bluuebunny/crossref_metadata_2025 huggingface dataset:
The disease management program for type 2 diabetes in Germany enhances process quality of diabetes care - a follow-up survey of patient's experiences
Authors: Schäfer Ingmar , Küver Claudia , Gedrose Benjamin , Hoffmann Falk , Ruß-Thiel Barbara , Brose Hans-Peter , van den Bussche Hendrik , Kaduszkiewicz Hanna
Published: March 2010

Background

In summer 2003 a disease management program (DMP) for type 2 diabetes was introduced on a nationwide basis in Germany. Patient participation and continuity of care within the DMP are important factors to achieve long-term improvements in clinical endpoints. Therefore it is of interest, if patients experience any positive or negative effects of the DMP on their treatment that would support or hamper further participation. The main objective of the study was to find out if the German Disease Management Program (DMP) for type 2 diabetes improves process and outcome quality of medical care for patients in the light of their subjective experiences over a period of one year.

Methods

Cohort study with a baseline interview and a follow-up after 10.4 ± 0.64 months. Data on process and outcome measures were collected by telephone interviews with 444 patients enrolled and 494 patients not enrolled in the German DMP for type 2 diabetes. Data were analyzed by multivariate logistic regression analyses.

Results

DMP enrolment was significantly associated with a higher process quality of care. At baseline enrolled patients more often reported that they had attended a diabetes education course (OR = 3.4), have ≥ 4 contacts/year with the attending physician (OR = 3.3), have at least one annual foot examination (OR = 3.1) and one referral to an ophthalmologist (OR = 3.4) and possess a diabetes passport (OR = 2.4). Except for the annual referral to an ophthalmologist these parameters were also statistically significant at follow-up. In contrast, no differences between enrolled and not enrolled patients were found concerning outcome quality indicators, e.g. self-rated health, Glycated hemoglobin (GHb) and blood pressure. However, 16-36% of the DMP participants reported improvements of body weight and/or GHb and/or blood pressure values due to enrolment - unchanged within one year of follow-up.

Conclusions

In the light of patient's experiences the DMP enhances the process quality of medical care for type 2 diabetes in Germany. The lack of significant differences in outcome quality between enrolled and not enrolled patients might be due to the short program duration. Our data suggest that the DMP for type 2 diabetes should not be withdrawn unless an evidently more promising approach is found.
Improving the yeast two-hybrid system with permutated fusions proteins: the Varicella Zoster Virus interactome
Authors: Stellberger Thorsten , Häuser Roman , Baiker Armin , Pothineni Venkata R , Haas Jürgen , Uetz Peter
Published: March 2010

Background

Yeast two-hybrid (Y2H) screens have been among the most powerful methods to detect and analyze protein-protein interactions. However, they suffer from a significant degree of false negatives, i.e. true interactions that are not detected, and to a certain degree from false positives, i.e. interactions that appear to take place only in the context of the Y2H assay. While the fraction of false positives remains difficult to estimate, the fraction of false negatives in typical Y2H screens is on the order of 70-90%. Here we present novel Y2H vectors that significantly decrease the number of false negatives and help to mitigate the false positive problem.

Results

We have constructed two new vectors (pGBKCg and pGADCg) that allow us to make both C-terminal fusion proteins of DNA-binding and activation domains. Both vectors can be combined with existing vectors for N-terminal fusions and thus allow four different bait-prey combinations: NN, CC, NC, and CN. We have tested all ~4,900 pairwise combinations of the 70 Varicella-Zoster-Virus (VZV) proteins for interactions, using all possible combinations. About ~20,000 individual Y2H tests resulted in 182 NN, 89 NC, 149 CN, and 144 CC interactions. Overlap between screens ranged from 17% (NC-CN) to 43% (CN-CC). Performing four screens (i.e. permutations) instead of one resulted in about twice as many interactions and thus much fewer false negatives. In addition, interactions that are found in multiple combinations confirm each other and thus provide a quality score. This study is the first systematic analysis of such N- and C-terminal Y2H vectors.

Conclusions

Permutations of C- and N-terminal Y2H vectors dramatically increase the coverage of interactome studies and thus significantly reduce the number of false negatives. We suggest that future interaction screens should use such vector combinations on a routine basis, not the least because they provide a built-in quality score for Y2H interactions that can provide a measure of reproducibility without additional assays.
Highly pathogenic avian influenza A virus H5N1 NS1 protein induces caspase-dependent apoptosis in human alveolar basal epithelial cells
Authors: Zhang Chuanfu , Yang Yutao , Zhou Xiaowei , Liu Xuelin , Song Hongbin , He Yuxian , Huang Peitang
Published: March 2010

Background

It is widely considered that the multifunctional NS1 protein of influenza A viruses contributes significantly disease pathogenesis by modulating a number of virus and host-cell processes, but it is highly controversial whether this non-structural protein is a proapoptotic or antiapoptotic factor in infected cells.

Results

NS1 protein of influenza A/chicken/Jilin/2003 virus, a highly pathogenic H5N1 strain, could induce apoptosis in the carcinomic human alveolar basal epithelial cells (A549) by electron microscopic and flow cytometric analyses. NS1 protein-triggered apoptosis in A549 cells is via caspase-dependent pathway.

