bluuebunny/crossref_metadata_2025 huggingface dataset:
Promoting Appropriate Drug Use Through the Application of the Spanish Drug-Related Problem Classification System in the Primary Care Setting
Authors: Gómez Marciana Alodia , Villafaina Antonio , Hernández Jesús , Salgado Rosa María , González Miguel Ángel , Rodríguez Jesús , Concha Manuel Martínez de la , Tarriño Alejandra , Gervasini Guillermo , Carrillo Juan Antonio
Published: February 2009

Background:

According to the Second Consensus of Granada (2002), the term drug-related problem (DRP) is defined as a health problem resulting from pharmacotherapy and is considered a negative clinical outcome (ie, a therapeutic objective is not achieved or adverse effects are reported). DRP classification systems used in primary care settings can be useful tools to detect, evaluate, and resolve DRPs.

Objective:

To encourage appropriate drug use in the ambulatory clinical setting through DRP detection and evaluation by means of the Spanish DRP classification system, and to document how pharmacists can help resolve DRPs through interventions with both general practitioners (GPs) and patients.

Methods:

Four pharmacists investigated DRPs in polymedicated patients over a 6-month period. All detected DRPs were grouped into 3 major categories: necessity, effectiveness, and safety. To resolve DRPs, pharmacists performed interventions on GPs and patients. GPs received verbal and written information about DRPs; patient interventions were in the form of private meetings on health education.

Results:

Four hundred twenty-two patients, 80% of whom were aged 65 years or older, were included in the study. Each patient was taking a mean ± SD of 8.1 ± 2.4 medications. Three hundred four medications were associated with 245 DRPs; medications indicated for digestive/metabolic or cardiovascular pathologies were the most prevalent. Most (60%) of the identified DRPs belonged to the effectiveness category, whereas safety issues accounted for 28.6%. The most frequently reported DRP was pathology resistant to treatment (19.6%), followed by nonadherence (16.3%). Of the 215 interventions carried out to resolve these DRPs, 173 (80.5%) were addressed to GPs, who agreed to change therapy regimens on 90.2% of the occasions. Forty-two (19.5%) interventions were addressed to patients. Furthermore, the interventions accepted by GPs and patients resolved 176 (82%) DRPs.

Conclusions:

The current Spanish DRP classification system is a useful tool to systematically detect and document DRPs in daily general practice, in addition, the interventions addressed by pharmacists to GPs and patients resolved most of the detected DRPs.
Identification and Evaluation of Pharmacists' Commonly Used Drug Information Sources
Authors: Wong Peck-Sze Jacqueline , Ko Yu , Sklar Grant E
Published: February 2009

Background:

Given the rate at which new medications are introduced to the market, as well as the diversity of existing drugs, pharmacists frequently need to consult drug information (Dl) sources. Currently, there is a lack of information about pharmacists' needs for and sources of DI in Singapore.

Objective:

To examine where practicing pharmacists in Singapore usually obtain DI and how useful and satisfactory the source is to pharmacists and to determine the kind of drug-related questions pharmacists usually receive.

Methods:

An online survey was sent to registered hospital and community pharmacists who were members of the Pharmaceutical Society of Singapore. The survey consisted of questions about the pharmacists' demographics, what DI source they used most often, their satisfaction with that DI source, and how frequently they received various DI questions.

Results:

A total of 156 pharmacists responded to the survey, for a response rate of 27.4%. The majority (82.7%) of the respondents chose reference texts as their most commonly used DI source; of these, 38.0% used the Drug Information Handbook. Reference texts were mostly rated very comprehensive (34.1%) or somewhat comprehensive (54.3%), whereas Web sites or search engines were mostly rated somewhat comprehensive (69.6%) or brief (21.7%). Most pharmacists believed that the information from reference texts could usually (51.2%) or always (48.8%) be trusted. Community pharmacists received questions on over-the-counter drugs and comparisons of drug efficacy more frequently than did hospital pharmacists (p < 0.001 and p = 0.001, respectively), whereas hospital pharmacists more frequently received questions on pharmacokinetics (p = 0.001).

Conclusions:

Most pharmacists in Singapore use reference texts when searching for general DI, and they find these texts more comprehensive and trustworthy than other available sources. The results also show that pharmacists in different settings receive different types of DI questions and have adequate resources to answer general DI questions.
Clinical Utility of Rituximab in Chronic Graft-Versus-Host Disease
Authors: Bates Jill S , Engemann Ashley Morris , Hammond Julia M
Published: February 2009

Objective:

To evaluate the use of rituximab in the clinical management of steroid-refractory chronic graft-versus-host disease (GVHD).

Data Sources:

Literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1990–September 2008), both indexed and nonindexed citations, using the terms rituximab, graft-versus-host disease, monoclonal antibodies, and CD20. In addition, reference citations from the publications identified were reviewed.

Study Selection and Data Extraction:

All articles discussing rituximab as a therapeutic option in the treatment of GVHD that were published in English and enrolled human study participants were evaluated.

Data Synthesis:

Rituximab is a genetically engineered chimeric murine monoclonal antibody that binds to the CD20 differentiation antigen found on B-lymphocytes. GVHD is the leading cause of procedural-related morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Chronic GVHD (cGVHD) occurs in up to 70% of individuals undergoing HSCT, and approximately 40% of those patients are refractory to conventional T-lymphocyte–directed therapies. Limited treatments are available for individuals with steroid-refractory cGVHD. Rituximab therapy in individuals with extensive cGVHD has demonstrated clinical efficacy with manageable toxicities in retrospective and prospective studies.

