bluuebunny/crossref_metadata_2025 huggingface dataset:
A Habermasian analysis of the deliberative democratic potential of ICT-enabled services in Swedish municipalities
Authors: Wiklund Hans
Published: September 2005

The aim of this article is to derive a critical standard against which institutional arrangements of e-government can be assessed in terms of democratic potential from Jürgen Habermas’s discursive model of deliberative democracy, and to illustrate how this standard can be applied through an assessment of the information and communication technology-(ICT) enabled services found on Swedish municipal websites. The assessment focuses on the potential of the ICT infrastructure to support deliberative democratic ideals and is based on a quantitative exploration of all 289 Swedish municipal websites. The results suggest that, if correctly designed, ICT-enabled services have a deliberative democratic potential. But this does not overshadow the fact that the services existing today only support to a limited extent processes of social learning through rational argumentation, the core idea in Habermas’s discursive model of deliberative democracy.
Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis
Authors: Mihara Keichiro , Chowdhury Moniruddin , Nakaju Nanae , Hidani Sachiko , Ihara Akihiro , Hyodo Hideo , Yasunaga Shin'ichiro , Takihara Yoshihiro , Kimura Akiro
Published: September 2005

The International Prognostic Scoring System (IPSS) has been widely used to predict the prognosis of patients with myelodysplastic syndrome (MDS). However, IPSS does not always provide a sufficiently precise evaluation of patients to allow the appropriate choice of clinical interventions. Here, we analyzed the expression of Bmi-1, which is required to regulate the self-renewal in CD34+ cells from 51 patients with cases of MDS and acute myeloid leukemia preceded by MDS (MDS-AML). Higher positivity rate of Bmi-1 was preferentially seen in refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), and MDS-AML compared with refractory anemia (RA) and RA with ringed sideroblasts (RARS). IPSS score was positively correlated with the percentage of Bmi-1 expression. Patients with RA and RARS with a higher percentage of Bmi-1+ cells showed disease progression to RAEB. Here, we propose Bmi-1 as a novel molecular marker to predict the progression and prognosis of MDS.
Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2)
Authors: Iolascon Achille , d'Apolito Maria , Servedio Veronica , Cimmino Flora , Piga Antonio , Camaschella Clara
Published: September 2005

Divalent metal transporter 1 (DMT1) mediates apical iron uptake in duodenal enterocytes and iron transfer from the transferrin receptor endosomal cycle into the cytosol in erythroid cells. Both mk mice and Belgrade rats, which carry an identical DMT1 mutation, exhibit severe microcytic anemia at birth and defective intestinal iron use and erythroid iron use. We report the hematologic phenotype of a child, compound heterozygote for 2 DMT1 mutations, who was affected by severe anemia since birth and showed hepatic iron overload. The novel mutations were a 3-bp deletion in intron 4 (c.310-3_5del CTT) resulting in a splicing abnormality and a C>T transition at nucleotide 1246(p. R416C). A striking reduction of DMT1 protein in peripheral blood mononuclear cells was demonstrated by Western blot analysis. The proband required blood transfusions until erythropoietin treatment allowed transfusion independence when hemoglobin levels between 75 and 95 g/L (7.5 and 9.5 g/dL) were achieved. Hematologic data of this patient at birth and in the first years of life strengthen the essential role of DMT1 in erythropoiesis. The early onset of iron overload indicates that, as in animal models, DMT1 is dispensable for liver iron uptake, whereas its deficiency in the gut is likely bypassed by the up-regulation of other pathways of iron use.
KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas
Authors: Sarek Grzegorz , Järviluoma Annika , Ojala Päivi M.
Published: September 2005

Kaposi sarcoma herpesvirus (KSHV) infection is consistently associated with primary effusion lymphomas (PELs) that are non-Hodgkin lymphomas of B-cell origin. All PEL cells are latently infected with KSHV and express latent viral proteins such as the viral cyclin (v-cyclin), which has previously been implicated in down-regulation of cell-cycle inhibitor p27KIP1 levels via phosphorylation on Thr187. PEL cells retain high levels of p27KIP1 but yet proliferate actively, which has left the biologic significance of this p27KIP1 destabilization somewhat elusive. We have recently demonstrated that v-cyclin and p27KIP1 stably associate in PEL cells. Here we demonstrate that v-cyclin together with its kinase partner CDK6 phosphorylates the associated p27KIP1 in PEL cells, which represent a biologically relevant model system for KSHV pathobiology. During latent viral replication p27KIP1 was phosphorylated by v-cyclin-CDK6 predominantly on Ser10, which enhances its cytoplasmic localization. Interestingly, upon reactivation of KSHV lytic cycle, v-cyclin-CDK6 phosphorylated p27KIP1 on Thr187, which resulted in down-regulation of p27KIP1 protein levels. These findings indicate that v-cyclin modulates the cell-cycle inhibitory function of p27KIP1 by phosphorylation in PELs, and also suggest a novel role for v-cyclin in the lytic reactivation of KSHV. (Blood. 2006;107:725-732)
XenDB: Full length cDNA prediction and cross species mapping in Xenopus laevis
Authors: Sczyrba Alexander , Beckstette Michael , Brivanlou Ali H , Giegerich Robert , Altmann Curtis R
Published: September 2005

Background

Research using the model system Xenopus laevis has provided critical insights into the mechanisms of early vertebrate development and cell biology. Large scale sequencing efforts have provided an increasingly important resource for researchers. To provide full advantage of the available sequence, we have analyzed 350,468 Xenopus laevis Expressed Sequence Tags (ESTs) both to identify full length protein encoding sequences and to develop a unique database system to support comparative approaches between X. laevis and other model systems.

