bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Tibial Osteotomy for Unloading Osteochondral Defects in the Medial Compartment of the Knee
Authors: Mina Curtis , Garrett William E. , Pietrobon Ricardo , Glisson Richard , Higgins Laurence 
Published: April 2008

Background High tibial osteotomy is a well-established method for the treatment of symptomatic medial unicompartmental cartilage degeneration. While the findings of several outcome studies have led to the widely practiced postoperative goal alignment of 8° to 10° of valgus, there exists no literature to account for patient-specific measurements such as body weight, baseline geometry, and medial chondral defect size. Furthermore, there is a lack of literature to support the ideal goal alignment when using high tibial osteotomy to unload isolated chondral defects. Purpose To identify a relationship between these patient-specific factors and the ideal postoperative alignment. Study Design Controlled laboratory study. Methods High tibial osteotomy was performed on 8 human cadaveric knees and was fixed with a dynamic external fixator. The fixator was used to vary the tibiofemoral alignment from 12° valgus to 10° varus. At each alignment, force, contact area, and pressure distribution were recorded. This pattern was repeated for a range of applied loads (0.8–1.8 x ideal body weight) and across a range of medial chondral defect sizes (10–20 cm). Results As tibiofemoral alignment was shifted from varus to valgus alignment, we found a decrease in medial contact pressure ( P < .001) and a decrease in medial contact area ( P < .001). For all defect sizes, all contact pressure within the medial compartment was shifted to the lateral compartment at between 6° and 10° of valgus. Contact pressure was found to concentrate around the defect rims for all defect sizes. Conclusion We show that regardless of condylar width, baseline tibiofemoral alignment, body weight, or chondral defect size, all specimens demonstrated complete unloading of the medial compartment at between 6° and 10° of valgus, which favors cartilage repair at these alignments. In addition, regarding the use of high tibial osteotomy for unloading isolated chondral defects, we find that contact pressure is approximately equally distributed between the medial and lateral compartments for alignments of 0° to 4° of valgus. Clinical Relevance This loading situation most closely approximates physiologic loading and therefore represents an ideal outcome for patients with isolated chondral defects. Reduction in stress concentration around chondral defects has been found to favor cartilage repair.
ParaKMeans: Implementation of a parallelized K-means algorithm suitable for general laboratory use
Authors: Kraj Piotr , Sharma Ashok , Garge Nikhil , Podolsky Robert , McIndoe Richard A 
Published: April 2008

Abstract

Background
During the last decade, the use of microarrays to assess the transcriptome of many biological systems has generated an enormous amount of data. A common technique used to organize and analyze microarray data is to perform cluster analysis. While many clustering algorithms have been developed, they all suffer a significant decrease in computational performance as the size of the dataset being analyzed becomes very large. For example, clustering 10000 genes from an experiment containing 200 microarrays can be quite time consuming and challenging on a desktop PC. One solution to the scalability problem of clustering algorithms is to distribute or parallelize the algorithm across multiple computers.

Results
The software described in this paper is a high performance multithreaded application that implements a parallelized version of the K-means Clustering algorithm. Most parallel processing applications are not accessible to the general public and require specialized software libraries (e.g. MPI) and specialized hardware configurations. The parallel nature of the application comes from the use of a web service to perform the distance calculations and cluster assignments. Here we show our parallel implementation provides significant performance gains over a wide range of datasets using as little as seven nodes. The software was written in C# and was designed in a modular fashion to provide both deployment flexibility as well as flexibility in the user interface.

Conclusion
ParaKMeans was designed to provide the general scientific community with an easy and manageable client-server application that can be installed on a wide variety of Windows operating systems.
Transcriptional regulation by Poly(ADP-ribose) polymerase-1 during T cell activation
Authors: Saenz Luis , Lozano Juan J , Valdor Rut , Baroja-Mazo Alberto , Ramirez Pablo , Parrilla Pascual , Aparicio Pedro , Sumoy Lauro , Yélamos José 
Published: April 2008

Abstract

Background
Accumulating evidence suggests an important role for the enzyme poly(ADP-ribose) polymerase-1 (PARP-1) as an integral part of the gene expression regulatory machinery during development and in response to specific cellular signals. PARP-1 might modulate gene expression through its catalytic activity leading to poly(ADP-ribosyl)ation of nuclear proteins or by its physical association with relevant proteins. Recently, we have shown that PARP-1 is activated during T cell activation. However, the proposed role of PARP-1 in reprogramming T cell gene expression upon activation remains largely unexplored.