Conclusions:

Available data suggest that rituximab is a treatment option for patients with extensive steroid-refractory cGVHD. Rituximab may be particularly effective for individuals with steroid-refractory cGVHD manifesting as thrombocytopenia or with sclerodermatous, cutaneous, and rheumatologic involvement.
Use of Hormone Replacement Therapy, 1998–2007: Sustained Impact of the Women's Health Initiative Findings
Authors: Silverman Barbara G , Kokia Ehud S
Published: February 2009

Background:

Trials of hormone replacement therapy (HRT) for prevention of chronic disease in postmenopausal women have suggested that the risks of treatment outweigh the benefits. The publication in 2002 of the Women's Health Initiative (WHI) study sparked a rapid decline in HRT purchases among American women.

Objective:

To examine the impact of the WHI findings on patterns of HRT use in Israeli women.

Methods:

We linked purchases of estrogen preparations from 1998 to 2007 by female Israeli health maintenance organization members aged 45 years and older to membership data. For each year, we calculated total annual purchases and rate of HRT utilization, characterized new users by age and mode of therapy, and examined rates of switching between modes of therapy.

Results:

Twenty percent of women aged 45 years and older purchased estrogen products in 2001, versus 10% in 2007 (p < 0.001; χ2). Vaginally administered products accounted for a rising percentage of purchases, from 5% in 1999 to 18% in 2007. An increasing percentage of new users aged 55 years and older started with a vaginal product (62% in 1999, 82% in 2007). After 2002, new users of oral therapy discontinued use more quickly than those who started oral therapy before 2002. Tibolone accounted for an increasing percentage of oral drugs purchased (12% in 2003, 29% in 2007).

Conclusions:

The WHI findings had a rapid and sustained impact on HRT utilization in a large population of Israeli women, including a sharp decrease in the rate of use, particularly of oral preparations, as well as reduced duration of therapy and increased use of vaginal preparations and tibolone as first choices for treatment.
Geriatrics: Is There an Association Between Inappropriate Prescription Drug use and Adherence in Discharged Elderly Patients?
Authors: Mansur Nariman , Weiss Avraham , Beloosesky Yichayaou
Published: February 2009

Background:

Inappropriate prescription drug (IPD) use is very common among older patients. However, its impact on medication continuity and adherence after hospitalization has not been researched, with little known regarding readmissions and mortality.

Objective:

To investigate the prevalence and clinical characteristics of patients discharged with IPDs and examine whether use of these drugs is related to medication continuity and adherence 1 month postdischarge as well as to readmissions and mortality 3 months postdischarge.

Methods:

Clinical and demographic data, postdischarge medication modification, and adherence were prospectively obtained on interview of 212 unselected elderly (aged ≥65 y) patients or, if necessary, their caregivers. Nonadherence was defined as the percentage of drug doses less than or equal to 70% or greater than or equal to 110%. Medication appropriateness was assessed retrospectively using the Beers' criteria,

Results:

Use of IPDs occurred in 43.5% and 44.4% of patients on admission and discharge, respectively. At discharge, the numbers of IPDs and prescribed drugs were correlated (R = 0.39; p < 0.01). No relationship was found between IPDs at discharge and age, sex, functional and cognitive status, number of chronic diseases, and reason for admission. Sixty percent of patients who were nonadherent to at least one drug had at least one IPD, compared with 37.4% of the adherent patients (p = 0.008). Nonadherence to at least one drug increased as the number of IPDs on discharge increased (p = 0.004). No relationship was found between IPD use and postdischarge medication modifications, readmissions, and mortality.

Conclusions:

A high number of hospitalized elderly patients are discharged with IPDs that are directly correlated with the number of prescribed drugs at discharge and postdischarge nonadherence. Further studies are needed to assess the impact of postdischarge IPD use on health outcome, and healthcare providers should work to decrease its prevalence.
Allergic Cross-Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What are the Chances?
Authors: Frumin Jane , Gallagher Jason C
Published: February 2009

Objective:

To evaluate the literature on the allergic cross-reactivity between penicillin, carbapenem, and monobactam antibiotics.

Data Sources:

A MEDLINE search (1950–June 2008) of the English literature was performed using the search terms β-lactam, penicillin, monobactam, carbapenem, allergy, and cross-reactivity. References of review articles were also screened for inclusion.

Study Selection and Data Extraction:

All articles in English from the data source were identified. Studies whose primary goal was to evaluate drug hypersensitivity and the potential for cross-reactivity were evaluated.

Data Synthesis:

Many patients have reported penicillin allergies that have not been verified by skin testing; many healthcare providers avoid the use of other β-lactam antibiotics, namely carbapenems, in these patients due to fear of the potential for immunoglobulin E-mediated allergic cross-reactivity. A wide range of cross-reactivity between penicillins and carbapenems has been reported in various studies; however, more recent prospective studies have shown the incidence of cross-reactivity between penicillin and carbapenem skin tests to be around 1%. Additionally, many prescribers freely use the monobactam aztreonam in penicillin-allergic patients, believing there is no cross-reactivity between the 2 drugs. Although data support the lack of cross-reactivity between aztreonam and penicillins, immunology and some clinical data support an interaction between ceftazidime and aztreonam due to the similarity of their side chains.