Description

Using a suffix array based clustering approach, we have identified 25,971 clusters and 40,877 singleton sequences. Generation of a consensus sequence for each cluster resulted in 31,353 tentative contig and 4,801 singleton sequences. Using both BLASTX and FASTY comparison to five model organisms and the NR protein database, more than 15,000 sequences are predicted to encode full length proteins and these have been matched to publicly available IMAGE clones when available. Each sequence has been compared to the KOG database and ~67% of the sequences have been assigned a putative functional category. Based on sequence homology to mouse and human, putative GO annotations have been determined.

Conclusion

The results of the analysis have been stored in a publicly available database XenDB http://bibiserv.techfak.uni-bielefeld.de/xendb/. A unique capability of the database is the ability to batch upload cross species queries to identify potential Xenopus homologues and their associated full length clones. Examples are provided including mapping of microarray results and application of 'in silico' analysis. The ability to quickly translate the results of various species into 'Xenopus-centric' information should greatly enhance comparative embryological approaches.

Supplementary material can be found at http://bibiserv.techfak.uni-bielefeld.de/xendb/.
Comparative genomic analysis reveals a novel mitochondrial isoform of human rTS protein and unusual phylogenetic distribution of the rTS gene
Authors: Liang Ping , Nair Jayakumar R , Song Lei , McGuire John J , Dolnick Bruce J
Published: September 2005

Background

The rTS gene (ENOSF1), first identified in Homo sapiens as a gene complementary to the thymidylate synthase (TYMS) mRNA, is known to encode two protein isoforms, rTSα and rTSβ. The rTSβ isoform appears to be an enzyme responsible for the synthesis of signaling molecules involved in the down-regulation of thymidylate synthase, but the exact cellular functions of rTS genes are largely unknown.

Results

Through comparative genomic sequence analysis, we predicted the existence of a novel protein isoform, rTS, which has a 27 residue longer N-terminus by virtue of utilizing an alternative start codon located upstream of the start codon in rTSβ. We observed that a similar extended N-terminus could be predicted in all rTS genes for which genomic sequences are available and the extended regions are conserved from bacteria to human. Therefore, we reasoned that the protein with the extended N-terminus might represent an ancestral form of the rTS protein. Sequence analysis strongly predicts a mitochondrial signal sequence in the extended N-terminal of human rTSγ, which is absent in rTSβ. We confirmed the existence of rTS in human mitochondria experimentally by demonstrating the presence of both rTSγ and rTSβ proteins in mitochondria isolated by subcellular fractionation. In addition, our comprehensive analysis of rTS orthologous sequences reveals an unusual phylogenetic distribution of this gene, which suggests the occurrence of one or more horizontal gene transfer events.

Conclusion

The presence of two rTS isoforms in mitochondria suggests that the rTS signaling pathway may be active within mitochondria. Our report also presents an example of identifying novel protein isoforms and for improving gene annotation through comparative genomic analysis.
Differential effects of intragastric acid and capsaicin on gastric emptying and afferent input to the rat spinal cord and brainstem
Authors: Holzer Peter , Painsipp Evelin , Schuligoi Rufina
Published: September 2005

Background

Hydrochloric acid (HCl) is a potential threat to the integrity of the gastric mucosa and is known to contribute to upper abdominal pain. We have previously found that gastric mucosal challenge with excess HCl is signalled to the rat brainstem, but not spinal cord, as visualized by expression of c-fos messenger ribonucleic acid (mRNA), a surrogate marker of neuronal excitation. This study examined whether gastric mucosal exposure to capsaicin, a stimulant of nociceptive afferents that does not damage the gastric mucosa, is signalled to both brainstem and spinal cord and whether differences in the afferent signalling of gastric HCl and capsaicin challenge are related to different effects on gastric emptying.

Results

Rats were treated intragastrically with vehicle, HCl or capsaicin, activation of neurons in the brainstem and spinal cord was visualized by in situ hybridization autoradiography for c-fos mRNA, and gastric emptying deduced from the retention of intragastrically administered fluid. Relative to vehicle, HCl (0.5 M) and capsaicin (3.2 mM) increased c-fos transcription in the nucleus tractus solitarii by factors of 7.0 and 2.1, respectively. Capsaicin also caused a 5.2-fold rise of c-fos mRNA expression in lamina I of the caudal thoracic spinal cord, although the number of c-fos mRNA-positive cells in this lamina was very small. Thus, on average only 0.13 and 0.68 c-fos mRNA-positive cells were counted in 0.01 mm sections of the unilateral lamina I following intragastric administration of vehicle and capsaicin, respectively. In contrast, intragastric HCl failed to induce c-fos mRNA in the spinal cord. Measurement of gastric fluid retention revealed that HCl suppressed gastric emptying while capsaicin did not.

Conclusion

The findings of this study show that gastric mucosal exposure to HCl and capsaicin is differentially transmitted to the brainstem and spinal cord. Since only HCl blocks gastric emptying, it is hypothesized that the two stimuli are transduced by different afferent pathways. We infer that HCl is exclusively signalled by gastric vagal afferents whereas capsaicin is processed both by gastric vagal and intestinal spinal afferents.
Mortality following Campylobacter infection: a registry-based linkage study
Authors: Ternhag Anders , Törner Anna , Svensson Åke , Giesecke Johan , Ekdahl Karl
Published: September 2005

Background

Campylobacteriosis is one of the most commonly identified causes of bacterial diarrheal disease and a common cause of gastroenteritis in travellers from developed nations. Despite the widespread occurrence, there is little information on Campylobacter mortality.

