bluuebunny/crossref_metadata_2025 huggingface dataset:
High synovial expression of the inhibitory FcγRIIb in rheumatoid arthritis
Authors: Magnusson Sofia E , Engström Marianne , Jacob Uwe , Ulfgren Ann-Kristin , Kleinau Sandra
Published: May 2007

Activating Fc gamma receptors (FcγRs) have been identified as having important roles in the inflammatory joint reaction in rheumatoid arthritis (RA) and murine models of arthritis. However, the role of the inhibitory FcγRIIb in the regulation of the synovial inflammation in RA is less known. Here we have investigated synovial tissue from RA patients using a novel monoclonal antibody (GB3) specific for the FcγRIIb isoform. FcγRIIb was abundantly expressed in synovia of RA patients, in sharp contrast to the absence or weak staining of FcγRIIb in synovial biopsies from healthy volunteers. In addition, the expression of FcγRI, FcγRII and FcγRIII was analyzed in synovia obtained from early and late stages of RA. Compared with healthy synovia, which expressed FcγRII, FcγRIII but not FcγRI, all activating FcγRs were expressed and significantly up-regulated in RA, regardless of disease duration. Macrophages were one of the major cell types in the RA synovium expressing FcγRIIb and the activating FcγRs. Anti-inflammatory treatment with glucocorticoids reduced FcγR expression in arthritic joints, particularly that of FcγRI. This study demonstrates for the first time that RA patients do not fail to up-regulate FcγRIIb upon synovial inflammation, but suggests that the balance between expression of the inhibitory FcγRIIb and activating FcγRs may be in favour of the latter throughout the disease course. Anti-inflammatory drugs that target activating FcγRs may represent valuable therapeutics in this disease.
Analysis of 14 BAC sequences from the Aedes aegyptigenome: a benchmark for genome annotation and assembly
Authors: Lobo Neil F , Campbell Kathy S , Thaner Daniel , deBruyn Becky , Koo Hean , Gelbart William M , Loftus Brendan J , Severson David W , Collins Frank H
Published: May 2007

Background

Aedes aegypti is the principal vector of yellow fever and dengue viruses throughout the tropical world. To provide a set of manually curated and annotated sequences from the Ae. aegypti genome, 14 mapped bacterial artificial chromosome (BAC) clones encompassing 1.57 Mb were sequenced, assembled and manually annotated using a combination of computational gene-finding, expressed sequence tag (EST) matches and comparative protein homology. PCR and sequencing were used to experimentally confirm expression and sequence of a subset of these transcripts.

Results

Of the 51 manual annotations, 50 and 43 demonstrated a high level of similarity to Anopheles gambiae and Drosophila melanogaster genes, respectively. Ten of the 12 BAC sequences with more than one annotated gene exhibited synteny with the A. gambiae genome. Putative transcripts from eight BAC clones were found in multiple copies (two copies in most cases) in the Aedes genome assembly, which point to the probable presence of haplotype polymorphisms and/or misassemblies.

Conclusion

This study not only provides a benchmark set of manually annotated transcripts for this genome that can be used to assess the quality of the auto-annotation pipeline and the assembly, but it also looks at the effect of a high repeat content on the genome assembly and annotation pipeline.
Altered Activity of 11β-Hydroxysteroid Dehydrogenase Types 1 and 2 in Skeletal Muscle Confers Metabolic Protection in Subjects with Type 2 Diabetes
Authors: Jang Christina , Obeyesekere Varuni R. , Dilley Rodney J. , Krozowski Zygmunt , Inder Warrick J. , Alford Frank P.
Published: May 2007

Context: There is little information regarding the regulation of 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes in skeletal muscle in the setting of type 2 diabetes.

Objective: Our objective was to investigate whether there is differential mRNA expression and enzyme activity of 11β-HSD1 and 11β-HSD2 in the skeletal muscle of diabetic subjects compared with controls at baseline and in response to dexamethasone.

Design: Participants underwent muscle biopsy of vastus lateralis at baseline and after dexamethasone.

Setting: The study took place at a university teaching hospital.

Participants: Twelve subjects with type 2 diabetes and 12 age- and sex-matched controls participated.

Intervention: Subjects were given oral dexamethasone, 4 mg/d for 4 d.

Main Outcome Measures: We assessed 11β-HSD1, 11β-HSD2, and H6PDH mRNA levels by quantitative RT-PCR and enzyme activity by percent conversion of [3H]cortisone and [3H]cortisol, respectively.

Results: At baseline, mRNA levels were similar in diabetic and control subjects for 11β-HSD1, 11β-HSD2, and H6PDH. 11β-HSD1 activity was reduced in diabetic subjects (percent conversion of [3H]cortisone to [3H]cortisol was 11.4 ± 2.5% vs. 18.5 ± 2.2%; P = 0.041), and 11β-HSD2 enzyme activity was higher in diabetic subjects (percent conversion of [3H]cortisone to [3H]cortisol was 17.2 ± 2.6% vs. 9.2 ± 1.3%; P = 0.012). After dexamethasone, 11β-HSD1 mRNA increased in both groups (P < 0.001), whereas 11β-HSD2 mRNA decreased (P = 0.002). 11β-HSD1 activity increased in diabetic subjects (P = 0.021) but not in controls, whereas 11β-HSD2 activity did not change in either group. At baseline, there was a significant negative correlation between 11β-HSD1 and 11β-HSD2 enzyme activity (r = −0.463; P = 0.026).