Conclusions:

Although variability in cross-reactivity rates between β-lactam classes exists in the literature, the practice of avoiding carbapenems in penicillin-allergic patients should be reconsidered. With regard to monobactams, the administration of aztreonam in a patient with a ceftazidime allergy may carry an increased risk of type 1 hypersensitivity reactions and should be considered with caution. Additionally, the importance of obtaining a thorough patient history regarding the previous allergic event, proper documentation, and penicillin skin testing is re emphasized.
Cocaine-Related Vasculitis Causing Scrotal Gangrene
Authors: Chen Szu-Chia , Jang Mei-Yu , Wang Chuan-Sheng , Tsai Kun-Bow , Chuang Shu-Hui , Chen Huang-Chi , Chang Jer-Ming
Published: February 2009

Objective:

To describe a case of possible cocaine-related vasculitis resulting in gangrene of the scrotum and review the literature on cocaine-related vascular complications.

Case Summary:

A 22-year-old male presented with fever, painful swelling of the right scrotum, and a blackened ulcerated lesion on the right scrotum 3 hours after smoking crack cocaine. Blood and urine cultures and serologic tests were negative, and the D-dimer level was normal. Echocardiogram showed no evidence of vegetation and results of a chest X-ray were normal. Despite treatment for presumptive orchitis with intravenous levofloxacin 750 mg/day, the ulcerated lesion of the right scrotum progressed the next day. The patient received debridement of the necrotic tissue and pathology revealed some degenerated vessels with fibrinoid deposits and inflammatory infiltrates, suggestive of vasculitis. No further tenderness and swelling of the scrotum occurred and the patient was discharged after 10 days. When he returned for follow-up, the wound had healed completely.

Discussions:

Cocaine-related vascular complications, including ischemic stroke, myocardial infarction, and peripheral occlusive disease, all of which have various possible mechanisms, are of clinical importance. Vasculitis is one of the mechanisms of vascular complications associated with cocaine use. According to the Naranjo probability scale, cocaine was the possible causative agent of the patient's vasculitis, which led to scrotum gangrene. To our knowledge, this is the first report in the literature of scrotum gangrene developing after crack cocaine was smoked.

Conclusions:

This case report describes a rare occurrence of gangrene of the scrotum associated with cocaine smoking, which is consistent with cocaine's potent vasoconstrictive activity. Cocaine abuse has the potential to cause clinically significant ischemic events anywhere in the body, independent of the method of administration.
Randomized Trial Assessing the Effectiveness of a Pharmacist-Delivered Program for Smoking Cessation
Authors: Dent Larry A , Harris Kari Jo , Noonan Curtis W
Published: February 2009

Background:

As trained and accessible healthcare professionals, pharmacists are in an ideal position to provide tobacco cessation interventions. Of the 15 studies identified in the literature assessing the effectiveness of tobacco cessation interventions delivered by pharmacists, this is the first randomized controlled trial conducted in the US of a pharmacist-delivered program for smoking cessation using biochemical confirmation.

Objective:

To assess the effectiveness on smoking cessation of a face-to-face group program conducted by the pharmacist team compared with a brief standard care session delivered by a pharmacist over the telephone.

Methods:

An open-label, prospective, randomized, controlled trial was conducted at a Veterans Health Administration, community-based outpatient clinic in the Rocky Mountain region. Participants were randomly assigned to receive a 3-session face-to-face group program conducted by the pharmacist team or one 5- to 10-minute standard care session delivered by the pharmacist team over the telephone. Participants in both groups were offered either immediate-release bupropion or nicotine patch at no cost. The primary outcome of self-reported abstinence was biochemically confirmed by urinary cotinine at 6 months after the quit date.

Results:

One hundred one smokers were randomized from October 3, 2005, to March 30, 2007, with the last 6-month follow-up survey completed on November 6, 2007. Analysis of data was completed in December 2007. Using intent-to-treat procedures, confirmed abstinence rates at the end of 6 months were 28% in the pharmacist-delivered face-to-face treatment group and 11.8% in the standard care telephone session control group (p < 0.041).

Conclusions:

This study demonstrates that pharmacists are effective providers of tobacco cessation interventions. Greater utilization of pharmacists in tobacco cessation efforts could have a significant impact on smoking rates, prevention of tobacco-related diseases, and overall improvement in public health across the US.
The PCSK9 gene E670G polymorphism affects low-density lipoprotein cholesterol levels but is not a risk factor for coronary artery disease in ethnic Chinese in Taiwan
Authors: Hsu Lung-An , Teng Ming-Sheng , Ko Yu-Lin , Chang Chi-Jen , Wu Semon , Wang Chun-Li , Hu Chiao-Feng
Published: February 2009

: An E670G polymorphism of the exon 12 of the proprotein convertase subtilisin/kexin type 9 (

: The subjects included 202 CAD patients and 614 unrelated controls. Genotypes were determined via polymerase chain reaction, restriction mapping with

: Contradictory to the results of a previous report, a significantly lower level of LDL-C was noted in

: These results indicate that the E670G polymorphism of the

Clin Chem Lab Med 2009;47:154–8.
New European guidelines for cardiovascular disease prevention in clinical practice
Authors: De Backer Guy
Published: February 2009

In 2007, the Fourth Joint European Societies' Task Force on cardiovascular disease (CVD) prevention in clinical practice issued an update of the guidelines on how to prevent CVD. These guidelines are endorsed by 10 international societies interested in the subject. Particular attention is given to lifestyle changes, risk factor management, and the use of cardioprotective drugs. In this paper, the content of the guidelines is summarized with emphasis on what is new compared to the previous version and on what could be of particular interest to clinical chemists. For those who would like to read more on this, please refer to the full document (112 pages including 1105 references).

