses (0.1, 1.0 and 10 mg/kg) antagonised the bicuculline-induced convulsion effect. Taurine and tauropyrone had no effect on diazepam myorelaxing action, and they both exerted a comparable ‘anti-ethanol’ effect (shortening of the ethanol-sleeping time). Taurine and tauropyrone did not influence processes of mitochondrial bioenergetics.

Conclusions

The action of tauropyrone at the level of the GABA-A receptor differs qualitatively from that of taurine, probably because of its 1,4-dihydropyridine moiety, which may hinder access to the GABA-A receptor GABA site. Tauropyrone does not show improved pharmacological efficacy in in-vitro and in-vivo studies in comparison with taurine.
Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin
Authors: Steyn Minette , N'Da David D , Breytenbach Jaco C , Smith Peter J , Meredith Sandra , Breytenbach Wilma J
Published: January 2011

Objectives

The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains.

Methods

The ethers were synthesized in a one-step process by coupling ethylene glycol moieties of various chain lengths to carbon C-10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine-sensitive (D10) and moderately chloroquine-resistant (Dd2) strains of P. falciparum.

Key findings

The aqueous solubility within each series increased as the ethylene glycol chain lengthened. The IC50 values revealed that all the derivatives were active against both D10 and Dd2 strains. All were less potent than artemether irrespective of the strain. However, they proved to be more potent than chloroquine against the resistant strain. Compound 8, featuring three ethylene oxide units, was the most active of all the synthesized ethers.

Conclusions

The conjugation of dihydroartemisinin to ethylene glycol units of various chain lengths through etheral linkage led to water-soluble derivatives. The strategy did not result in an increase of antimalarial activity compared with artemether. It is nevertheless a promising approach to further investigate and synthesize water-soluble derivatives of artemisinin that may be more active than artemether by increasing the ethylene glycol chain length.
Ameliorative effects of glycyrrhizin on streptozotocin-induced diabetes in rats
Authors: Sen Subhrojit , Roy Moumita , Chakraborti Abhay Sankar
Published: January 2011

Objectives

Glycyrrhizin is the main water-soluble constituent of the root of liquorice (Glycyrrhiza glabra). The study investigates the effect of glycyrrhizin on streptozotocin (STZ)-induced diabetic changes and associated oxidative stress, including haemoglobin-induced free iron-mediated oxidative reactions.

Methods

Male Wistar rats were grouped as normal control, STZ-induced diabetic control, normal treated with glycyrrhizin, diabetic treated with glycyrrhizin and diabetic treated with a standard anti-hyperglycaemic drug, glibenclamide. Different parameters were studied in blood and tissue samples of the rats.

Key findings

Glycyrrhizin treatment improved significantly the diabetogenic effects of STZ, namely enhanced blood glucose level, glucose intolerant behaviour, decreased serum insulin level including pancreatic islet cell numbers, increased glycohaemoglobin level and enhanced levels of cholesterol and triglyceride. The treatment significantly reduced diabetes-induced abnormalities of pancreas and kidney tissues. Oxidative stress parameters, namely, serum superoxide dismutase, catalase, malondialdehyde and fructosamine in diabetic rats were reverted to respective normal values after glycyrrhizin administration. Free iron in haemoglobin, iron-mediated free radical reactions and carbonyl formation in haemoglobin were pronounced in diabetes, and were counteracted by glycyrrhizin. Effects of glycyrrhizin and glibenclamide treatments appeared comparable.

Conclusion

Glycyrrhizin is quite effective against hyperglycaemia, hyperlipidaemia and associated oxidative stress, and may be a potential therapeutic agent for diabetes treatment.
The extent of the uptake of plasmid into the skin determines the immune responses induced by a DNA vaccine applied topically onto the skin
Authors: Yu Zhen , Chung Woon-Gye , Sloat Brian R , Löhr Christiane V , Weiss Richard , Rodriguez B Leticia , Li Xinran , Cui Zhengrong
Published: January 2011

Objectives

Non-invasive immunization by application of plasmid DNA topically onto the skin is an attractive immunization approach. However, the immune responses induced are generally weak. Previously, we showed that the antibody responses induced by topical DNA vaccine are significantly enhanced when hair follicles in the application area are induced into the anagen (growth) stage by hair plucking. In the present study, we further investigated the mechanism of immune enhancement.

Methods

Three different methods – hair plucking or treatment with retinoic acid (RA) or O-tetradecanoylphorbol-13-acetate (TPA) – were used to induce mice hair follicles into the anagen stage before they were dosed with a β-galactosidase-encoding plasmid, and the specific antibody responses induced were evaluated.

Key findings

The hair-plucking method was more effective at enhancing the resultant antibody responses. Treatment with RA or TPA caused more damage to the skin and induced more severe local inflammation than hair plucking. However, hair plucking was most effective at enhancing the uptake or retention of the DNA in the application area.

Conclusions

The uptake of plasmid DNA in the application area correlated with the antibody responses induced by a topically applied DNA.