Conclusions

Influenza A virus NS1 protein serves as a strong inducer of apoptosis in infected human respiratory epithelial cells and plays a critical role in disease pathogenesis.
The usefulness of immunohistochemistry in tissue microarrays of Human Papillomavirus negative adenocarcinoma of the uterine cervix
Authors: Odida Michael , Lloveras Belen , Guimera Nuria , Weiderpass Elisabete
Published: March 2010

Background

The origin of adenocarcinomas presenting on the cervix uteri may be doubtful, i.e. whether it is of cervical or endometrial origin, due to the overlapping morphological features. In HPV negative samples, further tests may be needed to ascertain the nature of the tumours. We aimed to explore the use of immunohistochemistry profiles in tissue microarrays in archived samples of adenocarcinoma (ADC) of the cervix from Uganda that tested negative for HPV DNA.

Findings

Five commercially available antibodies were tested in tissue array sections immunostained utilizing the avidin-biotin (AB) technique. In 26 ADC samples, HPV was detected in 13, p16 in 15 (8 in HPV positive and 7 in HPV negative), CEA in 12, vimentin in 6, ER in 0, and PR in 2. Among the 13/25 HPV negative ADC samples, five were positive for CEA suggesting endocervical origin, and three were vimentin positive (one had a mucinous endocervical histological pattern and two were ADC, not otherwise specified, most likely of endometrial origin).

Conclusions

The immunoprofiles of ADC with the antibodies studied are rather nonspecific. By using immunohistochemistry in 13 HPV negative ADC, endocervical tumour origin was suspected in five CEA positive cases while two out of three vimentin positive samples were probably of endometrial origin, suggesting that CEA and vimentin may be valuable in distinguishing HPV negative cervical adenocarcinomas from endometrial adenocarcinomas.
Identification of a new mechanism for targeting myosin II heavy chain phosphorylation by Dictyostelium myosin heavy chain kinase B
Authors: Underwood Julie , Greene Jonathan , Steimle Paul A
Published: March 2010

Background

Heavy chain phosphorylation plays a central role in regulating myosin II bipolar filament assembly in Dictyostelium, as well as in higher eukaryotic nonmuscle cells. Our previous work has demonstrated that the WD-repeat domain of Dictyostelium myosin II heavy chain kinase B (MHCK-B), unlike its counterpart in MHCK-A, is not absolutely required for targeting of the kinase to phosphorylate MHC. Thus, we tested the hypothesis that an asparagine-rich and structurally disordered region that is unique to MHCK-B can by itself function in substrate targeting.

Findings

Biochemical assays comparing the activities of full-length MHCK-B, a truncation lacking only the WD-repeat domain (B-Δ-WD), and a truncation lacking both the N-rich region and the WD-repeat domain (B-Δ-N-WD) revealed that the N-rich region targets MHCK-B to phosphorylate MHC in a manner that leads to bipolar filament disassembly. This targeting is physiologically relevant since cellular over-expression of the B-Δ-WD truncation, but not the B-Δ-N-WD truncation, leads to dramatically reduced levels of myosin II filament assembly and associated defects in cytokinesis and multicellular development.

Conclusions

The results presented here demonstrate that an intrinsically unstructured, and asparagine-rich, region of a MHCK-B can mediate specific targeting of the kinase to phosphorylate myosin II heavy chain. This targeting involves a direct binding interaction with myosin II filaments. In terms of regulating myosin bipolar filament assembly, our results suggest that factors affecting the activity of this unique region of MHCK-B could allow for regulation of MHCK-B in a manner that is distinct from the other MHCKs in Dictyostelium.
Heel raises versus prefabricated orthoses in the treatment of posterior heel pain associated with calcaneal apophysitis (Sever's Disease): study protocol for a randomised controlled trial
Authors: James Alicia M , Williams Cylie M , Haines Terry P
Published: March 2010

Background

Posterior Heel pain can present in children of 8 to 14 years, associated with or clinically diagnosed as Sever's disease, or calcaneal apophysitis. Presently, there are no comparative randomised studies evaluating treatment options for posterior heel pain in children with the clinical diagnosis of calcaneal apophysitis or Sever's disease. This study seeks to compare the clinical efficacy of some currently employed treatment options for the relief of disability and pain associated with posterior heel pain in children.

Method

Design: Factorial 2 × 2 randomised controlled trial with monthly follow‐up for 3 months.

Participants: Children with clinically diagnosed posterior heel pain possibly associated with calcaneal apophysitis/Sever's disease (n = 124).

Interventions: Treatment factor 1 will be two types of shoe orthoses: a heel raise or prefabricated orthoses. Both of these interventions are widely available, mutually exclusive treatment approaches that are relatively low in cost. Treatment factor 2 will be a footwear prescription/replacement intervention involving a shoe with a firm heel counter, dual density EVA midsole and rear foot control. The alternate condition in this factor is no footwear prescription/replacement, with the participant wearing their current footwear.

Outcomes: Oxford Foot and Ankle Questionnaire and the Faces pain scale.

Discussion

This will be a randomised trial to compare the efficacy of various treatment options for posterior heel pain in children that may be associated with calcaneal apophysitis also known as Sever's disease.