Clin Chem Lab Med 2009;47:138–42.
Age and hormone replacement therapy as factors influencing androgen levels in the postmenopausal female
Authors: Ali Iaisha , James Tim , Meston Niki , Wojnarowska Fenella , Shine Brian
Published: February 2009

: The changes in androgen levels after the menopause and the effects of hormone replacement therapy (HRT) itself and the mode of HRT have not been established. The objectives of this study were to document the effect of age on androgen levels in a normal population of postmenopausal women and to investigate the effect of oral or transdermal HRT on androgen, oestradiol and sex hormone binding globulin (SHBG) values.

: A cross-sectional study was conducted on 182 postmenopausal females aged 45–100 years, randomly recruited from the community. Serum levels of dehydroepiandrosterone sulphate (DHEAS), androstenedione, testosterone, free androgen index (FAI) and SHBG in a reference group of women, subdivided by age, menopausal status, HRT replacement and mode of HRT replacement.

: Age was a significant factor affecting androstenedione (<55, ≥55 years) and DHEAS (<65, ≥65 years). HRT status was found to influence values for androstenedione, SHBG and FAI. Neither HRT nor age significantly influenced testosterone.

: The observations suggest the need to provide age-specific reference intervals for androstenedione and DHEAS but not for testosterone and SHBG. The significant effect of HRT treatment would also suggest a need for treatment associated reference intervals for androstenedione, SHBG and FAI. Suggested reference intervals for each of these partitioned groups are presented.

Clin Chem Lab Med 2009;47:202–7.
Abnormal Neural Filtering of Irrelevant Visual Information in Depression
Authors: Desseilles Martin , Balteau Evelyne , Sterpenich Virginie , Dang-Vu Thien Thanh , Darsaud Annabelle , Vandewalle Gilles , Albouy Geneviève , Salmon Eric , Peters Fréderic , Schmidt Christina , Schabus Manuel , Gais Stephen , Degueldre Christian , Phillips Christophe , Luxen Andre , Ansseau Marc , Maquet Pierre , Schwartz Sophie
Published: February 2009

The pathophysiology of major depressive disorder (MDD) includes both affective and cognitive dysfunctions. We aimed to clarify how regions regulating affective processing interact with those involved in attention, and how such interaction impacts perceptual processing within sensory cortices. Based on previous work showing that top-down influences from attention can determine the processing of external inputs within early sensory cortices, we tested with functional magnetic resonance imaging (fMRI) whether MDD alters attentional (“top-down”) effects on the neural filtering of irrelevant, nonemotional visual stimuli. The present fMRI study was conducted in 14 nonmedicated patients with a first episode of unipolar MDD and 14 matched controls. During scanning, subjects performed two tasks imposing two different levels of attentional load at fixation (easy or difficult), while irrelevant colored stimuli were presented in the periphery. Analyses of fMRI data revealed that MDD patients show (1) an abnormal filtering of irrelevant information in visual cortex, (2) an altered functional connectivity between frontoparietal networks and visual cortices, and (3) a hyperactivity in subgenual cingulate/medial orbitofrontal cortex that was modulated by attentional load. These results demonstrate that biological abnormalities contribute to the cognitive deficits seen in major depression, and clarify how neural networks implicated in mood regulation influence executive control and perceptual processes. These findings not only improve our understanding of the pathophysiological mechanisms underlying cognitive dysfunctions in MDD, but also shed new light on the interaction between cognition and mood regulation.
Phosphorylation of Highly Conserved Neurofilament Medium KSP Repeats Is Not Required for Myelin-Dependent Radial Axonal Growth
Authors: Garcia Michael L. , Rao Mala V. , Fujimoto Jiro , Garcia Virginia B. , Shah Sameer B. , Crum John , Gotow Takahiro , Uchiyama Yasuo , Ellisman Mark , Calcutt Nigel A. , Cleveland Don W.
Published: February 2009

Neurofilament medium (NF-M) is essential for the acquisition of normal axonal caliber in response to a myelin-dependent “outside-in” trigger for radial axonal growth. Removal of the tail domain and lysine-serine-proline (KSP) repeats of NF-M, but not neurofilament heavy, produced axons with impaired radial growth and reduced conduction velocities. These earlier findings supported myelin-dependent phosphorylation of NF-M KSP repeats as an essential component of axonal growth. As a direct test of whether phosphorylation of NF-M KSP repeats is the target for the myelin-derived signal, gene replacement has now been used to produce mice in which all serines of NF-M's KSP repeats have been replaced with phosphorylation-incompetent alanines. This substitution did not alter accumulation of the neurofilaments or their subunits. Axonal caliber and motor neuron conduction velocity of mice expressing KSP phospho-incompetent NF-M were also indistinguishable from wild-type mice. Thus, phosphorylation of NF-M KSP repeats is not an essential component for the acquisition of normal axonal caliber mediated by myelin-dependent outside-in signaling.
Regulate Axon Branching by the Cyclic GMP Pathway via Inhibition of Glycogen Synthase Kinase 3 in Dorsal Root Ganglion Sensory Neurons
Authors: Zhao Zhen , Wang Zheng , Gu Ying , Feil Robert , Hofmann Franz , Ma Le
Published: February 2009