Methods

Mortality among a cohort of Campylobacter cases were compared with the general population 0–1, 1–3, 3–12 and more than 12 month after the onset of the illness. The cases were sub-grouped according to if they had been infected domestically or abroad.

Results

The standardized mortality ratio for cases infected domestically was 2.9 (95% CI: 1.9–4.0) within the first month following the illness. The risk then gradually diminished and approached 1.0 after one year or more have passed since the illness. This initial excess risk was not attributable to any particular age group (such as the oldest).

In contrast, for those infected abroad, a lower standardized mortality ratio 0.3 (95% CI: 0.04–0.8) was shown for the first month after diagnosis compared to what would be expected in the general population.

Conclusion

Infection with Campylobacter is associated with an increased short-term risk of death among those who were infected domestically. On the contrary, for those infected abroad a lower than expected risk of death was evident. We suggest that the explanation behind this is a "healthy traveler effect" among imported cases, and effects of a more frail than average population among domestic cases.
Artesunate plus sulfadoxine-pyrimethamine for treatment of uncomplicated Plasmodium falciparum malaria in Sudan
Authors: Elamin Sakina B , Malik Elfatih M , Abdelgadir Tarig , Khamiss Ammar H , Mohammed Mamoun M , Ahmed Elderderi S , Adam Ishag
Published: September 2005

Background

Early diagnosis and effective treatment with an appropriate drug form the main components of the World Health Organization's strategy to reduce malaria related mortality. The few available drugs might be safeguarded if combined with artesunate. The addition of artesunate to a standard antimalarial treatment substantially reduces treatment failure, recrudescence and gametocyte carriage.

Methods

During late 2004, the efficacy of artesunate (4 mg/kg. day, on days 0–2) plus sulfadoxine-pyrimethamine (25 mg/kg, on day 0) for the treatment of uncomplicated Plasmodium falciparum malaria was investigated in four sentinel areas in Sudan, with different malaria transmission (Damazin, Kassala, Kosti, and Malakal).

Results

Two hundreds and sixty-nine patients completed the 28-day follow-up. On day one, 60 (22.3%) patients were febrile and 15 (5.5%) patients were parasitaemic. On day three, all the patients were afebrile and aparasitaemic. While two patients (0.7%, Kassala) showed late Clinical and Parasitological Failures, the rest (99.3%) of the patients demonstrated Adequate Clinical and Parasitological Response. A gametocytaemia were detected during the follow-up in one patient (0.37%, Kassala). Adverse drug effects were detected in 32 (11.9%) patients

Conclusion

The study showed that AS plus SP is an effective, safe drug in the treatment of uncomplicated P. falciparum malaria in Sudan.
Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection
Authors: Crockett Seth D , Keeffe Emmet B
Published: September 2005

Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is not uncommon as a result of similar routes of infection. Patients who are coinfected represent a unique group with diverse serologic profiles. Combined chronic hepatitis B and C leads to more severe liver disease and an increased risk of hepatocellular carcinoma. Furthermore, coinfected patients represent a treatment challenge. No standard recommendations exist for treatment of viral hepatitis due to dual HBV/HCV infection, and therefore treatment must be individualized based on patient variables such as serologic and virologic profiles, patient's prior exposure to antiviral treatment, and the presence of other parenterally transmitted viruses such as hepatitis D virus and human immunodeficiency virus. The natural history and treatment of patients with HBV and HCV coinfection is reviewed.
The Integrated System for Public Health Monitoring of West Nile Virus (ISPHM-WNV): a real-time GIS for surveillance and decision-making
Authors: Gosselin Pierre , Lebel Germain , Rivest Sonia , Douville-Fradet Monique
Published: September 2005

Background

After its first detection in North America in New York in 1999, West Nile virus was detected for the first time in 2002 in the province of Quebec, Canada. This situation forced the Government of Quebec to adopt a public health protection plan against the virus. The plan comprises several fields of intervention including the monitoring of human cases, Corvidae and mosquitoes in order to ensure the early detection of the presence of the virus in a particular area. To help support the monitoring activities, the Integrated System for Public Health Monitoring of West Nile Virus (ISPHM-WNV) has been developed.

Results

The ISPHM-WNV is a real-time geographic information system for public health surveillance of West Nile virus and includes information on Corvidae, mosquitoes, humans, horses, climate, and preventive larvicide interventions. It has been in operation in the province of Quebec, Canada, since May 2003. The ISPHM-WNV facilitates the collection, localization, management and analysis of monitoring data; it also allows for the display of the results of analyses on maps, tables and statistical diagrams.

Conclusion

The system is very helpful for field workers in all regions of the province, as well as for central authorities. It represents the common authoritative source of data for analysis, exchange and decision-making.
The Physical Activity Resource Assessment (PARA) instrument: Evaluating features, amenities and incivilities of physical activity resources in urban neighborhoods
Authors: Lee Rebecca E , Booth Katie M , Reese-Smith Jacqueline Y , Regan Gail , Howard Hugh H
Published: September 2005

Background

Neighborhood environment factors may influence physical activity (PA). The purpose of this study was to develop and test a brief instrument to systematically document and describe the type, features, amenities, quality and incivilities of a variety of PA resources.