Trial Registration

Trial Number: ACTRN12609000696291

Ethics Approval Southern Health: HREC Ref: 09271B
A scaling normalization method for differential expression analysis of RNA-seq data
Authors: Robinson Mark D , Oshlack Alicia
Published: March 2010

The fine detail provided by sequencing-based transcriptome surveys suggests that RNA-seq is likely to become the platform of choice for interrogating steady state RNA. In order to discover biologically important changes in expression, we show that normalization continues to be an essential step in the analysis. We outline a simple and effective method for performing normalization and show dramatically improved results for inferring differential expression in simulated and publicly available data sets.
An Innovative Method to Classify SERMs Based on the Dynamics of Estrogen Receptor Transcriptional Activity in Living Animals
Authors: Rando Gianpaolo , Horner David , Biserni Andrea , Ramachandran Balaji , Caruso Donatella , Ciana Paolo , Komm Barry , Maggi Adriana
Published: March 2010

Using a mouse model engineered to measure estrogen receptor (ER) transcriptional activity in living organisms, we investigated the effect of long-term (21 d) hormone replacement on ER signaling by whole-body in vivo imaging. Estrogens and selective ER modulators were administered daily at doses equivalent to those used in humans as calculated by the allometric approach. As controls, ER activity was measured also in cycling and ovariectomized mice. The study demonstrated that ER-dependent transcriptional activity oscillated in time, and the frequency and amplitude of the transcription pulses was strictly associated with the target tissue and the estrogenic compound administered. Our results indicate that the spatiotemporal activity of selective ER modulators is predictive of their structure, demonstrating that the analysis of the effect of estrogenic compounds on a single surrogate marker of ER transcriptional activity is sufficient to classify families of compounds structurally and functionally related. For more than one century, the measure of drug structure-activity relationships has been based on mathematical equations describing the interaction of the drug with its biological receptor. The understanding of the multiplicity of biological responses induced by the drug-receptor interaction demonstrated the limits of current approach and the necessity to develop novel concepts for the quantitative analysis of drug action. Here, a systematic study of spatiotemporal effects is proposed as a measure of drug efficacy for the classification of pharmacologically active compounds. The application of this methodology is expected to simplify the identification of families of molecules functionally correlated and to speed up the process of drug discovery.
Molecular mechanisms underlying nucleocytoplasmic shuttling of actinin-4
Authors: Kumeta Masahiro , Yoshimura Shige H. , Harata Masahiko , Takeyasu Kunio
Published: March 2010

In addition to its well-known role as a crosslinker of actin filaments at focal-adhesion sites, actinin-4 is known to be localized to the nucleus. In this study, we reveal the molecular mechanism underlying nuclear localization of actinin-4 and its novel interactions with transcriptional regulators. We found that actinin-4 is imported into the nucleus through the nuclear pore complex in an importin-independent manner and is exported by the chromosome region maintenance-1 (CRM1)-dependent pathway. Nuclear actinin-4 levels were significantly increased in the late G2 phase of the cell cycle and were decreased in the G1 phase, suggesting that active release from the actin cytoskeleton was responsible for increased nuclear actinin-4 in late G2. Nuclear actinin-4 was found to interact with the INO80 chromatin-remodeling complex. It also directs the expression of a subset of cell-cycle-related genes and interacts with the upstream-binding factor (UBF)-dependent rRNA transcriptional machinery in the M phase. These findings provide molecular mechanisms for both nucleocytoplasmic shuttling of proteins that do not contain a nuclear-localization signal and cell-cycle-dependent gene regulation that reflects morphological changes in the cytoskeleton.
MAPK scaffolding by BIT1 in the Golgi complex modulates stress resistance
Authors: Yi Ping , Nguyên Duc Thang , Higa-Nishiyama Arisa , Auguste Patrick , Bouchecareilh Marion , Dominguez Michel , Bielmann Regula , Palcy Sandrine , Liu Jian Feng , Chevet Eric
Published: March 2010

The endoplasmic reticulum (ER) is an essential organelle whose major functions are to ensure proper secretory protein folding and trafficking. These mechanisms involve the activation of specific ER-resident molecular machines, which might be regulated by their membranous environments. Based on this observation, we aimed to characterize the proteome of ER-membrane microdomains to identify new components of the ER that have a role in secretory pathway-associated functions. Using this approach with dog pancreatic rough microsomes, we found that mitochondrial Bcl-2 inhibitor of transcription (BIT1) localized in the early secretory pathway and accumulated in the Golgi complex. Using both a chimeric protein of the luminal and transmembrane domains of ER-resident TRAPα and the cytosolic domain of BIT1, and silencing of BIT1 expression, we perturbed endogenous BIT1 oligomerization and localization to the Golgi. This led to enhanced ERK signaling from the Golgi complex, which resulted in improved stress resistance. This work provides the first evidence for the existence of ER microdomains that are involved in the regulation of BIT1 structure and trafficking, and identifies BIT1 as a negative regulator of the ERK-MAPK signaling pathway in the Golgi.
cdc-25.2, aC. elegansortholog ofcdc25, is required to promote oocyte maturation
Authors: Kim Jiyoung , Kawasaki Ichiro , Shim Yhong-Hee
Published: March 2010