Cyclic GMP has been proposed to regulate axonal development, but the molecular and cellular mechanisms underlying the formation of axon branches are not well understood. Here, we report the use of rodent embryonic sensory neurons from the dorsal root ganglion (DRG) to demonstrate the role of cGMP signaling in axon branching and to identify the downstream molecular pathway mediating this novel regulation. Pharmacologically, a specific cGMP analog promotes DRG axon branching in culture, and this activity can be achieved by activating the endogenous soluble guanylyl cyclase that produces cGMP. At the molecular level, the cGMP-dependent protein kinase 1 (PrkG1) mediates this activity, as DRG neurons isolated from the kinase-deficient mouse fail to respond to cGMP activation to make branches, whereas overexpression of a PrkG1 mutant with a higher-than-normal basal kinase activity is sufficient to induce branching. In addition, cGMP activation in DRG neurons leads to phosphorylation of glycogen synthase kinase 3 (GSK3), a protein that normally suppresses branching. This interaction is direct, because PrkG1 binds GSK3 in heterologous cells and the purified kinase can phosphorylate GSK3in vitro. More importantly, overexpression of a dominant active form of GSK3 suppresses cGMP-dependent branching in DRG neurons. Thus, our study establishes an intrinsic signaling cascade that links cGMP activation to GSK3 inhibition in controlling axon branching during sensory axon development.
Frequency-Dependent Inversion of Net Striatal Output by Endocannabinoid-Dependent Plasticity at Different Synaptic Inputs
Authors: Adermark Louise , Lovinger David M
Published: February 2009

Understanding how striatal neurons integrate glutamatergic and GABAergic inputs is essential for understanding the control of movement and the formation of striatal-based memories. Here we show that GABAergic synapses on striatal medium spiny neurons (MSNs) are more sensitive than glutamatergic synapses on the same cells to endocannabinoid (eCB) signaling, and that protocols that induce short-lasting cannabinoid 1 receptor (CB1R)-dependent depression at glutamatergic synapses are sufficient to induce long-term depression (LTD) at GABAergic synapses. We also show that the frequency and duration of glutamatergic input are strong determinants of the net effect of eCB signaling, and key factors in determining if LTD has a net disinhibitory or inhibitory action in striatum. Plastic changes in net output from striatal MSNs are thus a complex function of disinhibitory and inhibitory LTD combined with other forms of synaptic plasticity such as long-term potentiation at excitatory synapses.
The Role of Interphotoreceptor Retinoid-Binding Protein on the Translocation of Visual Retinoids and Function of Cone Photoreceptors
Authors: Jin Minghao , Li Songhua , Nusinowitz Steven , Lloyd Marcia , Hu Jane , Radu Roxana A. , Bok Dean , Travis Gabriel H.
Published: February 2009

The first event in light perception is absorption of a photon by the retinaldehyde chromophore of an opsin pigment in a rod or cone photoreceptor cell. This induces isomerization of the chromophore, rendering the bleached pigment insensitive to light. Restoration of light sensitivity requires chemical reisomerization of retinaldehyde via a multistep enzyme pathway, called the visual cycle, in cells of the retinal pigment epithelium (RPE). Interphotoreceptor retinoid-binding protein (IRBP) is present in the extracellular space between photoreceptors and the RPE. IRBP is known to bind visual retinoids. Previous studies onirbp−/−mice suggested that IRBP plays an insignificant role in opsin-pigment regeneration. However, the mice in these studies were uncontrolled for a severe mutation in therpe65gene. Rpe65 catalyzes the rate-limiting step in the visual cycle. Here, we examined the phenotype inirbp−/−mice homozygous for the wild-type (Leu450)rpe65gene. We show that lack of IRBP causes delayed transfer of newly synthesized chromophore from RPE to photoreceptors. Removal of bleached chromophore from photoreceptors is also delayed inirbp−/−retinas after light exposure. It was previously shown that rods degenerate inirbp−/−mice. Here, we show that cones and rods degenerate at similar rates. However, cones are more affected functionally and show greater reductions in outer segment length than rods inirbp−/−mice. The disproportionate reductions in cone function and outer-segment length appear to result from mistrafficking of cone opsins due to impaired delivery of retinaldehyde chromophore, which functions as a chaperone for cone opsins but not rhodopsin.
Positron Emission Tomography Imaging Demonstrates Correlation between Behavioral Recovery and Correction of Dopamine Neurotransmission after Gene Therapy
Authors: Leriche Ludovic , Björklund Tomas , Breysse Nathalie , Besret Laurent , Grégoire Marie-Claude , Carlsson Thomas , Dollé Frédéric , Mandel Ronald J. , Déglon Nicole , Hantraye Philippe , Kirik Deniz
Published: February 2009