Results
In the present study we use oligonucleotide microarray analysis to gain more insight into the role played by PARP-1 during the gene expression reprogramming that takes place in T cells upon activation with anti-CD3 stimulation alone, or in combination with anti-CD28 co-stimulation. We have identified several groups of genes with expression modulated by PARP-1. The expression of 129 early-response genes to anti-CD3 seems to be regulated by PARP-1 either in a positive (45 genes) or in a negative manner (84 genes). Likewise, in the presence of co-stimulation (anti-CD3 + anti-CD28 stimulation), the expression of 203 genes is also regulated by PARP-1 either up (173 genes) or down (30 genes). Interestingly, PARP-1 deficiency significantly alters expression of genes associated with the immune response such as chemokines and genes involved in the Th1/Th2 balance.

Conclusion
This study provides new insights into changes in gene expression mediated by PARP-1 upon T cell activation. Pathway analysis of PARP-1 as a nuclear signalling molecule in T cells would be of relevance for the future development of new therapeutic approaches targeting PARP-1 in the acquired immune response.
Non-random retention of protein-coding overlapping genes in Metazoa
Authors: Soldà Giulia , Suyama Mikita , Pelucchi Paride , Boi Silvia , Guffanti Alessandro , Rizzi Ermanno , Bork Peer , Tenchini Maria Luisa , Ciccarelli Francesca D 
Published: April 2008

Abstract

Background
Although the overlap of transcriptional units occurs frequently in eukaryotic genomes, its evolutionary and biological significance remains largely unclear. Here we report a comparative analysis of overlaps between genes coding for well-annotated proteins in five metazoan genomes (human, mouse, zebrafish, fruit fly and worm).

Results
For all analyzed species the observed number of overlapping genes is always lower than expected assuming functional neutrality, suggesting that gene overlap is negatively selected. The comparison to the random distribution also shows that retained overlaps do not exhibit random features: antiparallel overlaps are significantly enriched, while overlaps lying on the same strand and those involving coding sequences are highly underrepresented. We confirm that overlap is mostly species-specific and provide evidence that it frequently originates through the acquisition of terminal, non-coding exons. Finally, we show that overlapping genes tend to be significantly co-expressed in a breast cancer cDNA library obtained by 454 deep sequencing, and that different overlap types display different patterns of reciprocal expression.

Conclusion
Our data suggest that overlap between protein-coding genes is selected against in Metazoa. However, when retained it may be used as a species-specific mechanism for the reciprocal regulation of neighboring genes. The tendency of overlaps to involve non-coding regions of the genes leads to the speculation that the advantages achieved by an overlapping arrangement may be optimized by evolving regulatory non-coding transcripts.
Elucidating a normal function of huntingtin by functional and microarray analysis of huntingtin-null mouse embryonic fibroblasts
Authors: Zhang Hua , Das Sudipto , Li Quan-Zhen , Dragatsis Ioannis , Repa Joyce , Zeitlin Scott , Hajnóczky György , Bezprozvanny Ilya 
Published: April 2008

AbstractBackgroundThe polyglutamine expansion in huntingtin (Htt) protein is a cause of Huntington's disease (HD). Htt is an essential gene as deletion of the mouse Htt gene homolog (Hdh) is embryonic lethal in mice. Therefore, in addition to elucidating the mechanisms responsible for polyQ-mediated pathology, it is also important to understand the normal function of Htt protein for both basic biology and for HD.ResultsTo systematically search for a mouse Htt function, we took advantage of theHdh+/- andHdh-floxed mice and generated four mouse embryonic fibroblast (MEF) cells lines which contain a single copy of theHdhgene (Hdh-HET) and four MEF lines in which theHdhgene was deleted (Hdh-KO). The function of Htt in calcium (Ca2+) signaling was analyzed in Ca2+imaging experiments with generated cell lines. We found that the cytoplasmic Ca2+spikes resulting from the activation of inositol 1,4,5-trisphosphate receptor (InsP3R) and the ensuing mitochondrial Ca2+signals were suppressed in theHdh-KO cells when compared toHdh-HET cells. Furthermore, in experiments with permeabilized cells we found that the InsP3-sensitivity of Ca2+mobilization from endoplasmic reticulum was reduced inHdh-KO cells. These results indicated that Htt plays an important role in modulating InsP3R-mediated Ca2+signaling. To further evaluate function of Htt, we performed genome-wide transcription profiling of generatedHdh-HET andHdh-KO cells by microarray. Our results revealed that 106 unique transcripts were downregulated by more than two-fold with p < 0.05 and 173 unique transcripts were upregulated at least two-fold with p < 0.05 inHdh-KO cells when compared toHdh-HET cells. The microarray results were confirmed by quantitative real-time PCR for a number of affected transcripts. Several signaling pathways affected byHdhgene deletion were identified from annotation of the microarray results.ConclusionFunctional analysis of generated Htt-null MEF cells revealed that Htt plays a direct role in Ca2+signaling by modulating InsP3R sensitivity to InsP3. The genome-wide transcriptional profiling of Htt-null cells yielded novel and unique information about the normal function of Htt in cells, which may contribute to our understanding and treatment of HD.
Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa
Authors: Haveri Hanna , Westerholm-Ormio Mia , Lindfors Katri , Mäki Markku , Savilahti Erkki , Andersson Leif C , Heikinheimo Markku 
Published: April 2008