Cdc25 is an evolutionarily conserved protein phosphatase that promotes progression through the cell cycle. Some metazoans have multiple isoforms of Cdc25, which have distinct functions and different expression patterns during development. C. elegans has four cdc-25 genes. cdc-25.1 is required for germline mitotic proliferation. To determine if the other members of the cdc-25 family also contribute to regulation of cell division in the germ line, we examined phenotypes of loss-of-function mutants of the other cdc-25 family genes. We found that cdc-25.2 is also essential for germline development. cdc-25.2 homozygous mutant hermaphrodites exhibited sterility as a result of defects in oogenesis: mutant oocytes were arrested as endomitotic oocytes that were not fertilized successfully. Spermatogenesis and male germline development were not affected. Through genetic interaction studies, we found that CDC-25.2 functions upstream of maturation-promoting factor containing CDK-1 and CYB-3 to promote oocyte maturation by counteracting function of WEE-1.3. We propose that cdc-25 family members function as distinct but related cell cycle regulators to control diverse cell cycles in C. elegans germline development.
Polarity proteins and Rho GTPases cooperate to spatially organise epithelial actin-based protrusions
Authors: Georgiou Marios , Baum Buzz
Published: March 2010

Different actin-filament-based structures co-exist in many cells. Here, we characterise dynamic actin-based protrusions that form at distinct positions within columnar epithelial cells, focusing on basal filopodia and sheet-like intermediate-level protrusions that extend between surrounding epithelial cells. Using a genetic analysis, we found that the form and distribution of these actin-filament-based structures depends on the activities of apical polarity determinants, not on basal integrin signalling. Bazooka/Par3 acts upstream of the RacGEF Sif/TIAM1 to limit filopodia to the basal domain, whereas Cdc42, aPKC and Par6 are required for normal protrusion morphology and dynamics. Downstream of these polarity regulators, Sif/TIAM1, Rac, SCAR and Arp2/3 complexes catalyse actin nucleation to generate lamellipodia and filopodia, whose form depends on the level of Rac activation. Taken together, these data reveal a role for Baz/Par3 in the establishment of an intercellular gradient of Rac inhibition, from apical to basal, and an intimate association between different apically concentrated Par proteins and Rho-family GTPases in the regulation of the distribution and structure of the polarised epithelial actin cytoskeleton.
Chemotactic activation ofDictyosteliumAGC-family kinases AKT and PKBR1 requires separate but coordinated functions of PDK1 and TORC2
Authors: Liao Xin-Hua , Buggey Jonathan , Kimmel Alan R.
Published: March 2010

Protein kinases AKT and PKBR1 of Dictyostelium belong to the AGC protein kinase superfamily. AKT and PKBR1 are phosphorylated at similar sites by phosphoinositide-dependent kinase 1 (PDK1) and TORC2 kinases; however, they have different subcellular localizing domains. AKT has a phosphoinositide 3-kinase (PI3K)/phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3]-regulated PH (pleckstrin homology) domain whereas PKBR1 is myristoylated and persistently membrane localized. Using strains defective for PI3K/PtdIns(3,4,5)P3-, PDK1- and TORC2-signaling or strains that express phospho-site mutants of AKT and PKBR1, we dissect the different roles of PI3K/PtdIns(3,4,5)P3, PDK1 and TORC2. We show that activation of AKT and PKBR1 requires PDK1-site phosphorylation, but that phosphorylation by TORC2 is insufficient for AKT or PKBR1 activation. However, PDK1-site phosphorylation is dependent on phosphorylation by TORC2, which suggests that there is regulatory coordination among PDK1, TORC2 and their phospho-site targets. This defines a separate input for signaling in control of chemotaxis and dependency on PDK1 function. We also demonstrate that PDK1 in Dictyostelium functions independently of PI3K/PtdIns(3,4,5)P3. Finally, we show that AKT and PKBR1 exhibit substrate selectivity and identify two novel lipid-interacting proteins preferentially phosphorylated by AKT. Despite certain similarities, AKT and PKBR1 have distinct regulatory paths that impact activation and effector targeting, with PDK1 serving a central role.
Welcome to a new kind of tension: translating kinetochore mechanics into a wait-anaphase signal
Authors: Maresca Thomas J. , Salmon E. D.
Published: March 2010

Recent high-resolution studies of kinetochore structure have transformed the way researchers think about this crucial macro-molecular complex, which is essential for ensuring chromosome segregation occurs faithfully during cell division. Kinetochores mediate the interaction between chromosomes and the plus-ends of dynamic spindle microtubules and control the timing of anaphase onset by regulating the spindle assembly checkpoint (SAC). There is much debate in the SAC research community as to whether mitotic cells sense only microtubule attachment at the kinetochore, or both attachment and tension, before committing to anaphase. In this Commentary, we present a brief history of the tension-versus-attachment debate, summarize recent advances in our understanding of kinetochore structure and focus on the implications of a phenomenon known as intrakinetochore stretch for SAC regulation. We also hypothesize how intrakinetochore stretch might impact SAC function by regulating both microtubule attachment stability and the localization and activity of checkpoint components at the kinetochore.
Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation
Authors: Radtke Simone , Wüller Stefan , Yang Xiang-ping , Lippok Barbara E. , Mütze Barbara , Mais Christine , de Leur Hildegard Schmitz-Van , Bode Johannes G. , Gaestel Matthias , Heinrich Peter C. , Behrmann Iris , Schaper Fred , Hermanns Heike M.
Published: March 2010

