bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Physiologically Based Pharmacokinetic Analysis for In Vivo Organ Disposition of Nitroxyl Spin Probes in Mice as Measured by Multisite Detection L-band ESR (MSD-LESR)
Authors: Kamatari Masayuki , Yasui Hiroyuki , Nakamura Masahiro , Ogata Tateaki , Sakurai Hiromu 
Published: September 2006

Abstract
We developed a physiologically based pharmacokinetic (PB-PK) model for spin-labeled drugs in animals and applied it for analyzing the decay curves of spin probes in the organs of mice as measured by multisite detection L-band ESR (MSD-LESR). The proposed method will be useful for not only understanding the PK features of nitroxyl radicals as spin probes but also developing spin-labeled drugs as a substitute for radioisotope-labeled drugs.
Training Opportunities in the Management of Paediatric Fractures: A District General Hospital Perspective
Authors: Kim WY , Zenios M 
Published: September 2006

INTRODUCTION Increasing subspecialisation, the introduction of reforms to surgical training, centralisation of hospitals and the reduction of working hours brought about by the European Working Time Directive (EWTD) has direct implications on the training of surgeons in the UK. The aim of this study was to determine the range and number of procedures performed for paediatric orthopaedic fractures, degree of supervision and possible implications for training. PATIENTS AND METHODS A retrospective review of procedures for paediatric orthopaedic fractures performed in a district general hospital in a year was conducted. RESULTS A total of 210 paediatric fracture procedures were performed, including 99 distal radius/ulna procedures, 28 shaft radius/ulna, 25 supracondylar procedures, 15 hand fracture procedures, 14 tibial shaft procedures. Middle grade/registrars and senior house officers performed 188 (89.5%) of all procedures. Consultant supervision was documented in 29 (13.8%) of all procedures performed. The number and type of common, as well as unusual, injuries was documented. The educational value of a training post may only be confirmed by reliable data which would provide an indication of operative opportunities and degree of supervision available to a trainee. CONCLUSIONS This study provided a model upon which all operative training opportunities in the orthopaedic department is documented. It is suggested that such data should form the basis of the establishment of training posts within a region. To maintain the high standard of orthopaedic training in the UK, the maintenance of such posts, number of trainees and seniority of trainees appointed to any hospital within a training region should be on the basis of data such as reported in this study.
Setting the Standard – UK Neurosurgical Acoustic Neuroma Practice
Authors: Goodden JR , Tranter R , Hardwidge C 
Published: September 2006

INTRODUCTION The aim of this study was to determine how current practice in the UK and Ireland complies with the Clinical Effectiveness Guidelines for the Management of Acoustic Neuromas. MATERIALS AND METHODS A survey of units and consultants using a standardised questionnaire was carried out. RESULTS Fifty-six neurosurgeons treat acoustic neuromas in 33 out of 34 units. In 27 units, one or two surgeons specialise in this area. Caseload per annum per surgeon ranged from 2 to 30, median 15. Forty-one neurosurgeons (75%) work with an ENT surgeon. All surgeons use facial nerve monitoring during surgery. All neurosurgeons informed patients about stereotactic radiosurgery, tending to recommend it for medically unfit patients, and those with small tumours. CONCLUSIONS Overall, 26 units (79%) and 40 surgeons (73%) met the criteria for good surgical practice. The main reasons for non-compliance were a lack of teamwork with ENT, and insufficient caseload to maintain surgical expertise.
Medullary Thyroid Carcinoma – Update and Present Management Controversies
Authors: Al-Rawi Mahir , Wheeler Malcolm H 
Published: September 2006