In vivogene transfer using viral vectors is an emerging therapy for neurodegenerative diseases with a clinical impact recently demonstrated in Parkinson's disease patients. Recombinant adeno-associated viral (rAAV) vectors, in particular, provide an excellent tool for long-term expression of therapeutic genes in the brain. Here we used the [11C]raclopride [(S)-(−)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-6-methoxybenzamide] micro-positron emission tomography (PET) technique to demonstrate that delivery of the tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) enzymes using an rAAV5 vector normalizes the increased [11C]raclopride binding in hemiparkinsonian rats. Importantly, we showin vivoby microPET imaging and postmortem by classical binding assays performed in the very same animals that the changes in [11C]raclopride after viral vector-based enzyme replacement therapy is attributable to a decrease in the affinity of the tracer binding to the D2receptors, providing evidence for reconstitution of a functional pool of endogenous dopamine in the striatum. Moreover, the extent of the normalization in this non-invasive imaging measure was highly correlated with the functional recovery in motor behavior. The PET imaging protocol used in this study is fully adaptable to humans and thus can serve as anin vivoimaging technique to follow TH + GCH1 gene therapy in PD patients and provide an additional objective measure to a potential clinical trial using rAAV vectors to deliverl-3,4-dihydroxyphenylanaline in the brain.
Three Distinct Amine Receptors Operating at Different Levels within the Locomotory Circuit Are Each Essential for the Serotonergic Modulation of Chemosensation inCaenorhabditis elegans
Authors: Harris Gareth P. , Hapiak Vera M. , Wragg Rachel T. , Miller Sarah B. , Hughes Lindsay J. , Hobson Robert J. , Steven Robert , Bamber Bruce , Komuniecki Richard W.
Published: February 2009

Serotonin modulates behavioral plasticity in both vertebrates and invertebrates and inCaenorhabditis elegansregulates key behaviors, including locomotion, aversive learning and olfaction through at least four different 5-HT receptors. In the present study, we examined the serotonergic stimulation of aversive responses to dilute octanol in animals containing null alleles of these 5-HT receptors. Bothser-1andmod-1null animals failed to increase sensitivity to dilute octanol on food/5-HT, in contrast to wild-type,ser-4orser-7null animals. 5-HT sensitivity was restored by the expression of MOD-1 and SER-1 in the AIB or potentially the AIY, and RIA interneurons ofmod-1andser-1null animals, respectively. Because none of these 5-HT receptors appear to be expressed in the ASH sensory neurons mediating octanol sensitivity, we identified a 5-HT6-like receptor, F16D3.7(SER-5), that was required for food/5-HT-dependent increases in octanol sensitivity.ser-5null animals failed to increase octanol sensitivity in the presence of food/5-HT and sensitivity could be restored by expression of SER-5 in the ASHs. Similarly, the RNAi knockdown ofser-5expression in the ASHs of wild-type animals also abolished 5-HT-dependent increases in octanol sensitivity, suggesting that SER-5 modulates the octanol responsiveness of the ASHs directly. Together, these results suggest that multiple amine receptors, functioning at different levels within the locomotory circuit, are each essential for the serotonergic modulation of ASH-mediated aversive responses.
CB1Receptors Mediate the Analgesic Effects of Cannabinoids on Colorectal Distension-Induced Visceral Pain in Rodents
Authors: Brusberg Mikael , Arvidsson Susanne , Kang Daiwu , Larsson Håkan , Lindström Erik , Martinez Vicente
Published: February 2009

Activation of cannabinoid receptors (CB1, CB2and GPR55) produces analgesic effects in several experimental pain models, including visceral pain arising from the gastrointestinal tract. We assessed the role of CB1, CB2, and GPR55receptors and the endogenous cannabinoid system on basal pain responses and acute mechanical hyperalgesia during colorectal distension (CRD) in rodents. The effects of cannabinoid receptor agonists and antagonists on pain-related responses to CRD were assessed in rats and in wild-type and CB1receptor knock-out mice. The dual CB1/2agonist, WIN55,212-2, and the peripherally acting CB1-selective agonist, SAB-378, inhibited pain-related responses to repetitive noxious CRD (80 mmHg) in a dose-related manner in rats. The analgesic effects of WIN55,212-2 and SAB-378 were blocked by the selective CB1antagonist SR141716, but were not affected by the selective CB2antagonist SR144528. SR141716, per se, increased the responses to repetitive noxious CRD, indicative of hyperalgesia, and induced pain-related responses during non-noxious CRD (20 mmHg), indicative of allodynia. The cannabinoid receptor agonists anandamide, virodhamine and O-1602 had no effect. At analgesic doses, WIN55,212-2 did not affect colonic compliance. In accordance to the rat data, WIN55,212-2 produced analgesia, whereas SR141716 induced hyperalgesia, during noxious CRD (55 mmHg) in wild-type but not in CB1-knock-out mice. These data indicate that peripheral CB1receptors mediate the analgesic effects of cannabinoids on visceral pain from the gastrointestinal tract. The allodynic and hyperalgesic responses induced by SR141716 suggest the existence of an endogenous cannabinoid tone and the activation of CB1receptors during noxious CRD.
Lateral Hypothalamus Is Required for Context-Induced Reinstatement of Extinguished Reward Seeking
Authors: Marchant Nathan J. , Hamlin Adam S. , McNally Gavan P.
Published: February 2009