The inflammatory response involves a complex interplay of different cytokines which act in an auto- or paracrine manner to induce the so-called acute phase response. Cytokines are known to crosstalk on multiple levels, for instance by regulating the mRNA stability of targeted cytokines through activation of the p38-MAPK pathway. In our study we discovered a new mechanism that answers the long-standing question how pro-inflammatory cytokines and environmental stress restrict immediate signalling of interleukin (IL)-6-type cytokines. We show that p38, activated by IL-1β, TNFα or environmental stress, impairs IL-6-induced JAK/STAT signalling through phosphorylation of the common cytokine receptor subunit gp130 and its subsequent internalisation and degradation. We identify MK2 as the kinase that phosphorylates serine 782 in the cytoplasmic part of gp130. Consequently, inhibition of p38 or MK2, deletion of MK2 or mutation of crucial amino acids within the MK2 target site or the di-leucine internalisation motif blocks receptor depletion and restores IL-6-dependent STAT activation as well as gene induction. Hence, a novel negative crosstalk mechanism for cytokine signalling is described, where cytokine receptor turnover is regulated in trans by pro-inflammatory cytokines and stress stimuli to coordinate the inflammatory response.
Changes in Bni4 localization induced by cell stress in Saccharomyces cerevisiae
Authors: Larson Jennifer R. , Kozubowski Lukasz , Tatchell Kelly
Published: March 2010

Septin complexes at the bud neck in Saccharomyces cerevisiae serve as a scaffold for proteins involved in signaling, cell cycle control, and cell wall synthesis. Many of these bind asymmetrically, associating with either the mother- or daughter-side of the neck. Septin structures are inherently apolar so the basis for the asymmetric binding remains unknown. Bni4, a regulatory subunit of yeast protein phosphatase type 1, Glc7, binds to the outside of the septin ring prior to bud formation and remains restricted to the mother-side of the bud neck after bud emergence. Bni4 is responsible for targeting Glc7 to the mother-side of the bud neck for proper deposition of the chitin ring. We show here that Bni4 localizes symmetrically, as two distinct rings on both sides of the bud neck following energy depletion or activation of cell cycle checkpoints. Our data indicate that loss of Bni4 asymmetry can occur via at least two different mechanisms. Furthermore, we show that Bni4 has a Swe1-dependent role in regulating the cell morphogenesis checkpoint in response to hydroxyurea, which suggests that the change in localization of Bni4 following checkpoint activation may help stabilize the cell cycle regulator Swe1 during cell cycle arrest.
The small nucleolar ribonucleoprotein (snoRNP) database
Authors: Ellis J. Christopher , Brown Daniel D. , Brown James W.
Published: March 2010

Small nucleolar ribonucleoproteins (snoRNPs) are widely studied and characterized as guide RNAs for sequence-specific 2′-O-ribose methylation and psuedouridylation of ribosomal RNAs. In addition, snoRNAs have also been shown to interact with some tRNAs and direct alternative splicing in mRNA biogenesis. Recent advances in bioinformatics have resulted in new algorithms able to rapidly identify noncoding RNAs generally and snoRNAs specifically in genomic and metagenomic sequences, resulting in a rapid increase in the number and diversity of identified snoRNA sequences. The snoRNP database is a web-based collection of snoRNA and snoRNA-associated protein sequences from a wide range of species. The database currently contains 8994 snoRNA sequences from Bacteria, Archaea, and Eukaryotes and 589 snoRNA-associated protein sequences. The snoRNP database can be found at: http://evolveathome.com/snoRNA/snoRNA.php.
Four exons of the serotonin receptor 4 gene are associated with multiple distant branch points
Authors: Hallegger Martina , Sobala Andrew , Smith Christopher W.J.
Published: March 2010

Splicing of vertebrate introns involves recognition of three consensus elements at the 3′ end. The branch point (BP) and polypyrimidine tract (PPT) are usually located within 40 nucleotides (nt) of the 3′ splice site (3′ ss), AG, but can be much more distant. A characteristic of the region between distant BPs (dBPs) and the 3′ ss is the absence of intervening AG dinucleotides, leading to its designation as the “AG exclusion zone” (AGEZ). The human HTR4 gene, which encodes serotonin receptor 4 and has been associated with schizophrenia, bipolar disease, and gastrointestinal disorders, has four exons with extensive AGEZs. We have mapped the BPs for HTR4 exons 3, 4, 5, and g generated by in vitro splicing, and validated them by mutagenesis in exon-trapping vectors. All exons used dBPs up to 273 nt upstream of the exon. Strikingly, exons 4 and 5 used combinations of both distant and conventionally located BPs, suggesting that successful splicing of these exons can occur by distinct pathways. Our results emphasize the importance for single nucleotide polymorphism resequencing projects to take account of potential dBPs, as the extended AGEZs are vulnerable to mutations that could affect splicing itself or regulation of alternative splicing.
Costs of Gastrointestinal Events after Outpatient Opioid Treatment for Non-Cancer Pain
Authors: Kwong Winghan Jacqueline , Diels Joris , Kavanagh Shane
Published: March 2010

Background

Gastrointestinal (GI) adverse effects are common with oral opioid treatment.

Objective

To estimate the costs associated with GI events after oral short-acting opioid treatment, from the payer perspective.