Conclusions: The activities of skeletal muscle 11β-HSD1 and 11β-HSD2 are altered in diabetes, which together may reduce intracellular cortisol generation, potentially conferring metabolic protection.
Sleep Loss Alters Basal Metabolic Hormone Secretion and Modulates the Dynamic Counterregulatory Response to Hypoglycemia
Authors: Schmid Sebastian M. , Hallschmid Manfred , Jauch-Chara Kamila , Bandorf Nadine , Born Jan , Schultes Bernd
Published: May 2007

Context: Sleep loss has immediate effects on metabolic function that in the long run may contribute to the development of obesity and type 2 diabetes.

Objective: Our objective was to explore the neuroendocrine mechanisms mediating the acute effects of sleep deprivation on blood glucose regulation under basal and hypoglycemic conditions.

Methods: In a randomized, crossover study in 10 healthy young men, plasma concentrations of relevant hormones were examined during basal rest, a subsequent stepwise hypoglycemic clamp after one night of total sleep deprivation (SD) and one night of regular sleep.

Results: Basal glucagon concentrations were decreased (P = 0.022) and C-peptide levels were slightly reduced after SD (P = 0.085), compared with regular sleep. During hypoglycemia after SD, the glucagon increase relative to baseline was enhanced (P = 0.034) and the relative decrease in C-peptide was reduced (P = 0.013). Also, the relative increase in norepinephrine was reduced (P = 0.031). SD did not affect epinephrine, ACTH, cortisol, lactate, β-hydroxybutyrate, or nonesterified fatty acids during hypoglycemia, but overall, plasma nonesterified fatty acid levels were reduced after SD (P = 0.009). SD markedly increased rated hunger during basal rest (P < 0.008), resulting in a dampened relative increase during hypoglycemia (P < 0.009). Unexpectedly, despite distinct alterations in basal secretory activity, the absolute amplitude of hormonal counterregulation and hunger responses to hypoglycemia was not affected by SD.

Conclusion: Short-term SD distinctly alters hormonal glucose regulation, affecting especially pancreatic islet secretion, and also increases hunger. Immediate perturbations in the dynamic regulation of energy metabolism caused by acute sleep curtailment may contribute to the association between chronic sleep loss and metabolic disorders.
Growth Hormone Treatment in Adolescent Males with Idiopathic Short Stature: Changes in Body Composition, Protein, Fat, and Glucose Metabolism
Authors: Hannon Tamara S. , Danadian Kapriel , Suprasongsin Chittiwat , Arslanian Silva A.
Published: May 2007

Context: Cross-sectional observations show an inverse relationship between pubertal increase in GH and insulin sensitivity, suggesting that pubertal insulin resistance may be mediated by GH.

Objective: Our objective was to assess longitudinally the effects of short-term GH supplementation in adolescent males with non-GH-deficient idiopathic short stature (ISS) on body composition, substrate metabolism, and insulin sensitivity. Children with ISS were studied to simulate the pubertal increase in GH secretion.

Participants and Setting: Eight males with ISS (10.8–16.5 yr) were recruited from pediatric endocrinology clinics at an academic medical center.

Study Design: Participants were evaluated in the General Clinical Research Center before and after 4 months of GH supplementation (0.3 mg/kg·wk). Body composition was assessed with dual-energy x-ray absorptiometry. Whole-body glucose, protein, and fat turnover were measured using stable isotopes. In vivo insulin action was assessed during a 3-h hyperinsulinemic (40 mU/m2·min) euglycemic clamp.

Results: GH supplementation led to 1) increase in hepatic glucose production and fasting insulin levels, 2) increase in lean body mass and decrease in fat mass, and 3) improvement in cardiovascular lipid risk profile. Plasma IGF-I levels correlated positively with insulin levels.

Conclusions: Four months of GH supplementation in adolescent males with ISS is associated with significant body composition changes and hepatic insulin resistance.
The Janus Kinase 2 Is Required for Expression and Nuclear Accumulation of Cyclin D1 in Proliferating Mammary Epithelial Cells
Authors: Sakamoto Kazuhito , Creamer Bradley A. , Triplett Aleata A. , Wagner Kay-Uwe
Published: May 2007

Using a conditional knockout approach, we previously demonstrated that the Janus kinase 2 (Jak2) is crucial for prolactin (PRL) signaling and normal mammary gland development. PRL is suggested to synchronously activate multiple signaling cascades that emerge on the PRL receptor (PRLR). This study demonstrates that Jak2 is essential for the activation of the signal transducer and activator of transcription 5 (Stat5) and expression of Cish (cytokine-inducible SH2-containing protein), a Stat5-responsive negative regulator of Jak/Stat signaling. However, Jak2 is dispensable for the PRL-induced activation of c-Src, focal adhesion kinase, and the MAPK pathway. Despite activation of these kinases that are commonly associated with proliferative responses, the ablation of Jak2 reduces the multiplication of immortalized mammary epithelial cells (MECs). Our studies show that signaling through Jak2 controls not only the transcriptional activation of the Cyclin D1 gene, but, more importantly, it regulates the accumulation of the Cyclin D1 protein in the nucleus by altering the activity of signal transducers that mediate the phosphorylation and subsequent nuclear export of Cyclin D1. In particular, the levels of activated Akt (protein kinase B) and inactive glycogen synthase kinase-3β (i.e. a kinase that regulates the nuclear export and degradation of Cyclin D1) are reduced in MECs lacking Jak2. The proliferation of Jak2-deficient MECs can be rescued by expressing of a mutant form of Cyclin D1 that cannot be phosphorylated by glycogen synthase kinase-3β and therefore constitutively resides in the nucleus. Besides discriminating Jak2-dependent and Jak2-independent signaling events emerging from the PRLR, our observations provide a possible mechanism for phenotypic similarities between Cyclin D1 knockouts and females lacking individual members of the PRLR signaling cascade, in particular the PRLR, Jak2, and Stat5.
A Common Polymorphism in the Bile Acid Receptor Farnesoid X Receptor Is Associated with Decreased Hepatic Target Gene Expression
Authors: Marzolini Catia , Tirona Rommel G. , Gervasini Guillermo , Poonkuzhali Balasubramanian , Assem Mahfoud , Lee Wooin , Leake Brenda F. , Schuetz John D. , Schuetz Erin G. , Kim Richard B.
Published: May 2007