INTRODUCTION Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy arising from the parafollicular C cells. It accounts for 5–10% of thyroid malignancies and occurs in sporadic and hereditary forms. There are still many controversial aspects relating to the diagnosis and management of this unusual tumour in its various forms. The present article addresses the more important of these issues. METHODS A literature review was performed using Pubmed database combined with additional original papers obtained from citations in those articles identified in the original literature search. Only those articles which related specifically to the controversial issues addressed in this review were included. RESULTS Genetically determined tumours constitute approximately 25% of MTC and have special clinical interest because of their association with other endocrinopathies including phaeochromocytoma and hyperparathyroidism in the multiple endocrine neoplasia syndromes (MEN IIa and MEN IIb). Familial medullary thyroid carcinoma (FMTC) is a rare form not associated with any other endocrinopathies. The genetic basis for these familial tumours derives from a series of missense germline mutations in the RET proto-oncogene. Genetic testing by DNA analysis facilitates identification of family members at risk who can now be offered early ‘prophylactic thyroidectomy’ with an increased prospect of surgical success and long-term survival. MTC is a tumour which does not take up radioactive iodine, is relatively radioresistant and poorly responsive to chemotherapy. Therefore, surgery is the only treatment which can offer the prospect of cure. Total thyroidectomy with central and lateral nodal dissection can achieve biochemical cure (normocalcitonaemia) in more than 80% of cases. Compartmental orientated microdissection of cervical nodes has significantly improved the results of primary surgery but even so a group of 20% of patients will prove to have recurrent or residual disease. These cases require detailed investigation by a variety of techniques including ultrasound, cross-sectional imaging, nuclear imaging and laparoscopy with liver biopsy to exclude disseminated disease and select those patients who can be offered a prospect of cure by further neck surgery. Such an approach may be associated with successful normalisation of calcitonin levels in about 40%. CONCLUSIONS It is hoped that in the near future new medical therapies may become available to treat MTC which still has a 10-year survival of only 60–80% in spite of the application of meticulous surgical techniques.
Systematic Review of Medication Errors in Pediatric Patients
Authors: Ghaleb Maisoon Abdullah , Barber Nick , Franklin Bryony D , Yeung Vincent WS , Khaki Zahra F , Wong Ian CK 
Published: September 2006

Objective: To systematically locate and review studies that have investigated the incidence of medication errors (MEs) in pediatric inpatients and identify common errors. Methods: A systematic search of studies related to MEs in children was performed using the following databases: MEDLINE (1951–April 2006), EMBASE (1966–April 2006), Pharm-line (1978–April 2006), International Pharmaceutical Abstracts (1970–April 2006), Cumulative Index to Nursing and Allied Health Literature (1982–April 2006), and British Nursing Index (1994–April 2006). Studies of the incidence and nature of MEs in pediatrics were included. The title, abstract, or full article was reviewed for relevance; any study not related to MEs in children was excluded. Results: Three methods were used to detect MEs in the studies reviewed: spontaneous reporting (n = 10), medication order or chart review (n = 14), or observation (n = 8). There was great variation in the definitions of ME used and the error rates reported. The most common type of ME was dosing error, often involving 10 times the actual dose required. Antibiotics and sedatives were the most common classes of drugs associated with MEs; these are probably among the most common drugs prescribed. Conclusions: Interpretation of the literature was hindered by variation in definitions employed by different researchers, varying research methods and setting, and a lack of theory-based research. Overall, it would appear that our initial concern about MEs in pediatrics has been validated; however, we do not know the actual size of the problem. Further work to determine the incidence and causes of MEs in pediatrics is urgently needed, as well as evaluation of the best interventions to reduce them.
Formulary Forum: Exenatide: A New Option for the Treatment of Type 2 Diabetes
Authors: Yoo Bong Kyu , Triller Darren Michael , Yoo Dong Joo 
Published: September 2006