Method

The one-page Physical Activity Resource Assessment (PARA) instrument was developed to assess all publicly available PA resources in thirteen urban lower income, high ethnic minority concentration neighborhoods that surrounded public housing developments (HDs) and four higher income, low ethnic minority concentration comparison neighborhoods. Neighborhoods had similar population density and connectivity. Trained field coders rated 97 PA resources (including parks, churches, schools, sports facilities, fitness centers, community centers, and trails) on location, type, cost, features, amenities, quality and incivilities. Assessments typically took about 10 minutes to complete.

Results

HD neighborhoods had a mean of 4.9 PA resources (n = 73) with considerable variability in the type of resources available for each neighborhood. Comparison neighborhoods had a mean of 6 resources (n = 24). Most resources were accessible at no cost (82%). Resources in both types of neighborhoods typically had about 2 to 3 PA features and amenities, and the quality was usually mediocre to good in both types of neighborhoods. Incivilities at PA resources in HD neighborhoods were significantly more common than in comparison neighborhoods.

Conclusion

Although PA resources were similar in number, features and amenities, the overall appearance of the resources in HD neighborhoods was much worse as indicated by substantially worse incivilities ratings in HD neighborhoods. The more comprehensive assessment, including features, amenities and incivilities, provided by the PARA may be important to distinguish between PA resources in lower and higher deprivation areas.
Direct involvement of the isotype-specific C-terminus of β tubulin in ciliary beating
Authors: Vent Julia , Wyatt Todd A. , Smith D. David , Banerjee Asok , Ludueña Richard F. , Sisson Joseph H. , Hallworth Richard
Published: September 2005

In previous studies in Drosophila, Nielsen et al. hypothesized that the β tubulin C-terminal axonemal motif `EGEFXXX', where X is an acidic amino acid, is required for ciliary function and assembly (Nielsen et al., 2001, Curr. Biol. 11, 529-533). This motif is present in some but not all mammalian β tubulin isotypes. We therefore investigated whether this motif is important in ciliary function in mammals. In a preparation of isolated, ATP-reactivated bovine tracheal cilia, we found that monoclonal antibodies directed against the C-terminus of βI, βIV and βV tubulin blocked ciliary beating in a concentration dependent manner. Antibodies against other epitopes of β tubulin were ineffective, as were antibodies against α tubulin. Peptides consisting of the axonemal motif and motif-like sequences of these isotypes blocked ciliary beating. These results suggest that the axonemal motif sequences of βI, βIV and βV tubulin are essential for ciliary function. Peptides consisting of corresponding C-terminal sequences in α tubulin isotypes were also ineffective in blocking ciliary beating, which suggests that the C-terminus of α tubulin is not directly involved in cilia function in mammals.
Stimulatory effects of a three-dimensional microenvironment on cell-mediated fibronectin fibrillogenesis
Authors: Mao Yong , Schwarzbauer Jean E.
Published: September 2005

The assembly of fibronectin into a fibrillar matrix is a regulated step-wise process that involves binding to integrin receptors and interactions between fibronectin molecules. This process has been studied extensively using cells in two-dimensional (2D) monolayer culture. In most situations in vivo, however, matrix assembly occurs within existing three-dimensional (3D) extracellular matrix networks. In an attempt to mimic this environment, we analyzed matrix assembly by fibroblasts cultured on a pre-assembled 3D fibronectin matrix and found significant stimulation of fibronectin fibril assembly compared to cells in 2D culture. Lower amounts of fibronectin were needed to initiate the assembly process, fibrils accumulated to higher density, and the 3D fibril organization played a key role in the stimulatory effect. Moreover, cells expressing activation-dependent integrins were able to assemble fibronectin matrix without exogenous stimulation, suggesting regulatory effects of the 3D fibronectin matrix on integrin activity. These results provide evidence for an additional level of control of fibronectin deposition through cell interactions with the local microenvironment.
Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration
Authors: Thomas Tamsin , Jordan Karen , Simek Jamie , Shao Qing , Jedeszko Chris , Walton Paul , Laird Dale W.
Published: September 2005

Previous reports have suggested that Cx26 exhibits unique intracellular transport pathways en route to the cell surface compared with other members of the connexin family. To directly examine and compare nascent and steady-state delivery of Cx43 and Cx26 to the plasma membrane and gap junction biogenesis we expressed fluorescent-protein-tagged Cx43 and Cx26 in BICR-M1Rk and NRK cells. Static and time-lapse imaging revealed that both connexins were routed through the Golgi apparatus prior to being transported to the cell surface, a process inhibited in the presence of brefeldin A (BFA) or the expression of a dominant-negative form of Sar1 GTPase. During recovery from BFA, time-lapse imaging of nascent connexin Golgi-to-plasma membrane delivery revealed many dynamic post-Golgi carriers (PGCs) originating from the distal side of the Golgi apparatus consisting of heterogeneous vesicles and long, tubular-like extensions. Vesicles and tubular extensions were also observed in HBL-100 cells expressing a human, disease-linked, Golgi-localized Cx26 mutant, D66H-GFP. A diffuse cell surface rim of fluorescent-protein-tagged wild-type connexins was observed prior to the appearance of punctate gap junctions, which suggests that random fusion of PGCs occurred with the plasma membrane followed by lateral diffusion of connexins into clusters. Fluorescence recovery after photobleaching studies revealed that Cx26-YFP was more mobile within gap junction plaques compared with Cx43-GFP. Intriguingly, Cx43-GFP delivery and gap junction regeneration was inhibited by BFA and nocodazole, whereas Cx26-GFP delivery was prevented by BFA but not nocodazole. Collectively, these studies suggest that during gap junction biogenesis two phylogenetically distinct members of the connexin family, Cx43 and Cx26, share common secretory pathways, types of transport intermediates and turnover dynamics but differ in their microtubule-dependence and mobility within the plasma membrane, which might reflect differences in binding to protein scaffolds.
Ubiquilin recruits Eps15 into ubiquitin-rich cytoplasmic aggregates via a UIM-UBL interaction
Authors: Regan-Klapisz Elsa , Sorokina Irina , Voortman Jarno , de Keizer Peter , Roovers Rob C. , Verheesen Peter , Urbé Sylvie , Fallon Lara , Fon Edward A. , Verkleij Arie , Benmerah Alexandre , van Bergen en Henegouwen Paul M. P.
Published: September 2005