The farnesoid X receptor (FXR or NR1H4) is an important bile-acid-activated, transcriptional regulator of genes involved in bile acid, lipid, and glucose homeostasis. Accordingly, interindividual variations in FXR expression and function could manifest as variable susceptibility to conditions such as cholesterol gallstone disease, atherosclerosis, and diabetes. We performed an FXR polymorphism discovery analysis of European-, African-, Chinese-, and Hispanic-Americans and identified two rare gain-of-function variants and a common single nucleotide polymorphism resulting in a G-1T substitution in the nucleotide adjacent to the translation initiation site (FXR*1B) with population allelic frequencies ranging from 2.5 to 12%. In cell-based transactivation assays, FXR*1B (-1T) activity was reduced compared with FXR*1A (-1G). This reduced activity for FXR*1B resulted from neither decreased translational efficiency nor the potential formation of a truncated translational variant. To further define the relevance of this polymorphism, gene expression was examined in a human liver bank to reveal that levels of the FXR target genes small heterodimer partner and organic anion transporting polypeptide 1B3 were significantly reduced in livers harboring an FXR*1B allele. These findings are the first to identify the presence of a common genetic variant in FXR with functional consequences that could contribute to disease risk or therapeutic outcomes.
Response of SMRT (Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptor) and N-CoR (Nuclear Receptor Corepressor) Corepressors to Mitogen-Activated Protein Kinase Kinase Kinase Cascades Is Determined by Alternative mRNA Splicing
Authors: Jonas Brian A. , Varlakhanova Natalia , Hayakawa Fumihiko , Goodson Michael , Privalsky Martin L.
Published: May 2007

The SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) corepressors are important mediators of transcriptional repression by nuclear hormone receptors. SMRT is regulated by MAPK kinase kinase (MAPKKK) cascades that induce its release from its receptor partners, its export from nucleus to cytoplasm, and derepression of target gene expression. Intriguingly, the otherwise closely related N-CoR is refractory to MAPKKK signaling under the same conditions. However, both SMRT and N-CoR are expressed as a series of alternatively spliced protein variants differing in structure and function. We have now characterized the impact of this alternative mRNA splicing on the corepressor response to MAPKKK signaling. Whereas the SMRTα, SMRTτ, and SMRTsp2 splice variants are released from their nuclear receptor partners in response to MAPKKK activation, the SMRTsp18 variant, which resembles N-CoR in its overall molecular architecture, is relatively refractory to this kinase-induced release. Alternative splicing of N-CoR, in contrast, had only minimal effects on the resistance of this corepressor to MAPKKK inhibition. Notably, all of the SMRT splice variants examined redistributed from nucleus to cytoplasm in response to MAPKKK cascade signaling, but none of the N-CoR splice variants did so. Different tiers of the MAPKKK cascade hierarchy contributed to these different aspects of corepressor regulation, with MAP/ERK kinase kinase 1 and MAP/ERK kinase 1 regulating subcellular redistribution and ERK2 regulating nuclear receptor-corepressor interaction. We conclude that cells can customize their transcriptional response to MAPKKK cascade signaling by selective expression of the SMRT or N-CoR locus, by selective utilization of a specific corepressor splice variant, and by selective exploitation of specific tiers of the MAPK cascade.
Chitin synthase III requires Chs4p-dependent translocation of Chs3p into the plasma membrane
Authors: Reyes Abigail , Sanz Maria , Duran Angel , Roncero Cesar
Published: May 2007

In Saccharomyces cerevisiae, Chs4p is required for chitin synthase III (CSIII) activity and hence for chitin synthesis. This protein is transported in vesicles in a polarized fashion independently of the other Chs proteins. Its association with membranes depends not only on prenylation, but also on its interaction with other proteins, mainly Chs3p, which is the catalytic subunit of CSIII and is able to properly direct Chs4p to the bud neck in the absence of prenylation. Chs4p is present in functionally limiting amounts and its overexpression increases Chs3p accumulation at the plasma membrane with a concomitant increase in chitin synthesis. In the absence of Chs4p, Chs3p is delivered to the plasma membrane but fails to accumulate there because it is rapidly endocytosed and accumulates in intracellular vesicles. A blockade of endocytosis stops Chs3p internalization, triggering a significant increase in chitin synthesis. This blockade is independent of Chs4p function, allowing the accumulation of Chs3p at the plasma membrane even in the chs4Δ mutant. However, the absence of Chs4p renders CSIII functionally inactive, independently of Chs3p accumulation at the plasma membrane. Chs4p thus promotes Chs3p translocation into the plasma membrane in a stable and active form. Proper CSIII turnover is maintained through the endocytic internalization of Chs3p.
Identification of novel chromatin-associated proteins involved in programmed genome rearrangements inTetrahymena
Authors: Yao Meng-Chao , Yao Ching-Ho , Halasz Lia M. , Fuller Patrick , Rexer Charles H. , Wang Sidney H. , Jain Rajat , Coyne Robert S. , Chalker Douglas L.
Published: May 2007