Objective: To evaluate available literature characterizing the pharmacology, pharmacokinetics, drug interactions, efficacy, and safety of exenatide in patients with type 2 diabetes. Data Sources: A PubMed database search (1966–May 2006) was conducted, using exenatide as the search term. The manufacturer's prescribing information was also used. Study Selection and Data Extraction: English-language articles were selected and data were extracted with a focus on clinical outcomes associated with the treatment of patients with type 2 diabetes. Data Synthesis: Exenatide exerts a glucoregulatory effect by various mechanisms including secretion of glucose-dependent insulin, suppression of inappropriately high glucagon levels in patients with type 2 diabetes, delayed gastric emptying, and reduction of food intake. In placebo-controlled clinical studies, plasma exenatide concentrations appeared to exhibit dose-proportional kinetics, reaching peak plasma levels between 2 and 3 hours after a single subcutaneous injection. Exenatide's elimination half-life ranged from 3.3 to 4.0 hours, and the time to reach maximum concentration was about 2 hours. Interactions between exenatide and agents such as digoxin and lisinopril were not considered significant. In Phase III trials, exenatide demonstrated significant reduction of hemoglobin A1c levels from baseline and compared with placebo after 30 weeks of treatment in patients unable to achieve optimal glycemic control with metformin, a sulfonylurea, or oral combination therapy (0.4–0.9%). Patients' weight decreased with exenatide (0.9–2.8 kg), but adverse gastrointestinal (GI) events were common. Exenatide combined with thiazolidonediones, D-phenylalanine derivatives, meglitinides, or alpha glucosidase inhibitors has not been studied. Conclusions: Clinical trials have demonstrated that exenatide improves glycemic control when added to sulfonylureas and metformin, and it may be an alternative to insulin glargine in patients requiring additional therapy. Hypoglycemia has been encountered in clinical trials of exenatide, especially upon initiation of therapy with sulfonylureas (not with metformin); close patient monitoring is therefore recommended. Further studies should assess the impact of exenatide on clinical outcomes such as micro- and macrovascular disease.
A Deletion at the MouseXistGene ExposesTrans-effects That Alter the Heterochromatin of the Inactive X Chromosome and the Replication Time and DNA Stability of Both X Chromosomes
Authors: Diaz-Perez Silvia V , Ferguson David O , Wang Chen , Csankovszki Gyorgyi , Wang Chengming , Tsai Shih-Chang , Dutta Devkanya , Perez Vanessa , Kim SunMin , Eller C Daniel , Salstrom Jennifer , Ouyang Yan , Teitell Michael A , Kaltenboeck Bernhard , Chess Andrew , Huang Sui , Marahrens York 
Published: September 2006

AbstractThe inactive X chromosome of female mammals displays several properties of heterochromatin including late replication, histone H4 hypoacetylation, histone H3 hypomethylation at lysine-4, and methylated CpG islands. We show that cre-Lox-mediated excision of 21 kb from both Xist alleles in female mouse fibroblasts led to the appearance of two histone modifications throughout the inactive X chromosome usually associated with euchromatin: histone H4 acetylation and histone H3 lysine-4 methylation. Despite these euchromatic properties, the inactive X chromosome was replicated even later in S phase than in wild-type female cells. Homozygosity for the deletion also caused regions of the active X chromosome that are associated with very high concentrations of LINE-1 elements to be replicated very late in S phase. Extreme late replication is a property of fragile sites and the 21-kb deletions destabilized the DNA of both X chromosomes, leading to deletions and translocations. This was accompanied by the phosphorylation of p53 at serine-15, an event that occurs in response to DNA damage, and the accumulation of γ-H2AX, a histone involved in DNA repair, on the X chromosome. The Xist locus therefore maintains the DNA stability of both X chromosomes.
Test of Association Between Haplotypes and Phenotypes in Case–Control Studies: Examination of Validity of the Application of an Algorithm for Samples From Cohort or Clinical Trials to Case–Control Samples Using Simulated and Real Data
Authors: Furihata Shiori , Ito Toshikazu , Kamatani Naoyuki 
Published: September 2006

Abstract
The use of haplotype information in case–control studies is an area of focus for the research on the association between phenotypes and genetic polymorphisms. We examined the validity of the application of the likelihood-based algorithm, which was originally developed to analyze the data from cohort studies or clinical trials, to the data from case–control studies. This algorithm was implemented in a computer program called PENHAPLO. In this program, haplotype frequencies and penetrances are estimated using the expectation-maximization algorithm, and the haplotype–phenotype association is tested using the generalized likelihood ratio. We show that this algorithm was useful not only for cohort studies but also for case–control studies. Simulations under the null hypothesis (no association between haplotypes and phenotypes) have shown that the type I error rates were accurately estimated. The simulations under alternative hypotheses showed that PENHAPLO is a robust method for the analysis of the data from case–control studies even when the haplotypes were not in HWE, although real penetrances cannot be estimated. The power of PENHAPLO was higher than that of other methods using the likelihood-ratio test for the comparison of haplotype frequencies. Results of the analysis of real data indicated that a significant association between haplotypes in the SAA1 gene and AA-amyloidosis phenotype was observed in patients with rheumatoid arthritis, thereby suggesting the validity of the application of PENHAPLO for case–control data.
The Large Isoform of Drosophila melanogaster Heterochromatin Protein 2 Plays a Critical Role in Gene Silencing and Chromosome Structure
Authors: Shaffer Christopher D , Cenci Giovanni , Thompson Brandi , Stephens Gena E , Slawson Elizabeth E , Adu-Wusu Kwame , Gatti Maurizio , Elgin Sarah C R 
Published: September 2006