Eps15 and its related protein Eps15R are key components of the clathrin-mediated endocytic pathway. We searched for new binding partners of Eps15 using a yeast two-hybrid screen. We report here that ubiquilin (hPLIC1), a type-2 ubiquitin-like protein containing a ubiquitin-like domain (UBL) and a ubiquitin-associated domain (UBA), interacts with both Eps15 and Eps15R. Using glutathione-S-transferase pull-down experiments, we show that the first ubiquitin-interacting motif of Eps15 (UIM1) interacts directly with the UBL domain of ubiquilin, whereas it does not bind to ubiquitinated proteins. The second UIM of Eps15 (UIM2) binds poorly to the UBL domain but does bind to ubiquitinated proteins. Two other UIM-containing endocytic proteins, Hrs and Hbp, also interact with ubiquilin in a UIM-dependent manner, whereas epsin does not. Immunofluorescence analysis showed that endogenous Eps15 and Hrs, but not epsin, colocalize with green-fluorescent-protein-fused ubiquilin in cytoplasmic aggregates that are not endocytic compartments. We have characterized these green-fluorescent-protein-fused-ubiquilin aggregates as ubiquitin-rich intracytoplasmic inclusions that are recruited to aggresomes upon proteasome inhibition. Moreover, we show that endogenous Eps15 and endogenous ubiquilin colocalize to cytoplasmic aggregates and aggresomes. Finally, we show that the recruitment of Eps15 into ubiquilin-positive aggregates is UIM dependent. Altogether, our data identify ubiquilin as the first common UIM-binding partner of a subset of UIM-containing endocytic proteins. We propose that this UIM/UBL-based interaction is responsible for the sequestration of certain UIM-containing endocytic proteins into cytoplasmic ubiquitin-rich protein aggregates.
Differential Association Between Statin Exposure and Elevated Levels of Creatine Kinase
Authors: Chan James , Hui Rita L , Levin Eleanor
Published: September 2005

BACKGROUND:

Although hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are generally well tolerated, myopathy can be a serious adverse event. The association among different statins, doses, and related risk factors is not well understood.

Objective:

To determine the prevalence of elevated creatine kinase (CK) levels in patients taking statins, specific doses of these drugs, and other factors. Simvastatin and lovastatin were the drugs of primary interest.

METHODS:

In a modified prevalence (cross-sectional) study, prescriptions and laboratory data for 215 191 patients exposed to a statin in 2002 were reviewed. A log-linear Poisson regression model was used to determine the statistical relationship of an elevated CK level to other independent variables.

RESULTS:

Prevalence of high elevation of CK levels (ie, n of cases/1000 pts. exposed to statins) was 1.6; prevalence of mild to moderate elevation of CK levels was 6.4. For high elevations, the prevalence ratios were lower for low doses of lovastatin than for high doses of simvastatin. A higher prevalence ratio was associated with elevated serum creatinine (SCr) levels (2.44), exposure to interacting drugs (1.62), male gender (1.48), and evidence of diabetes (1.34). For mild to moderate elevation, a higher prevalence ratio was associated with elevated SCr (1.45), exposure to interacting drugs (1.21), male gender (3.19), age ≤65 years (1.35), and evidence of diabetes (1.34). Lower prevalence ratios were associated with all doses of lovastatin compared with those of high doses of simvastatin.

CONCLUSIONS:

Compared with simvastatin, lovastatin was generally associated with a lower prevalence of high elevation and mild to moderate elevation of CK levels. An elevated SCr level, exposure to interacting drugs, male gender, evidence of diabetes, and age ≤65 years were associated with higher prevalence ratios.
Disease and Intolerability Documentation in Electronic Patient Records
Authors: Buurma Henk , De Smet Peter AGM , Kruijtbosch Martine , Egberts Antoine CG
Published: September 2005

BACKGROUND:

Documentation of diseases and intolerabilities in electronic patient records (EPRs) in pharmacies is needed to produce an alert in case a contraindicated medicine is prescribed. Limited research is available concerning EPRs in pharmacies.

Objective:

To study the prevalence and quality of documentation of diseases and intolerabilities in EPRs in a sample of Dutch community pharmacies.

METHODS:

Each participating pharmacy (N = 79) collected data on one day in May 2003 for each patient enrolled into the study (N = 687) concerning demographics, drug use, and documentation of diseases and intolerabilities.

RESULTS:

In 57.4% of the EPRs, at least one disease and, in 7.9%, at least one intolerability was documented. Higher age, number of drugs used, and chronic disease score were associated with any documentation of a disease/intolerability in the EPR. The highest sensitivity scores (completeness) were found for diabetes (84.7%), asthma/chronic obstructive pulmonary disease (strict definition: 75.9%), and hypothyroidism (75.0%). Rather low values were found for prostatic hyperplasia (55.6%) and heart failure (29.4%). The positive predictive value (reliability) was high for hypothyroidism (100%) and diabetes (87.1%).