Extensive DNA rearrangements occur during the differentiation of the developing somatic macronuclear genome from the germ line micronuclear genome of Tetrahymena thermophila. To identify genes encoding proteins likely to be involved in this process, we devised a cytological screen to find proteins that specifically localize in macronuclear anlagen (Lia proteins) at the stage when rearrangements occur. We compared the localization of these with that of the chromodomain protein, Pdd1p, which is the most abundant known participant in this genome reorganization. We show that in live cells, Pdd1p exhibits dynamic localization, apparently shuttling from the parental to the developing nuclei through cytoplasmic bodies called conjusomes. Visualization of GFP-tagged Pdd1p also highlights the substantial three-dimensional nuclear reorganization in the formation of nuclear foci that occur coincident with DNA rearrangements. We found that late in macronuclear differentiation, four of the newly identified proteins are organized into nuclear foci that also contain Pdd1p. These Lia proteins are encoded by primarily novel genes expressed at the beginning of macronuclear differentiation and have properties or recognizable domains that implicate them in chromatin or nucleic acid binding. Three of the Lia proteins also localize to conjusomes, a result that further implicates this structure in the regulation of DNA rearrangement.
Evaluation of Consultation in Community Pharmacies with Mystery Shoppers
Authors: Alte Dietrich , Weitschies Werner , Ritter Christoph A
Published: May 2007

BACKGROUND:

Consultation of patients in community pharmacies (CPs) must meet standards, especially in selling over-the-counter drugs; however, there has been no information as to whether northeastern German CPs meet these standards.

OBJECTIVE:

To estimate aspects of consultation quality in CPs in Mecklenburg-Vorpommern, located in northeastern Germany, study factors related to consultation quality, and check compliance with Pharmacy Practice Law, because not all pharmaceutical professions may legally sell drugs.

METHODS:

In 2005, 6 mystery shoppers (pharmacy students) presented with a headache to 146 of 398 CPs; they requested a sleeping pill plus an antihistaminic drug and completed data collection forms. Consultation scores were calculated and effects of pharmacy/staff characteristics on consultation were modeled with linear (consultation score) and logistic regression (failure to detect a drug—drug interaction). Variables used in models were staff profession, pharmacy size (number of staff), city/town size (number of pharmacies), and day of the week in which shoppers visited the pharmacy.

RESULTS:

Despite a high willingness of pharmacy staff to provide consultation (83% spontaneously offered advice), northeastern German CPs did not achieve their professional mission. Extreme variation was evident in their questioning of the mystery shoppers regarding use of important single items (from 1% for pregnancy/breast-feeding considerations to 56% for dosing instructions). In all cases, drugs were sold to the shoppers; most (91%) were single agents. Drug—drug interaction detection was low: 43 (30%) counselors informed mystery shoppers about the interaction. The profession of the consulting staff and the size of the pharmacy were associated with consultation quality (highest for pharmacists; lowest for small pharmacies [2–4 staff]). For interaction detection, consulting staff profession was relevant: pharmacists had OR of 3.2 for the detection compared with pharmacy engineers/assistants. In 7 pharmacies, staff illegally sold drugs to customers.

CONCLUSIONS:

Northeastern German CPs have much need and potential for improvement in consultation quality and drug—drug interaction detection. In-depth elicitation of symptoms and details of patients' situations must be improved. Relevant training should be provided, including use of software to identify drug interactions. Mystery shopper studies give valuable information for tailoring training schemes.
Acetaminophen and Ibuprofen for Prevention of Adverse Reactions Associated with Childhood Immunization
Authors: Manley Jennifer , Taddio Anna
Published: May 2007

Objective:

To evaluate the literature examining prophylactic use of acetaminophen and ibuprofen for prevention of adverse reactions associated with childhood immunization.

Data Sources:

Articles were identified via MEDLINE/PubMed/EMBASE (1966–March 2007) using the following key terms: vaccination, immunization, diphtheria–tetanus toxoids–whole pertussis (DTwP), diphtheria tetan us–toxoid. whole pertussis, diphtheria-tetanus toxoids–acellular pertussis (DTaP), acellular pertussis, Haemophilus influenzae type B, inactivated poliovirus, pneumococcal 7-valent conjugate, measles, mumps, rubella, meningococcal C-conjugate, varicella zoster, hepatitis B, influenza, pneumococcal polysaccharide, adverse reactions, analgesics, antipyretics, acetaminophen, ibuprofen, infant, and child.

Study Selection and Data Extraction:

No limitations were placed on article selection.

Data Synthesis:

Five articles examining the effects of prophylactic acetaminophen or ibuprofen for adverse effects associated with either DTaP or DTwP vaccine were retrieved. In one randomized controlled trial of children aged 4–6 years given DTaP, no effect of prophylactic acetaminophen 15 mg/kg/dose, up to 450 mg, or ibuprofen 10 mg/kg/dose, up to 300 mg, was found on the incidence of fever, redness, pain, swelling, or itching. In 3 randomized studies of DTwP, either acetaminophen 10–15 mg/kg/dose or ibuprofen 20 mg/kg/24 hours, given in 3 equal doses before or at the time of immunization and every 4–8 hours thereafter for 12 or more hours, reduced fever, pain, fussiness, and local redness in infants 2–7 months of age compared with placebo. Results were not duplicated in older infants/children. No studies investigated use of prophylactic acetaminophen or ibuprofen for any other vaccine.