Abstract
Drosophila melanogaster heterochromatin protein 2 (HP2) interacts with heterochromatin protein 1 (HP1). In polytene chromosomes, HP2 and HP1 colocalize at the chromocenter, telomeres, and the small fourth chromosome. We show here that HP2 is present in the arms as well as the centromeric regions of mitotic chromosomes. We also demonstrate that Su(var)2-HP2 exhibits a dosage-dependent modification of variegation of a yellow reporter transgene, indicating a structural role in heterochromatin formation. We have isolated and characterized 14 new mutations in the Su(var)2-HP2 gene. Using wm4h, many (but not all) mutant alleles show dominant Su(var) activity. Su(var)2-HP2 mutant larvae show a wide variety of mitotic abnormalities, but not the telomere fusion seen in larvae deficient for HP1. The Su(var)2-HP2 gene codes for two isoforms: HP2-L (∼365 kDa) and HP2-S (∼175 kDa), lacking exons 5 and 6. In general, mutations that affect only the larger isoform result in more pronounced defects than do mutations common to both isoforms. This suggests that an imbalance between large and small isoforms is particularly deleterious. These results indicate a role for HP2 in the structural organization of chromosomes and in heterochromatin-induced gene silencing and show that the larger isoform plays a critical role in these processes.
Identification of a Novel Gene Family Involved in Osmotic Stress Response inCaenorhabditis elegans
Authors: Wheeler Jeanna M , Thomas James H 
Published: September 2006

AbstractOrganisms exposed to the damaging effects of high osmolarity accumulate solutes to increase cytoplasmic osmolarity. Yeast accumulates glycerol in response to osmotic stress, activated primarily by MAP kinase Hog1 signaling. A pathway regulated by protein kinase C (PKC1) also responds to changes in osmolarity and cell wall integrity. C. elegans accumulates glycerol when exposed to high osmolarity, but the molecular pathways responsible for this are not well understood. We report the identification of two genes, osm-7 and osm-11, which are related members of a novel gene family. Mutations in either gene lead to high internal levels of glycerol and cause an osmotic resistance phenotype (Osr). These mutants also have an altered defecation rhythm (Dec). Mutations in cuticle collagen genes dpy-2, dpy-7, and dpy-10 cause a similar Osr Dec phenotype. osm-7 is expressed in the hypodermis and may be secreted. We hypothesize that osm-7 and osm-11 interact with the cuticle, and disruption of the cuticle causes activation of signaling pathways that increase glycerol production. The phenotypes of osm-7 are not suppressed by mutations in MAP kinase or PKC pathways, suggesting that C. elegans uses signaling pathways different from yeast to mount a response to osmotic stress.
The Meiotic Bouquet Promotes Homolog Interactions and Restricts Ectopic Recombination inSchizosaccharomyces pombe
Authors: Davis Luther , Smith Gerald R 
Published: September 2006

AbstractChromosome architecture undergoes extensive, programmed changes as cells enter meiosis. A highly conserved change is the clustering of telomeres at the nuclear periphery to form the “bouquet” configuration. In the fission yeast Schizosaccharomyces pombe the bouquet and associated nuclear movement facilitate initial interactions between homologs. We show that Bqt2, a meiosis-specific protein required for bouquet formation, is required for wild-type levels of homolog pairing and meiotic allelic recombination. Both gene conversion and crossing over are reduced and exhibit negative interference in bqt2Δ mutants, reflecting reduced homolog pairing. While both the bouquet and nuclear movement promote pairing, only the bouquet restricts ectopic recombination (that between dispersed repetitive DNA). We discuss mechanisms by which the bouquet may prevent deleterious translocations by restricting ectopic recombination.
Nonneutral Evolution of Organelle Genes in Silene vulgaris
Authors: Houliston Gary J , Olson Matthew S 
Published: September 2006