CONCLUSIONS:

In a selection of Dutch pharmacies, at least one documented disease and/or intolerability was found in the EPR of almost 60% of the patients. Certain diseases were documented to a relatively high degree; others had poorer levels of documentation. For optimal surveillance of drug–disease interactions in pharmacies, the frequency and quality of disease and intolerability documentation need further improvement.
Reliability of Nesiritide Infusion via Non-Primed Tubing and Heparin-Coated Catheters
Authors: Onat Duygu , Stathopoulos John , Rose Andrew , Newman Karel , Sciacca Robert R , Jorde Ulrich P , Colombo Paolo C
Published: September 2005

BACKGROUND:

Prescribing information for nesiritide mandates priming of intravenous tubing prior to connecting to the patient's intravenous access because the drug may adsorb to the line. As of this writing, no published study has quantified the binding effect of nesiritide to intravenous tubing.

Objective:

To investigate whether priming of peripheral intravenous tubing is necessary and whether nesiritide can be reliably delivered through central intravenous lines, including heparin-coated catheters, where priming cannot occur.

METHODS:

A 23.3-mL bolus of nesiritide followed by a 7-mL/h 2-hour infusion were run through (1) polyvinylchloride (PVC) peripheral intravenous tubing primed with nesiritide, (2) non-primed PVC peripheral intravenous tubing, (3) non-primed polyethylene peripheral intravenous tubing, (4) non-primed PVC peripheral intravenous tubing connected to a central intravenous polyurethane catheter, and (5) non-primed PVC peripheral intravenous tubing connected to a heparin-coated pulmonary artery PVC catheter. Nesiritide concentrations were measured in the intravenous bags and in samples collected from the 5 intravenous settings.

RESULTS:

Priming of intravenous tubing with nesiritide did not increase drug recovery: at least 94% of the bolus dose and 96% of the total drug were recovered from all intravenous sets.

CONCLUSIONS:

Infusion of nesiritide via non-primed peripheral and central intravenous tubing, including heparin-coated pulmonary catheter, is reliable. Changes in nesiritide labeling appear to be warranted.
Evaluation of Herbal Dietary Supplements Marketed on the Internet for Recreational Use
Authors: Dennehy Cathi E , Tsourounis Candy , Miller Amy E
Published: September 2005

BACKGROUND:

The Internet is a popular tool for marketing and purchasing herbal dietary supplements (DS). Various Web sites sell these products purely for recreational use.

Objective:

To describe the content of Web sites that advertise and market herbal DS for recreational use (ie, for the purpose of altering mood/behavior/or perception, “getting high,” or as a substitute for a drug of abuse).

METHODS:

Four major search engines and the search terms “buy herbal high” and “buy legal high” were used to identify Web sites selling herbal DS for recreational use. Web sites were evaluated for their country of origin and for compliance with the Dietary Supplement Health and Education Act (DSHEA). Products were evaluated for their ingredient lists, effect claims, comparisons with illicit drugs, adverse effects, drug interactions, and contraindications.

RESULTS:

Twenty-eight unique Web sites with 119 products were evaluated. Most sites were in the US (54%) and were in compliance with DSHEA. Forty-seven percent of the products were likened to illicit drugs, typically marijuana (48%) or 3-,4-methylene dioxyamphetamine (Ecstasy; 23%). The most common product ingredients were ephedra alkaloids (27%), Salvia divinorum (17%), kava (10%), guarana (10%), Acorus calamus (10%), and damiana (10%). Effect claims frequently involved the products' use as a hallucinogen (51%) or stimulant (39%). Sixty-four percent of the sites mentioned adverse effects, and 54% mentioned drug interactions.

CONCLUSIONS:

This study demonstrates that herbal DS are being marketed for use as legal alternatives to illicit drugs of abuse. Healthcare professionals need to be aware of this trend and the products that are involved.
Effect of Freezing, Long-Term Storage, and Microwave Thawing on the Stability of Ketorolac Tromethamine
Authors: Hecq Jean-Daniel , Boitquin Laurence P , Vanbeckbergen Danielle F , Jamart Jacques , Galanti Laurence M
Published: September 2005

BACKGROUND:

Ketorolac tromethamine is a nonsteroidal agent with potent analgesic and moderate antiinflammatory activity. Advance preparation of intravenous solution could be useful to improve quality assurance, time management, and cost-savings of drug delivery.

Objective:

To investigate the effect of freezing, long-term storage, and microwave thawing on the stability of ketorolac tromethamine in dextrose 5% infusion.

METHODS:

Five polyolefin bags of solution containing ketorolac tromethamine 20 mg per 100 mL of dextrose 5% were frozen for 3 months at −20 °C, thawed in a microwave oven with a validated cycle, and stored at 4 °C. The concentration of ketorolac was measured by HPLC. Visual inspection and pH measurement were also carried out.

RESULTS:

No color change or precipitation was observed. Ketorolac was stable for at least 60 days under refrigeration after freeze–thaw. Throughout this period, the lower confidence limit of the estimated regression line of the concentration–time profile remained >90% of the initial concentration, and the pH value decreased slightly without affecting chromatographic parameters.