Conclusions:

Use of prophylactic acetaminophen and ibuprofen may reduce the incidence of adverse reactions in young infants receiving DTwP vaccine; however, DTwP has been replaced with DTaP, and no benefits have been demonstrated for this vaccine when evaluated in children aged 4–6 years, or with any other vaccine currently in use. Thus, neither drug can be recommended prophylactically to prevent vaccine-associated adverse reactions. Individuals at high risk for seizures may, however, warrant special consideration.
Evolution of Peroxisome Proliferator-Activated Receptor Agonists
Authors: Chang Feng , Jaber Linda A , Berlie Helen D , O'Connell Mary Beth
Published: May 2007

OBJECTIVE:

To discuss the evolution of peroxisome proliferator-activated receptor (PPAR) agonists from single site to multiple subtype or partial agonists for the treatment of type 2 diabetes, dyslipidemia, obesity, and the metabolic syndrome.

DATA SOURCES:

Information was obtained from MEDLINE (1966-March 2007) using search terms peroxisome proliferator-activated receptor agonist, PPAR dual agonist, PPAR α/γ agonist, PPAR pan agonist, partial PPAR, and the specific compound names. Other sources included pharmaceutical companies, the Internet, and the American Diabetes Association 64th-66th Scientific Sessions abstract books.

STUDY SELECTION AND DATA EXTRACTION:

Animal data, abstracts, clinical trials, and review articles were reviewed and summarized.

DATA SYNTHESIS:

PPAR α, γ, and δ receptors play an important role in lipid metabolism, regulation of adipocyte proliferation and differentiation, and insulin sensitivity. The PPAR dual agonists were developed to combine the triglyceride lowering and high-density lipoprotein cholesterol elevation from the PPAR-α agonists (fibrates) with the insulin sensitivity improvement from the PPAR-γ agonists (thiazolidinediones). Although the dual agonists reduced hemoglobin A1C(A1C) and improved the lipid profile, adverse effects led to discontinued development. Currently, PPAR-γ agonists (GW501516 in Phase I trials), partial PPAR-γ agonists (metaglidasen in Phase II and III trials), and pan agonists (α, γ, δ netoglitazone in Phase II and III trials) with improved cell and tissue selectivity are undergoing investigation to address multiple aspects of the metabolic syndrome with a single medication. By decreasing both A1C and triglycerides, metaglidasen did improve multiple aspects of the metabolic syndrome with fewer adverse effects than compared with placebo. Metaglidasen is now being compared with pioglitazone.

CONCLUSIONS:

Influencing the various PPARs results in improved glucose, lipid, and weight management, with effects dependent on full or partial agonist activity at single or multiple receptors. Although the dual PPAR compounds have been associated with unacceptable toxicities, new PPAR agonist medications continue to be developed and investigated to discover a safe drug with benefits in multiple disease states.
Assessing the Validity of Self-Reported Medication Adherence in Hepatitis C Treatment
Authors: Smith Scott R , Wahed Abdus S , Kelley Stephanie S , Conjeevaram Hari S , Robuck Patricia R , Fried Michael W
Published: May 2007

Objective:

To assess the validity of self-reported medication adherence provided by individuals in treatment for hepatitis C virus (HCV) infection with a regimen of peginterferon and ribavirin.

Methods:

Adherence was evaluated prospectively among 196 African American and 205 white subjects enrolled in Virahep-C (Viral Resistance to Antiviral Therapy of Chronic Hepatitis C), a treatment study for genotype 1 HCV infection. Adherence to the prescribed dose was measured by 2 methods: self-report questions administered during multiple clinic visits, using a touch screen computer; and recordings of bottle openings, using an electronic monitor placed inside the cap of prescription containers. Self-reported responses were compared with the electronic monitor data. Nonparametric tests were used to test the association between adherence measures at 4, 12, 24, 36, and 48 weeks of treatment.

Results:

The estimated proportion of participants who were adherent prior to a given visit ranged from 85% to 97% (ribavirin) and 97% to 100% (peginterferon) by self report and from 69% to 90% (ribavirin) and 64% to 100% (peginterferon) by electronic monitors. For ribavirin, the percentage of cases in which the 2 measurement methods agreed varied from 68% to 90%; peginterferon agreement was from 84% to 100%. Overall, adherence was higher for peginterferon than for ribavirin but decreased over time for both medications. Self-reported adherence was usually higher than that assessed by electronic measures, and the level of discrepancy increased during the course of treatment.

Conclusions:

Adherence to peginterferon and ribavirin decreased gradually during therapy but remained relatively high. Simple self-reported measures can be used to screen for nonadherence to HCV drug therapy, but should be considered as overestimation of the actual amounts taken.
Lubiprostone: A Chloride Channel Activator for Treatment of Chronic Constipation
Authors: Ambizas Emily M , Ginzburg Regina
Published: May 2007

OBJECTIVE:

To review lubiprostone's pharmacology, pharmacokinetics, efficacy, and safety in the treatment of chronic constipation.

DATA SOURCES:

A literature search was conducted using PubMed/MEDLINE (1966–January 2007), IngentaConnect, and International Pharmaceutical Abstracts (1977–January 2007). Key words used included lubiprostone, Amitiza, and chronic constipation.

STUDY SELECTION AND DATA EXTRACTION:

All articles identified from the data sources that were published in English were evaluated.