Abstract
Knowledge of mitochondrial gene evolution in angiosperms has taken a dramatic shift within the past decade, from universal slow rates of nucleotide change to a growing realization of high variation in rates among lineages. Additionally, evidence of paternal inheritance of plant mitochondria and recombination among mitochondrial genomes within heteroplasmic individuals has led to speculation about the potential for independent evolution of organellar genes. We report intraspecific mitochondrial and chloroplast sequence variation in a cosmopolitan sample of 42 Silene vulgaris individuals. There was remarkably high variation in two mitochondrial genes (atp1, atp9) and additional variation within a third gene (cob). Tests for patterns of nonneutral evolution were significant for atp1 and atp9, indicative of the maintenance of balanced polymorphisms. Two chloroplast genes (matK, ndhF) possessed less, but still high, variation and no divergence from neutral expectations. Phylogenetic patterns of organelle genes in both the chloroplast and mitochondria were incongruent, indicating the potential for independent evolutionary trajectories. Evidence indicated reassociation among cytoplasmic genomes and recombination between mitochondrial genes and within atp1, implying transient heteroplasmy in ancestral lineages. Although the mechanisms for long-term maintenance of mitochondrial polymorphism are currently unknown, frequency-dependent selection on linked cytoplasmic male sterility genes is a potential candidate.
A Thurstonian Model for Quantitative Genetic Analysis of Ranks: A Bayesian Approach
Authors: Gianola Daniel , Simianer Henner 
Published: September 2006

AbstractA fully Bayesian method for quantitative genetic analysis of data consisting of ranks of, e.g., genotypes, scored at a series of events or experiments is presented. The model postulates a latent structure, with an underlying variable realized for each genotype or individual involved in the event. The rank observed is assumed to reflect the order of the values of the unobserved variables, i.e., the classical Thurstonian model of psychometrics. Parameters driving the Bayesian hierarchical model include effects of covariates, additive genetic effects, permanent environmental deviations, and components of variance. A Markov chain Monte Carlo implementation based on the Gibbs sampler is described, and procedures for inferring the probability of yet to be observed future rankings are outlined. Part of the model is rendered nonparametric by introducing a Dirichlet process prior for the distribution of permanent environmental effects. This can lead to potential identification of clusters of such effects, which, in some competitions such as horse races, may reflect forms of undeclared preferential treatment.
Estimating Recombination Rates From Single-Nucleotide Polymorphisms Using Summary Statistics
Authors: Padhukasahasram Badri , Wall Jeffrey D , Marjoram Paul , Nordborg Magnus 
Published: September 2006

AbstractWe describe a novel method for jointly estimating crossing-over and gene-conversion rates from population genetic data using summary statistics. The performance of our method was tested on simulated data sets and compared with the composite-likelihood method of R. R. Hudson. For several realistic parameter values, the new method performed similarly to the composite-likelihood approach for estimating crossing-over rates and better when estimating gene-conversion rates. We used our method to analyze a human data set recently genotyped by Perlegen Sciences.
A Gain-of-Function Screen Identifying Genes Required for Vein Formation in the Drosophila melanogaster Wing
Authors: Molnar Cristina , López-Varea Ana , Hernández Rosario , de Celis Jose F 
Published: September 2006

Abstract
The formation of the Drosophila wing involves developmental processes such as cell proliferation, pattern formation, and cell differentiation that are common to all multicellular organisms. The genes controlling these cellular behaviors are conserved throughout the animal kingdom, and the genetic analysis of wing development has been instrumental in their identification and functional characterization. The wing is a postembryonic structure, and most loss-of-function mutations are lethal in homozygous flies before metamorphosis. In this manner, loss-of-function genetic screens aiming to identify genes affecting wing formation have not been systematically utilized. As an alternative, a number of genetic searches have utilized the phenotypic consequences of gene gain-of-expression, as a method more efficient to search for genes required during imaginal development. Here we present the results of a gain-of-function screen designed to identify genes involved in the formation of the wing veins. We generated 13,000 P-GS insertions of a P element containing UAS sequences (P-GS) and combined them with a Gal4 driver expressed mainly in the developing pupal veins. We selected 500 P-GSs that, in combination with the Gal4 driver, result in modifications of the veins, changes in the morphology of the wing, or defects in the differentiation of the trichomes. The P-element insertion sites were mapped to the genomic sequence, identifying 373 gene candidates to participate in wing morphogenesis and vein formation.