CONCLUSIONS:

Within these limits, ketorolac tromethamine in dextrose 5% infusion may be prepared and frozen in advance by a centralized intravenous admixture service, then thawed before use in clinical units.
Muscle Fiber and Motor Unit Behavior in the Longest Human Skeletal Muscle
Authors: Harris A. John , Duxson Marilyn J. , Butler Jane E. , Hodges Paul W. , Taylor Janet L. , Gandevia Simon C.
Published: September 2005

The sartorius muscle is the longest muscle in the human body. It is strap-like, up to 600 mm in length, and contains five to seven neurovascular compartments, each with a neuromuscular endplate zone. Some of its fibers terminate intrafascicularly, whereas others may run the full length of the muscle. To assess the location and timing of activation within motor units of this long muscle, we recorded electromyographic potentials from multiple intramuscular electrodes along sartorius muscle during steady voluntary contraction and analyzed their activity with spike-triggered averaging from a needle electrode inserted near the proximal end of the muscle. Approximately 30% of sartorius motor units included muscle fibers that ran the full length of the muscle, conducting action potentials at 3.9 ± 0.1 m/s. Most motor units were innervated within a single muscle endplate zone that was not necessarily near the midpoint of the fiber. As a consequence, action potentials reached the distal end of a unit as late as 100 ms after initiation at an endplate zone. Thus, contractile activity is not synchronized along the length of single sartorius fibers. We postulate that lateral transmission of force from fiber to endomysium and a wide distribution of motor unit endplates along the muscle are critical for the efficient transmission of force from sarcomere to tendon and for the prevention of muscle injury caused by overextension of inactive regions of muscle fibers.
Cannabinoid Action Depends on Phosphorylation of Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa at the Protein Kinase A Site in Striatal Projection Neurons
Authors: Andersson Mikael , Usiello Alessandro , Borgkvist Anders , Pozzi Laura , Dominguez Cecilia , Fienberg Allen A. , Svenningsson Per , Fredholm Bertil B. , Borrelli Emiliana , Greengard Paul , Fisone Gilberto
Published: September 2005

Herbal cannabis, smoked in the form of marihuana or hashish, is the most common illicit drug consumed in the Western world. In the brain, cannabinoids interact with neuronal CB1 receptors, thereby producing a marked reduction of motor activity. Here, we report that the motor depressant effect produced by the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) is attenuated by genetic inactivation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), which is abundantly expressed in the medium spiny neurons of the striatum. Point mutation of Thr34, the protein kinase A (PKA) phosphorylation site of DARPP-32, produces a similar reduction in the effect of the CB1 agonist. In contrast, point mutation of Thr75, a site on DARPP-32 specifically phosphorylated by cyclin-dependent kinase 5, does not affect the behavioral response to CP55,940. Activation of CB1 receptors, either by an agonist or by inhibition of reuptake of endogenous cannabinoids, stimulates phosphorylation at Thr34, thereby converting DARPP-32 into an inhibitor of protein phosphatase-1. Genetic inactivation either of dopamine D2receptors or of adenosine A2Areceptors reduces the phosphorylation of DARPP-32 at Thr34 and the motor depression produced by CP55,940. Our data indicate that a considerable proportion of the psychomotor effect of cannabinoids can be accounted for by a signaling cascade in striatal projection neurons involving PKA-dependent phosphorylation of DARPP-32, achieved via modulation of dopamine D2and adenosine A2Atransmission.
Endogenous Neuregulin Restores Radial Glia in a (Ferret) Model of Cortical Dysplasia
Authors: Gierdalski Marcin , Sardi Sergio Pablo , Corfas Gabriel , Juliano Sharon L.
Published: September 2005

Radial glia are integral components of the developing neocortex. During corticogenesis, they form an important scaffold for neurons migrating into the cortical plate. Recent attention has focused on neuregulin (NRG1), acting through erbB receptors, in maintaining their morphology. We developed a model of developmental radial glial disruption by delivering an antimitotic [methylazoxy methanol (MAM)] to pregnant ferrets on embryonic day 24 (E24). We previously found that normal ferret cortex contains a soluble factor capable of realigning the disorganized radial glia back toward their normal morphology. Characterization of the reorganizing activity in normal cortex demonstrated that the probable factor mediating these responses was a 30–50 kDa protein. To test whether this endogenous soluble factor was NRG1, we used organotypic cultures of E24 MAM-treated ferret neocortex supplemented with the endogenous factor obtained from normal cortical implants, exogenous NRG1β, antibodies that either blocked or stimulated erbB receptors, or a soluble erbB subtype that binds to available NRG1. We report that exogenous NRG1 or antibodies that stimulate erbB receptors dramatically improve the morphology of disrupted radial glia, whereas blockade of NRG1-erbB signaling prevents the radial glial repair. Our results suggest that NRG1 is an endogenous factor in ferret neocortex capable of repairing damaged radial glia and that it acts via one or more erbB receptors.
Repair of the Injured Adult Hippocampus through Graft-Mediated Modulation of the Plasticity of the Dentate Gyrus in a Rat Model of Temporal Lobe Epilepsy
Authors: Shetty Ashok K. , Zaman Vandana , Hattiangady Bharathi
Published: September 2005