DATA SYNTHESIS:

Lubiprostone is a chloride channel activator approved by the Food and Drug Administration for the treatment of chronic constipation. A randomized, double-blind, parallel-group, placebo-controlled study evaluating the effect of lubiprostone on gastric function showed slowed gastric emptying and increased small bowel and colonic transit time. Peak plasma concentration was shown to be around 1.14 hours, with a majority of the drug excreted in the urine within 48 hours. Phase III trials have noted that most patients with chronic constipation have a spontaneous bowel movement within 24 hours after taking lubiprostone. The most common adverse events in these trials were nausea, diarrhea, abdominal pain, and headache. Lubiprostone use has not been studied in the pediatric population.

CONCLUSIONS:

Lubiprostone may be a reasonable alternative for use in patients who either fail or are intolerant of standard therapy for chronic constipation. Head-to-head comparison studies with conventional therapy are needed to contrast clinical efficacy and safety of this medication.
A New Deal for Commons? Common Resource Management and the Commons Act 2006
Authors: Rodgers Christopher P.
Published: May 2007

Common land has considerable environmental significance, and a potentially key role in the delivery of the UK government's overall strategy for improving the environmental quality of wildlife habitats in England and Wales. Common land has a unique legal status. Establishing schemes for the conservation management of sensitive habitats and landscapes on common land is complicated by the unusual nature of property rights in commons. A key objective of the Commons Act 2006 is the establishment of a new management regime for the governance of commons based on a self-regulatory model and statutory commons councils. This is an integral – and important – element not only of the government's strategy for improving the protection of wildlife habitats but also for implementing EC Directives on wildlife, including the Habitats and Species Directive of 1992. This article examines the new law on environmental governance in the 2006 Act and concludes with an appraisal of its likely impact.
Out of Sight, Out of Mind: A Study of the Transposition and Implementation of the Groundwater Directive in the United Kingdom
Authors: Bell Stuart , Etherington Laurence
Published: May 2007

EC environmental law has been the subject of close scrutiny for many years, with inadequate transposition and implementation of directives highlighted by the European Court and others. This scrutiny has played a part in the incremental development of the nature of the obligations which directives place on Member States. Thus a history of transposition can be studied for the older directives, so that uncertainties and other problems with provisions; the evolving nature of transposing measures; and the experience of practical implementation can be brought together to identify failings in transposition and implementation, assess whether and how these have been addressed, and identify the continuing consequences of these failings. This article examines such a ‘life-cycle’ of transposition and implementation within the United Kingdom of one of the more mature environmental directives – the Groundwater Directive. This Directive is nearing the end of a lengthy life-cycle, with the transition to the Water Framework Directive under way. The Directive has not been the subject of significant attention by the courts or academic writers and so it might be assumed that it has proved less problematic than other directives. Yet there have been important, albeit latent, problems, which only become apparent when looking beneath the level of paper transposition at practical implementation. These problems could, however, have serious continuing consequences for the environment.
Striking Variations in Corticosteroid Modulation of Long-Term Potentiation along the Septotemporal Axis of the Hippocampus
Authors: Maggio Nicola , Segal Menahem
Published: May 2007

The ability to express long-term potentiation (LTP) of reactivity to afferent stimulation along the septotemporal axis was explored in transverse rat hippocampal slices. The ventral pole of the hippocampus (VH) was found to be much impaired in ability to express LTP compared with the rest of the hippocampus. An exposure to acute stress before the rat was killed reversed this trend, and slices from VH now expressed a large LTP, whereas in the rest of the hippocampus, it was much suppressed. The enhanced LTP in VH was mediated by activation of a mineralocorticoid receptor (MR), whereas the suppressed LTP was mediated by activation of a glucocorticoid receptor, and indeed selective agonists of the respective steroid receptors mimicked the effects of stress, whereas selective antagonists blocked them. The MR-enhanced LTP in VH was not mediated by activation of the NMDA receptor but by enhancement of voltage-gated calcium channels. Because the VH has an unique efferent system to the hypothalamus, these results indicate that stress may activate this system while suppressing the ability of the rest of the hippocampus to express plastic properties under stressful conditions.
Impaired Motor Learning in the Vestibulo-Ocular Reflex in Mice with Multiple Climbing Fiber Input to Cerebellar Purkinje Cells
Authors: Kimpo Rhea R. , Raymond Jennifer L.
Published: May 2007

A unique feature of the cerebellar architecture is that Purkinje cells in the cerebellar cortex each receive input from a single climbing fiber. In mice deficient in the γ isoform of protein kinase C (PKCγ−/−mice), this normal architecture is disrupted so that individual Purkinje cells receive input from multiple climbing fibers. These mice have no other known abnormalities in the cerebellar circuit. Here, we show thatPKCγ−/−mice are profoundly impaired in vestibulo-ocular reflex (VOR) motor learning. ThePKCγ−/−mice exhibited no adaptive increases or decreases in VOR gain at training frequencies of 2 or 0.5 Hz. This impairment was present across a broad range of peak retinal slip speeds during training. We compare the results for VOR motor learning with previous studies of the performance ofPKCγ−/−mice on other cerebellum-dependent learning tasks. Together, the results suggest that single climbing fiber innervation of Purkinje cells is critical for some, but not all, forms of cerebellum-dependent learning, and this may depend on the region of the cerebellum involved, the organization of the relevant neural circuits downstream of the cerebellar cortex, as well as the timing requirements of the learning task.
Multiple Effects of Ephrin-A5 on Cortical Neurons Are Mediated by Src Family Kinases
Authors: Zimmer Geraldine , Kästner Bettina , Weth Franco , Bolz Jürgen
Published: May 2007