Methods

Medical and pharmacy claims from the PharMetrics’ Patient-Centric Database were used to identify opioid-naïve patients who received a new prescription for oxycodone- or hydrocodone-containing immediate-release oral products between 2002 and 2006. Health-care resource use and costs were determined for patients with claims associated with ICD-9 CM (International Classification of Diseases—9th Clinical Modification) codes for nausea/vomiting (787.0x), constipation (564.0x), bowel obstruction (560, 560.1, 560.3, 560.39, 564.81), or antiemetic and laxative prescriptions during the 3 months after opioid index prescription and compared with patients without these GI event medical or prescription claims. Resource use data were compared using negative binomial regression and cost data were compared using ordinary least squares confirmed by generalized gamma regression analysis while controlling for demographics, treatment duration, and comorbidities.

Results

Data from 237,447 patients were analyzed. Patients with GI event claims had significantly more hospitalizations (adjusted mean 0.20 to 0.97 vs 0.17, respectively, p < 0.001), days in the hospital (1.12 to 12.05 vs 1.00 days, p < 0.001), emergency department visits (0,36 to 1.44 vs 0.25 visits, p < 0.001), outpatient office visits (5.68 to 11.81 vs 4.11 visits, p < 0.001), and prescription claims (7.46 to 8.21 vs 6.06 claims, p < 0.001) than did patients without any GI event claims in the 3 months after index opioid prescription. Compared with patients without any GI event claims, incremental adjusted mean total health-care costs for patients with any of the GI event claims ranged from $4,880 to $36,152 and were significant (p < 0.001).

Conclusions

The economic burden of GI events coincident with opioid treatment is significant for patients with a GI event recorded in claims. Reducing GI adverse effects has potential cost savings for the health-care system.
Symptomatic Hypoglycemia Associated with Trimethoprim/Sulfamethoxazole and Repaglinide in a Diabetic Patient
Authors: Roustit Matthieu , Blondel Emeline , Villier Céline , Fonrose Xavier , Mallaret Michel P
Published: March 2010

Objective

To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient.

Case summary

A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous d-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale).

Discussion

This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia.

Conclusions

This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction.
Die aktuelle Entscheidung Passivlegitimation bei Grundstücksveräußerung während Rechtshängigkeit einer Klage aus § 1004 i.V. m. § 906 BGB
Authors: Looff Franziska
Published: March 2010

Die Begriffe der Aktiv-/Passivlegitimation im Gegensatz zur Prozessführungsbefugnis sind auch für fortgeschrittene Studenten nicht immer leicht auseinanderzuhalten. Nicht zuletzt wegen der unterschiedlichen Rechtskraftwirkung der Abweisung einer Klage bei Fehlen des einen bzw. anderen Kriteriums ist die korrekte Einordnung jedoch wichtig. In diesem Zusammenhang können mitunter die § 265 und 266 ZPO eine Rolle spielen, deren Voraussetzungen und Rechtsfolgen wiederum nicht leicht zu verstehen sind. Der BGH hat sich in einer aktuellen Entscheidung eben mit diesen Normen befasst und sich zugleich zu einem alten Streit geäußert. Dies bietet Gelegenheit zur Wiederholung dieses – etwa für die mündliche Prüfung oder prozessuale Zusatzfragen in Klausuren – interessanten Themenbereiches.
Das Ende der Sittenwidrigkeit sog. Geliebtentestamente?
Authors: Schnabl Daniel , Hamelmann Uwe
Published: March 2010

Das Problem der Sittenwidrigkeit so genannter Geliebtentestamente hat Rechtsprechung und Schrifttum lange Zeit beschäftigt. Dabei stellte sich die Frage, unter welchen Voraussetzungen die Erbeinsetzung einer Geliebten gegen die guten Sitten verstößt und damit nach § 138 Abs. 1 BGB nichtig ist.

Der nachfolgende Beitrag gibt zunächst einen kurzen Überblick über den derzeitigen Stand der Rechtsprechung zu dieser Problematik und widmet sich anschließend der Frage, welche Auswirkungen das Inkrafttreten des Prostitutionsgesetzes auf diese Rechtsprechung hat. Angesichts sich mehrender Stimmen im Schrifttum und noch ausstehender Rechtsprechung zu dieser Frage, ist die Thematik der Geliebtentestamente wieder von besonderer Brisanz und Aktualität für juristische Prüfungsaufgaben, zumal sich in diesem Zusammenhang auch das Problem des maßgeblichen Zeitpunktes für die Beurteilung der Sittenwidrigkeit zwanglos abprüfen lässt.
ÖR Die Schadensersatzklage des Europäischen Gemeinschaftsrechts
Authors: Ehlers Dirk
Published: March 2010

Die Abhandlung knüpft an die Beiträge über den Rechtsschutz im Europäischen Unions- und Gemeinschaftsrecht (

jura

2007, 505 ff.), die Vertragsverletzungsklage des europäischen Gemeinschaftsrechts (

jura

2007, 684 ff.) und die Nichtigkeitsklage des europäischen Gemeinschaftsrechts (

jura

2009, 31) an und gibt einen Überblick über die Funktion und Bedeutung der Schadensersatzklage des europäischen Gemeinschaftsrecht, ihre Zulässigkeit und Begründetheit sowie die Wirkungen von Schadensersatzurteile.
ÖR Die Privatisierung kommunaler öffentlicher Einrichtungen: Formen – Grenzen – Probleme
Authors: Kahl Wolfgang , Weißenberger Christian
Published: March 2010