Intracerebroventricular kainate administration in rat, a model of temporal lobe epilepsy (TLE), causes degeneration of the hippocampal CA3 pyramidal and dentate hilar neurons. This leads to a robust but aberrant sprouting of the granule cell axons (mossy fibers) into the dentate supragranular layer and the CA3 stratum oriens. Because this plasticity is linked to an increased seizure susceptibility in TLE, strategies that restrain the aberrant mossy fiber sprouting (MFS) are perceived to be important for preventing the TLE development after the hippocampal injury. We ascertained the efficacy of fetal hippocampal CA3 or CA1 cell grafting into the kainate-lesioned CA3 region of the adult rat hippocampus at early post-kainic acid injury for providing a lasting inhibition of the aberrant MFS. Analyses at 12 months after grafting revealed that host mossy fibers project vigorously into CA3 cell grafts but avoid CA1 cell grafts. Consequently, in animals receiving CA3 cell grafts, the extent of aberrant MFS was minimal, in comparison with the robust MFS observed in both “lesion-only” animals and animals receiving CA1 cell grafts. Analyses of the graft axon growth revealed strong graft efferent projections into the dentate supragranular layer with CA3 cell grafting but not with CA1 cell grafting. Thus, the formation of reciprocal circuitry between the dentate granule cells and the grafted CA3 pyramidal neurons is likely the basis of inhibition of the aberrant MFS by CA3 cell grafts. The results also underscore that grafting of cells capable of differentiating into CA3 pyramidal neurons is highly efficacious for a lasting inhibition of the abnormal mossy fiber circuitry development in the injured hippocampus.
Developmental Pluripotency of the Nuclei of Neurons in the Cerebral Cortex of Juvenile Mice
Authors: Osada Tomoharu , Tamamaki Nobuaki , Song Si-Young , Kakazu Naoki , Yamazaki Yukiko , Makino Hatsune , Sasaki Ayako , Hirayama Teruyoshi , Hamada Shun , Nave Klaus-Armin , Yanagimachi Ryuzo , Yagi Takeshi
Published: September 2005

Nuclei isolated from green fluorescent protein-marked neurons in the cerebral cortex of juvenile mice (14–21 d after birth) were injected into enucleated oocytes that were allowed to develop into blastocysts. Embryonic stem (ES) cell lines were established from the inner cell mass of 76 cloned blastocysts after injecting 2026 neuronal nuclei. Some ES cells were injected individually into enucleated oocytes (nuclear transfer). Other ES cells were transferred into the blastocoeles of tetraploid blastocysts (tetraploid complementation). Two-cell embryos after nuclear transfer were transferred to the oviducts of surrogate mothers. Four (1.5%) of 272 nuclear-transferred two-cell embryos developed to term, and two (0.7%) developed into fertile adults. Nineteen (1.9%) of 992 tetraploid blastocysts receiving ES cells reached term, and 10 (1.0%) developed into adults. These findings demonstrate that some of the nuclei of differentiated neurons in the cerebral cortex of juvenile mice maintain developmental pluripotency.
Brainstem and Forebrain Contributions to the Generation of Learned Motor Behaviors for Song
Authors: Ashmore Robin C. , Wild J. Martin , Schmidt Marc F.
Published: September 2005

Brainstem nuclei have well established roles in generating nonlearned rhythmic behaviors or as output pathways for more complex, forebrain-generated behaviors. However, the role of the brainstem in providing information to the forebrain that is used to initiate or assist in the control of complex behaviors is poorly understood. In this study, we used electrical microstimulation in select nuclei of the avian song system combined with recordings of acoustic and respiratory output to examine how forebrain and brainstem nuclei interact in the generation of learned vocal motor sequences. We found that brief stimulation in the forebrain nuclei HVC (used as a proper name) and RA (robust nucleus of the arcopallium) caused a short-latency truncation of ongoing song syllables, which ultimately led to a cessation of the ongoing motor sequence. Stimulation within the brainstem inspiratory-related nucleus paraambigualis, which receives input from RA and projects back to HVC via the thalamus, caused syllable truncations and interruptions similar to those observed in HVC and RA. In contrast, stimulation in the tracheosyringal portion of the hypoglossal nucleus, which innervates the syrinx (the avian vocal organ) but possesses no known projections back into the song system, did not cause any significant changes in the song motor pattern. These findings suggest that perturbation of premotor activity in any nucleus within the recurrent song system motor network will disrupt the ongoing song motor sequence. Given the anatomical organization of this network, our results are consistent with a model in which the brainstem respiratory nuclei form an integral part of the song motor programming network by providing timing signals to song control nuclei in the forebrain.
Human Anterior Cingulate Cortex Neurons Encode Cognitive and Emotional Demands
Authors: Davis Karen D. , Taylor Keri S. , Hutchison William D. , Dostrovsky Jonathan O. , McAndrews Mary P. , Richter Erich O. , Lozano Andres M.
Published: September 2005

The cortical mechanisms and substrates of cognitive and emotional demands are poorly understood. Lesion studies and functional imaging implicate the anterior cingulate cortex (ACC). The caudal ACC (cACC) has been implicated in cognitive processes such as attention, salience, interference, and response competition, mostly on the basis of neuroimaging results. To test the hypothesis that individual cACC neurons subserve these functions, we monitored neuronal activity from single cells in the cACC while subjects were engaged in a mental arithmetic task, the cognitively demanding counting Stroop task, and/or the emotional Stroop interference task. We now report the first direct measures of single neurons in humans identifying a population of cACC neurons that respond differentially or in a graded manner to cognitively demanding high- and low-conflict Stroop tasks, including those with emotional valence. These data indicate that cACC neurons may be acting as salience detectors when faced with conflict and difficult or emotional stimuli, consistent with neuroimaging results of cACC responses to abrupt sensory, novel, task-relevant, or painful stimuli.