The Eph receptor tyrosine kinases and their membrane-bound ligands, the ephrins, are involved in a variety of developmental processes such as axonal guidance, cell migration, cell adhesion, proliferation, and differentiation. In addition to repulsive effects, ephrins can also induce attractive responses. Up to now, little was known about the underlying signaling mechanisms that regulate attractive versus repulsive effects. In this study, we show that ephrin-A5 enhances the motility of cortical neurons that is dependent on the activity of Src-family kinases (SFKs). Ephrin-A5 further changes the adhesive properties of neurons by inducing the formation of cell aggregates. Using the stripe assay, we found that the motogenic effect of ephrin-A5 is the result of repulsive ephrin-A interactions. Blocking SFK function leads to a conversion of repulsion into adhesion, suggesting that SFKs can act as a biological switch for the response of EphA receptors. Finally, we discovered a ligand-induced release of membrane particles containing EphA receptors, suggesting membrane ripping as a novel mechanism to overcome the “ephrin paradox” of repulsion after high-affinity receptor–ligand binding.
Sodium Valproate Exerts Neuroprotective EffectsIn Vivothrough CREB-Binding Protein-Dependent Mechanisms But Does Not Improve Survival in an Amyotrophic Lateral Sclerosis Mouse Model
Authors: Rouaux Caroline , Panteleeva Irina , René Frédérique , Gonzalez de Aguilar Jose-Luis , Echaniz-Laguna Andoni , Dupuis Luc , Menger Yannick , Boutillier Anne-Laurence , Loeffler Jean-Philippe
Published: May 2007

Amyotrophic lateral sclerosis (ALS) is characterized by motoneuron (MN) degeneration, generalized weakness, and muscle atrophy. The premature death of MNs is thought to be a determinant in the onset of this disease. In a transgenic mouse model of ALS expressing the G86R mutant superoxide dismutase 1 (mSOD1), we demonstrated previously that CREB (cAMP response element-binding protein)-binding protein (CBP) and histone acetylation levels were specifically decreased in nuclei of degenerating MNs. We show here that oxidative stress and mSOD1 overexpression can both impinge on CBP levels by transcriptional repression, in an MN-derived cell line. Histone deacetylase inhibitor (HDACi) treatment was able to reset proper acetylation levels and displayed an efficient neuroprotective capacity against oxidative stressin vitro. Interestingly, HDACi also upregulated CBP transcriptional expression in MNs. Moreover, when injected to G86R micein vivo, the HDACi sodium valproate (VPA) maintained normal acetylation levels in the spinal cord, efficiently restored CBP levels in MNs, and significantly prevented MN death in these animals. However, despite neuroprotection, mean survival of treated animals was not significantly improved (<5%), and they died presenting the classical ALS symptoms. VPA was not able to prevent disruption of neuromuscular junctions, although it slightly delayed the onset of motor decline and retarded muscular atrophy to some extent. Together, these data show that neuroprotection can improve disease onset, but clearly provide evidence that one can uncouple MN survival from whole-animal survival and point to the neuromuscular junction perturbation as a primary event of ALS onset.
Glial Cell Line-Derived Neurotrophic Factor and Neurturin Inhibit Neurite Outgrowth and Activate RhoA through GFRα2b, an Alternatively Spliced Isoform of GFRα2
Authors: Yoong Li Foong , Too Heng-Phon
Published: May 2007

The glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) belong to a structurally related family of neurotrophic factors. NTN exerts its effect through a multicomponent receptor system consisting of the GDNF family receptor α2 (GFRα2), RET, and/or NCAM (neural cell adhesion molecule). GFRα2 is alternatively spliced into at least three isoforms (GFRα2a, GFRα2b, and GFRα2c). It is currently unknown whether these isoforms share similar functional and biochemical properties. Using highly specific and sensitive quantitative real-time PCR, these isoforms were found to be expressed at comparable levels in various regions of the human brain. When stimulated with GDNF and NTN, both GFRα2a and GFRα2c, but not GFRα2b, promoted neurite outgrowth in transfected Neuro2A cells. These isoforms showed ligand selectivity in MAPK (mitogen-activated protein kinase) [ERK1/2 (extracellular signal-regulated kinase 1/2)] and Akt signaling. In addition, the GFRα2 isoforms regulated different early-response genes when stimulated with GDNF or NTN. In coexpression studies, GFRα2b was found to inhibit ligand-induced neurite outgrowth by GFRα2a and GFRα2c. Stimulation of GFRα2b also inhibited the neurite outgrowth induced by GFRα1a, another member of the GFRα. Furthermore, activation of GFRα2b inhibited neurite outgrowth induced by retinoic acid and activated RhoA. Together, these data suggest a novel paradigm for the regulation of growth factor signaling and neurite outgrowth via an inhibitory splice variant of the receptor. Thus, depending on the expressions of specific GFRα2 receptor spliced isoforms, GDNF and NTN may promote or inhibit neurite outgrowth through the multicomponent receptor complex.
A Dynamic Nonlinearity and Spatial Phase Specificity in Macaque V1 Neurons
Authors: Williams Patrick E. , Shapley Robert M.
Published: May 2007