Der Beitrag gibt einen Überblick über die vielfältigen, mit der Privatisierung öffentlicher Einrichtungen der Gemeinden verbundenen Rechtsfragen. Hierbei geht es in erster Linie um die Rechtsstellung der Benutzer (z. B. Zulassungsanspruch, Entgeltverhältnis, Anschluss- und Benutzungszwang). Erörtert werden aber auch die sich aus der Privatisierung für die öffentliche Hand bzw. für den Einrichtungsbetreiber ergebenden verfassungsrechtlichen Folgen.
Übungsklausur ZR »Download to own« – Online-Geschäfte unter fremdem Namen
Authors: Verse Dirk A. , Gaschler Andreas
Published: March 2010

Die Bestellung von Waren und Dienstleistungen über das Internet erfreut sich immer größerer Beliebtheit. Der Vertragsabschluss via Internet eröffnet allerdings auch zahlreiche Missbrauchsmöglichkeiten, so etwa, wenn sich ein Unbefugter mit den Benutzerdaten des Berechtigten Zugang zu entgeltlichen Leistungen eines Internet-Portals verschafft. Es stellen sich dann geradezu klassische Fragen der Rechtsgeschäftslehre des BGB, daneben aber auch Fragen des bereicherungsrechtlichen Ausgleichs. Die Möglichkeit, bewährte Klassiker der Rechtsgeschäftslehre und des Bereicherungsrechts im modernen Gewand des »e-commerce« wieder aufleben zu lassen, macht derartige Fallgestaltungen auch für Übungs- und Examensklausuren besonders reizvoll. Am Beispiel eines sog. Download-Portals, von dem die Nutzer gegen Entgelt Dateien herunterladen können, spricht der nachfolgende Fall einige typische, klausurrelevante Fragestellungen an.
Ageism in the American Workplace
Authors: Roscigno Vincent J.
Published: March 2010

When I wrote an article on age discrimination last year, I couldn't believe the response: countless emails and at least five phone calls a week for several months. These communications weren't coming from researchers in the field but from workers across the country, male and female, semi-skilled, skilled, and professional. They shared stories of age discrimination that they, a spouse, or a parent had experienced or were currently living through, asked for information about their rights and what could be done, and thanked me for bringing light to an issue that “nobody talks about.”
Policies and Politics for an Aging America
Authors:   Macarthur Foundation Research Netowrk on an Aging Society
Published: March 2010

In “Facts and Fictions About an Aging America” (Contexts, Fall 2009), our research group unpacked a series of widely held, inter–related misconceptions about our aging population and outlined the broad societal implications of the realities. With the realities articulated and myths exposed, we can start to explore how policy–makers can effectively invest across the life course to create a successful aging society. We call for a new approach to aging–one that involves not only newpolicies, but also newways to think about aging in America. Both our reframing and subsequent policy proposals will increase the likelihood that the United States, as it ages, will become amore productive and equitable society.
Mexican Americans and Immigrant Incorporation
Authors: Telles Edward E.
Published: March 2010

Sociologists, public policy-makers, and the general public usually try to anticipate how modern immigrants and their descendants will become part of American society by comparing their experiences to those of European immigrants a century or more ago.
Jewish Americans and the Holocaust
Authors: Bergerxy Ronald J.
Published: March 2010

When my father first arrived in the United States in 1946 after surviving Auschwitz and other concentration camps, no one, not even Jewish relatives, was particularly interested in hearing about his ordeal. People would say things like, “We suffered too. Did you know that we couldn't get sugar [during the war] and that gasoline was rationed?” So my father and other survivors like him stopped talking about their experiences.
Intellectual Icons
Authors: McLaughlin Neil
Published: March 2010

Margaret Mead: The Making of an American Icon By Nancy C. Lutkehaus Princeton University Press, 2008, 392 pages

Becoming Bucky Fuller By Loretta Lorance MIT Press, 2009, 304 pages
Creep of a C-S-H gel: a micromechanical approach
Authors: Sanahuja Julien , Dormieux Luc
Published: March 2010

Both clays and calcium silicate hydrates(the main hydration products of Portland cements) exhibit a microstructure made up of lamellar particles. The microscopic mechanism responsible for the macroscopic creep of such materials is often described as the relative sliding of the sheets. This paper proposes a micromechanical approach to estimate the macroscopic creep behavior rising from this microscopic mechanism. The asymptotic evolution of creep at both short- and long-term is especially investigated. More precisely, a non-vanishing initial elastic strain is retrieved. At long-term, a threshold on porosity appears. At lower porosities, the creep evolution admits an asymptotic strain. At higher porosities, it admits an asymptotic strain rate.
Bridging molecular and continuous descriptions: the case of dynamics in clays
Authors: Dufrêche Jean-François , Rotenberg Benjamin , Marry Virginie , Turq Pierre
Published: March 2010

The theory of transport in porous media such as clays depends on the level of description. On the macroscopic scale,hydrodynamics equations are used. These continuous descriptions are convenient to model the fluid motion in a confined system. Nevertheless, they are valid only if the pores of the material are much larger than the molecular size of the components of the system. Another approach consists in using molecular descriptions. These two methods which correspond to different levels of description are complementary. The link between them can be clarified by using a coarse-graining procedure where the microscopic laws are averaged over fast variables to get the long time macroscopic laws. We present such an approach in the case of clays. Firstly, we detail the various levels of description and the relations among them, by emphasizing the validity domain of the hydrodynamic equations. Secondly, we focus on the case of dehydrated clays where hydrodynamics is not relevant. We show that it is possible to derive a simple model for the motion of the cesium ion based on the difference on time scale between the solvent and the solute particles.
Steady electrodiffusion in hydrogel-colloid composites: macroscale properties from microscale electrokinetics
Authors: Hill Reghan J.
Published: March 2010