We studied the role of lateral hypothalamus (LH) in context-induced reinstatement (renewal) of reward seeking. Rats were trained to respond for 4% (v/v) alcoholic beer or 10% (w/v) sucrose reward in one context (Context A) before extinction training in a second context (Context B). On test, rats were returned to the training context, A (ABA), or the extinction context, B (ABB). Return to the training context (ABA) produced robust reinstatement. Reversible inactivation of LH via baclofen/muscimol infusion prevented context-induced reinstatement of beer and sucrose seeking. This prevention was specific to bilateral infusions into LH. We then used the retrograde neuronal tracer cholera toxin b subunit (CTb) combined with detection of the c-Fos protein to identify activated afferents to LH during context-induced reinstatement of beer seeking. Double labeling for c-Fos and CTb revealed a significant recruitment of LH-projecting neurons in nucleus accumbens shell (AcbSh) during reinstatement. These afferents could be classified into two anatomically and functionally distinct groups. First, afferents in the ventral AcbSh projecting to LH were activated during reinstatement. Second, afferents in the dorsomedial AcbSh projecting to LH were activated during test in the extinction context. These recruitments were specific to an AcbSh–LH pathway because they were not observed following CTb injection into the immediately adjacent perifornical hypothalamus. These results show that LH is critical for context-induced reinstatement of reward seeking and that parallel striatal-hypothalamic pathways are recruited following return to the training versus extinction contexts.
Inducible Prostaglandin E2Synthesis Interacts in a Temporally Supplementary Sequence with Constitutive Prostaglandin-Synthesizing Enzymes in Creating the Hypothalamic–Pituitary–Adrenal Axis Response to Immune Challenge
Authors: Elander Louise , Engström Linda , Ruud Johan , Mackerlova Ludmila , Jakobsson Per-Johan , Engblom David , Nilsberth Camilla , Blomqvist Anders
Published: February 2009

Inflammation-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E2-synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fosgene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which (1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and (2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE2synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.
Random Walk Behavior of Migrating Cortical Interneurons in the Marginal Zone: Time-Lapse Analysis in Flat-Mount Cortex
Authors: Tanaka Daisuke H. , Yanagida Mitsutoshi , Zhu Yan , Mikami Sakae , Nagasawa Takashi , Miyazaki Jun-ichi , Yanagawa Yuchio , Obata Kunihiko , Murakami Fujio
Published: February 2009

Migrating neurons are thought to travel from their origin near the ventricle to distant territories along stereotypical pathways by detecting environmental cues in the extracellular milieu. Here, we report a novel mode of neuronal migration that challenges this view. We performed long-term, time-lapse imaging of medial ganglionic eminence (MGE)-derived cortical interneurons tangentially migrating in the marginal zone (MZ) in flat-mount cortices. We find that they exhibit a diverse range of behaviors in terms of the rate and direction of migration. Curiously, a predominant population of these neurons repeatedly changes its direction of migration in an unpredictable manner. Trajectories of migration vary from one neuron to another. The migration of individual cells lasts for long periods, sometimes up to 2 d. Theoretical analyses reveal that these behaviors can be modeled by a random walk. Furthermore, MZ cells migrate from the cortical subventricular zone to the cortical plate, transiently accumulating in the MZ. These results suggest that MGE-derived cortical interneurons, once arriving at the MZ, are released from regulation by guidance cues and initiate random walk movement, which potentially contributes to their dispersion throughout the cortex.
Isoflurane-Sensitive Presynaptic R-Type Calcium Channels Contribute to Inhibitory Synaptic Transmission in the Rat Thalamus
Authors: Joksovic Pavle M. , Weiergräber Marco , Lee WooYong , Struck Henrik , Schneider Toni , Todorovic Slobodan M.
Published: February 2009

Because inhibitory synaptic transmission is a major mechanism of general anesthesia, we examined the effects of isoflurane on properties of GABAergic inhibitory currents in the reticular thalamic nucleus (nRT) in brain slices. The evoked IPSCs (eIPSCs) and spontaneous miniature synaptic currents (mIPSCs) of visualized nRT cells in young and adult rats were recorded. Consistent with postsynaptic effects on GABAAreceptors, isoflurane prolonged the decay-time constants of both eIPSCs and mIPCSs. Surprisingly, isoflurane completely inhibited the amplitude of eIPSCs at clinically relevant concentrations (IC50of 240 ± 20 μm), increased the paired-pulse ratio, and decreased the frequency of mIPSCs, indicating that presynaptic mechanisms may also contribute to the effects of isoflurane on IPSCs. The overall effect of isoflurane on eIPSCs in nRT cells was a decrease of net charge-transfer across the postsynaptic membrane. The application of 100 μmnickel (Ni2+) and the more specific R-type Ca2+channel blocker SNX-482 (0.5 μm) decreased eIPSC amplitudes, increased the paired-pulse ratio, and attenuated isoflurane-induced inhibition of eIPSCs. In addition, isoflurane potently blocked currents in recombinant human CaV2.3 (α1E) channels with an IC50of 206 ± 22 μm. Importantly,in vivoelectroencephalographic (EEG) recordings in adult CaV2.3 knock-out mice demonstrated alterations in isoflurane-induced burst-suppression activity. Because the thalamus has a key function in processing sensory information, sleep, and cognition, modulation of its GABAergic tone by presynaptic R-type Ca2+channels may contribute to the clinical effects of general anesthesia.
Decreased BDNF Levels Are a Major Contributor to the Embryonic Phenotype of Huntingtin Knockdown Zebrafish
Authors: Diekmann Heike , Anichtchik Oleg , Fleming Angeleen , Futter Marie , Goldsmith Paul , Roach Alan , Rubinsztein David C.
Published: February 2009