While studying the visual response dynamics of neurons in the macaque primary visual cortex (V1), we found a nonlinearity of temporal response that influences the visual functions of V1 neurons. Simple cells were recorded in all layers of V1; the nonlinearity was strongest in neurons located in layer 2/3. We recorded the spike responses to optimal sinusoidal gratings that were displayed for 100 ms, a temporal step response. The step responses were measured at many spatial phases of the grating stimulus. To judge whether simple cell behavior was consistent with linear temporal integration, the decay of the 100 ms step response at the preferred spatial phase was used to predict the step response at the opposite spatial phase. Responses in layers 4B and 4C were mostly consistent with a linear-plus-static-nonlinearity cascade model. However, this was not true in layer 2/3 where most cells had little or no step responses at the opposite spatial phase. Many layer 2/3 cells had transient preferred-phase responses but did not respond at the offset of the opposite-phase stimuli, indicating a dynamic nonlinearity. A different stimulus sequence, rapidly presented random sinusoids, also produced the same effect, with layer 2/3 simple cells exhibiting elevated spike rates in response to stimuli at one spatial phase but not 180° away. The presence of a dynamic nonlinearity in the responses of V1 simple cells indicates that first-order analyses often capture only a fraction of neuronal behavior. The visual implication of our results is that simple cells in layer 2/3 are spatial phase-sensitive detectors that respond to contrast boundaries of one sign but not the opposite.
CRC – Concepts and Evaluation of Processor-Like Reconfigurable Architectures (CRC – Konzepte und Bewertung prozessorartig rekonfigurierbarer Architekturen)
Authors: Oppold Tobias , Schweizer Thomas , Oliveira Filho Julio , Eisenhardt Sven , Rosenstiel Wolfgang
Published: May 2007

The CRC project focuses on the utilization of fast reconfiguration to optimize area, performance, and power. The results are quantified by a synthesizable architecture model and by a commercial architecture. In order to assure good applicability of the research, a C-compiler is co-developed with the architecture. This article provides an overview of the optimization techniques and a summary of current evaluation results.
Autovision – A Run-time Reconfigurable MPSoC Architecture for Future Driver Assistance Systems (Autovision – Eine zur Laufzeit rekonfigurierbare MPSoC Architektur für zukünftige Fahrerassistenzsysteme)
Authors: Claus Christopher , Stechele Walter , Herkersdorf Andreas
Published: May 2007

In this article the Autovision architecture is presented, a new Multi Processor System-on-Chip (MPSoC) architecture for future video-based driver assistance systems, using run-time reconfigurable hardware accelerator engines for video processing. According to various driving conditions (highway, city, sunlight, rain, tunnel entrance) different algorithms have to be used for video processing. These different algorithms require different hardware accelerator engines, which are loaded into the Autovision chip at run-time of the system, triggered by changing driving conditions. It was investigated how to use dynamic partial reconfiguration to load and operate the correct hardware accelerator engines in time, while removing unused engines in order to save precious chip area.
An Area Efficient Realisation of AES for Wireless Devices (Eine flächeneffiziente AES Hardwarerealisierung für drahtlose Geräte)
Authors: Vater Frank , Langendörfer Peter
Published: May 2007

In this paper we describe our own AES implementation, which supports encryption as well as decryption. Our major design goal was to reduce the area while still being capable to support high speed wireless networks such as IEEE 802.11a. Our AES solution provides a throughput of 54 MBit/s at 33 MHz and requires an area of 0.33 mm2 in a 0.25 μm technology. This version may be run at up to 66 MHz which gives a throughput of 108 MBit/s. During the design we took into account global as well as local optimisations, i. e., optimisations which could be done inside an individual operation without affecting the rest of the design.
Twain's Feast: ““The American”” at Table
Authors: beahrs andrew
Published: May 2007

While touring Europe in 1879, Mark Twain composed a long menu of the eighty American foods he professed to miss the most. Drawn from his own fondest memories of life in the United States, the menu allowed him to think of America without the bitterness that so often characterized his political commentary. Instead of a nation of hypocrisy and greed, he imagined a country of abundance and mighty appetite, the source of the folkways that he celebrated throughout his work. Maintaining this image required notable omissions, as he carefully constructed an image of America without details that could have undermined the contrast between the complex "shams" of Europe and his supposedly simple, genuine home country. The result was an idealized portrayal not only of the United States, but of Twain's own biography and authorial persona.
They Eat Horses, Don't They? Hippophagy and Frenchness
Authors: weil kari
Published: May 2007

In the Nineteenth Century, France became a nation that ate horse. The introduction of horsemeat into French cuisine marks a rare occurrence in history of a change in attitude, if not taste, towards a once tabooed food. Whether or not to permit hippophagy was, indeed, a matter of great debate at the time, having to do not only with the status of French cuisine, but also with the status of the horse. While the legalization of horsemeat for human food in 1866 was justified primarily on socioeconomic grounds -- horsemeat was a ready and cheap source of protein for those in need -- the consumption of horse remained a controversial idea because of the complex and conflicting affections horses inspired. The debates around hippophagy reveal an increasingly ambivalent attitude toward the horse and its potential subjectivity, especially since horses, in turn, had the power to represent the questionable subjectivity of certain "breeds" of humans and their status within the nation.
At the Prince's Table: Food in The Leopard
Authors: simeti mary taylor
Published: May 2007

The food so lovingly described by Tomasi di Lampedusa in his novel The Leopard is as rich in gastronomic history as it is in fragrance and flavor. The famous timbale gathers strands from all stages of Sicilian history, while the author also makes liberal use of other traditions such as that of pastries made by nuns. Each dish functions primarily as metaphor, most often for a decaying society and approaching death, but Lampedusa's own passionate love for good food fuels his sensuous descriptions, and his own tastes are revealed obliquely through the preferences of his protagonist.