A rigorous microscale electrokinetic model for hydrogel-colloid composites is adopted to compute macroscale profiles of electrolyte concentration, electrostatic potential, and hydrostatic pressure across membranes that separate electrolytes with different concentrations. The membranes are uncharged polymeric hydrogels in which charged spherical colloidal particles are immobilized and randomly dispersed with a low solid volume fraction. Bulk membrane characteristics and performance are calculated from a continuum microscale electrokinetic model (Hill 2006b, c). The computations undertaken in this paper quantify the streaming and membrane potentials. For the membrane potential, increasing the volume fraction of negatively charged inclusions decreases the differential electrostatic potential across the membrane under conditions where there is zero convective flow and zero electrical current. With low electrolyte concentration and highly charged nanoparticles, the membrane potential is very sensitive to the particle volume fraction. Accordingly, the membrane potential - and changes brought about by the inclusion size, charge and concentration - could be a useful experimental diagnostic to complement more recent applications of the microscale electrokinetic model for electrical microrheology and electroacoustics (Hill and Ostoja-Starzewski 2008, Wang and Hill 2008).
Dimeric and dipolar ground state orders in colloidal molecular crystals
Authors: Trizac Emmanuel , El Shawish Samir , Dobnikar Jure
Published: March 2010

A two dimensional colloidal suspension subject to a periodic substrate evolves into a colloidal molecular crystal under situationsofstrongconfinement. Wefocusonthelongrangeorientationalordertherebyemerging, inthegroundstate. We study by simulations the situations where in each trap lies a pair of identical colloids, or alternatively a pair of oppositelychargedmacroions. We consider square or triangular geometries for the periodic confinement, together with less symmetric distorted lattices.
Attraction between two similar particles in an electrolyte: effects of Stern layer absorption
Authors: Plouraboué Franck , Chang Hua-Chia
Published: March 2010

When Debye length is comparable or larger than the distance between two identical particles, the overlapping among the particles double-layers can play an important role in their interactions. This paper presents a theoretical analysis of the interaction among two identical particles with overlapped double-layers. We particularly focus on the effect of a Stern electro static condition from linearization of the adsorption isotherm near the isoelectric (neutrality) point in order to capture how polyvalent ion condensation affect sand reverses the surface charge. The stationary potential problem is solved within the framework of an asymptotic lubrication approach for a mean-field Poisson-Boltzmann model. Both spherical and cylindrical particles are analyzed. The results are finally discussed in the context of Debye-Hückel (D-H) limit and beyond it.
Ion-specific thermodynamical properties of aqueous proteins
Authors: Lima Eduardo R.A. , Biscaia Jr. Evaristo C. , Boström Mathias , Tavares Frederico W.
Published: March 2010

Ion-specific interactions between two colloidal particles are calculated using a modified Poisson-Boltzmann (PB)equationandMonteCarlo(MC)simulations. PBequationspresentgoodresultsofionicconcentration profiles around a macroion, especially for salt solutions containing monovalent ions. These equations include not only electrostatic interactions, but also dispersion potentials originated from polarizabilities of ions and proteins. This enables us to predict ion-specific properties of colloidal systems. We compared results obtained from the modified PB equation with those from MC simulations and integral equations. Phase diagrams and osmotic second virial coefficients are also presented for different salt solutions at different pH and ionic strengths, in agreement with the experimental results observed Hofmeister effects. In order to include the water structure and hydration effect, we have used an effective interaction obtained from molecular dynamics of each ion and a hydrophobic surface combined with PB equation. The method has been proved to be efficient and suitable for describing phenomena where the water structure close to the interface plays an essential role. Important thermodynamic properties related to protein aggregation, essential in biotechnology and pharmaceutical industries, can be obtained from the method shown here.
Biaxial testing of canine annulus fibrosus tissue under changing salt concentrations
Authors: Huyghe Jacques M.
Published: March 2010

The in vivo mechanics of the annulus fibrosus of the intervertebral disc is one of biaxial rather than uniaxial loading. The material properties of the annulus are intimately linked to the osmolarity in the tissue. This paper presents biaxial relaxation experiments of canine annulus fibrosus tissue under stepwise changes of external salt concentration. The force tracings show that stresses are strongly dependent on time, salt concentration and orientation. The force tracing signature of are sponse to a change instrain, is one of a jumpin stress that relaxes partly as the new strain is maintained. The force tracing signature of a stepwise change in salt concentration is a progressive monotonous change in stress towards a new equilibrium value. Although the number of samples does not allow any definitive quantitative conclusions, the trends may shed light on the complex interaction among the directionality of forces, strains and fiber orientation on one hand, and on the other hand, the osmolarity of the tissue. The dual response to a change in strain is understood as an immediate response before fluid flows in or out of the tissue, followed by a progressive readjustment of the fluid content in time because of the gradient in fluid chemical potential between the tissue and the surrounding solution.