Huntington's disease (HD) is an autosomal dominant, neurodegenerative condition caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract in the protein huntingtin. Genetic and transgenic studies suggest that the mutation causes disease predominantly via gain-of-function mechanisms. However, loss of normal huntingtin function resulting from the polyglutamine expansion might also contribute to the pathogenesis of HD. Here, we have studied the effects of huntingtin knockdown in zebrafish using morpholino antisense oligonucleotides, as its huntingtin orthologue has 70% amino acid identity with the human protein. Reduced huntingtin levels did not impact on gastrulation and early development, but caused massive apoptosis of neuronal cells by 24 hpf. This was accompanied by impaired neuronal development, resulting in small eyes and heads and enlargement of brain ventricles. Older huntingtin knockdown fish developed lower jaw abnormalities with most branchial arches missing. Molecular analysis revealed that BDNF expression was reduced by ∼50%. Reduction of BDNF levels by injection of a BDNF morpholino resulted in phenotypes very similar to those seen in huntingtin knockdown zebrafish. The phenotypes of both huntingtin- and BDNF-knockdown zebrafish showed significant rescue when treated with exogenous BDNF protein. This underscores the physiological importance of huntingtin as a regulator of BDNF production and suggests that loss of BDNF is a major cause of the developmental abnormalities seen with huntingtin knockdown in zebrafish. Increasing BDNF expression may represent a useful strategy for Huntington's disease treatment.
Rab11a and HSP90 Regulate Recycling of Extracellular α-Synuclein
Authors: Liu Jun , Zhang Jian-Peng , Shi Min , Quinn Thomas , Bradner Joshua , Beyer Richard , Chen Shengdi , Zhang Jing
Published: February 2009

Growing evidence suggests that extracellular α-synuclein (eSNCA) may play an important role in the pathogenesis of Parkinson's disease (PD) and related synucleinopathies by producing neurotoxicity directly or via activation of glia. However, the mechanisms involved in the trafficking of eSNCA in neurons and/or glia remain unclear. Here, we demonstrated that eSNCA could be resecreted out of neurons via a process modulated by a recycling endosome regulator rab11a in addition to being degraded by an endosome–lysosome system. A quantitative proteomic analysis also revealed numerous proteins through which rab11a might execute its function. One of the candidate proteins, heat shock protein 90 (HSP90), was validated to be interacting with rab11a. Furthermore, geldanamycin, an HSP90 inhibitor, not only prevented resecretion of eSNCA but also attenuated neurotoxicity induced by eSNCA.
Excitation function for the 74Se(18O,p3n)88gNb reaction
Authors: Gates J. M. , Dragojevic I. , Dvorak J. , Ellison P. A. , Gregorich K. E. , Stavsetra L. , Nitsche Heino
Published: February 2009

The 74Se( 18O,p3n)88gNb excitation function was measured and a maximum cross section of 495±5 mb was observed at and 18O energy of 74.0 MeV. Experimental cross sections were compared to theoretical calculations using the computer code ALICE-91 and the values were found to be in good agreement. The half-life of 88gNb was determined to be around 14.56±0.11 min.
Distúrbios cardiovasculares na acromegalia
Authors: Fedrizzi Daniela , Czepielewski Mauro Antonio
Published: February 2009

A acromegalia acarreta uma série de distúrbios ao sistema cardiovascular, decorrentes da exposição crônica a níveis elevados de GH e IGF-1. Estes distúrbios são os principais responsáveis pelo aumento da mortalidade de acromegálicos. Entre as várias formas de acometimento cardiovascular, destaca-se a miocardiopatia acromegálica, entidade caracterizada, inicialmente, pelo estado hiperdinâmico, seguido de hipertrofia ventricular esquerda concêntrica e disfunção diastólica por déficit de relaxamento, culminando com disfunção sistólica e, por vezes, insuficiência cardíaca franca. Além disso, são também relevantes as arritmias, as valvulopatias, sobretudo mitral e aórtica, a cardiopatia isquêmica, a hipertensão e os distúrbios dos metabolismos glicêmico e lipídico. Nesta revisão são abordados os principais aspectos clínicos e prognósticos destas entidades, os efeitos do tratamento da acromegalia sobre elas e as repercussões correspondentes sobre a sobrevida dos pacientes.
Orbital metastasis as primary clinical manifestation of thyroid carcinoma: case report and literature review
Authors: Rocha Filho Francisco Dário , Lima Gabrielle Gurgel , Ferreira Francisco V. de Almeida , Lima Michelle Gurgel , Hissa Miguel N.
Published: February 2009

Capillary thyroid carcinoma (PTC) is the most common neoplasm of thyroid. It usually grows slowly and is clinically indolent, although rare, its aggressive forms with local invasion or distant metastases can occur. Metastatic thyroid carcinoma rarely involves the orbit. We reported an uncommon case of orbital metastasis of PTC. A 66-years-old woman presented proptosis of the right eye. The biopsy of the tumor in orbit revealed metastatic thyroid carcinoma. The ultrasensitive TSH level was 1,34 mUI/L and free T4 level was 1,65 ng/dL. A total thyroidectomy was performed and histopathological analysis of the nodule revealed follicular variant of papillary thyroid carcinoma. Currently, the patient has been receiving palliative chemotherapy with Clodronate Disodium. The importance of the case is due to its unusual presentation, which emerged as a primary clinical manifestation. Although rare, thyroid carcinoma should be suspected in orbit metastasis.