Abstract

Background
Human gastrointestinal mucosa regenerates vigorously throughout life, but the factors controlling cell fate in mature mucosa are poorly understood. GATA transcription factors direct cell proliferation and differentiation in many organs, and are implicated in tumorigenesis. GATA-4 and GATA-6 are considered crucial for the formation of murine gastrointestinal mucosa, but their role in human gastrointestinal tract remains unexplored. We studied in detail the expression patterns of these two GATA factors and a GATA-6 down-stream target, Indian hedgehog (Ihh), in normal human gastrointestinal mucosa. Since these factors are considered important for proliferation and differentiation, we also explored the possible alterations in their expression in gastrointestinal neoplasias. The expression of the carcinogenesis-related protein Indian hedgehog was also investigated in comparison to GATA factors.

Methods
Samples of normal and neoplastic gastrointestinal tract from children and adults were subjected to RNA in situ hybridization with 33P labelled probes and immunohistochemistry, using an avidin-biotin immunoperoxidase system. The pathological tissues examined included samples of chronic and atrophic gastritis as well as adenomas and adenocarcinomas of the colon and rectum.

Results
GATA-4 was abundant in the differentiated epithelial cells of the proximal parts of the gastrointestinal tract but was absent from the distal parts. In contrast, GATA-6 was expressed throughout the gastrointestinal epithelium, and in the distal gut its expression was most intense at the bottom of the crypts, i.e. cells with proliferative capacity. Both factors were also present in Barrett's esophagus and metaplasia of the stomach. GATA-6 expression was reduced in colon carcinoma. Ihh expression overlapped with that of GATA-6 especially in benign gastrointestinal neoplasias.

Conclusion
The results suggest differential but overlapping functions for GATA-4 and GATA-6 in the normal gastrointestinal mucosa. Furthermore, GATA-4, GATA-6 and Ihh expression is altered in premalignant dysplastic lesions and reduced in overt cancer.
Structural insights on the pamoic acid and the 8 kDa domain of DNA polymerase beta complex: Towards the design of higher-affinity inhibitors
Authors: Hazan Corinne , Boudsocq François , Gervais Virginie , Saurel Olivier , Ciais Marion , Cazaux Christophe , Czaplicki Jerzy , Milon Alain 
Published: April 2008

Abstract

Background
DNA polymerase beta (pol beta), the error-prone DNA polymerase of single-stranded DNA break repair as well as base excision repair pathways, is overexpressed in several tumors and takes part in chemotherapeutic agent resistance, like that of cisplatin, through translesion synthesis. For this reason pol beta has become a therapeutic target. Several inhibitors have been identified, but none of them presents a sufficient affinity and specificity to become a drug. The fragment-based inhibitor design allows an important improvement in affinity of small molecules. The initial and critical step for setting up the fragment-based strategy consists in the identification and structural characterization of the first fragment bound to the target.

Results
We have performed docking studies of pamoic acid, a 9 micromolar pol beta inhibitor, and found that it binds in a single pocket at the surface of the 8 kDa domain of pol beta. However, docking studies provided five possible conformations for pamoic acid in this site. NMR experiments were performed on the complex to select a single conformation among the five retained. Chemical Shift Mapping data confirmed pamoic acid binding site found by docking while NOESY and saturation transfer experiments provided distances between pairs of protons from the pamoic acid and those of the 8 kDa domain that allowed the identification of the correct conformation.

Conclusion
Combining NMR experiments on the complex with docking results allowed us to build a three-dimensional structural model. This model serves as the starting point for further structural studies aimed at improving the affinity of pamoic acid for binding to DNA polymerase beta.
Implementation and evaluation of the SPRINT protocol for tight glycaemic control in critically ill patients: a clinical practice change
Authors: Chase JGeoffrey , Shaw Geoffrey , Le Compte Aaron , Lonergan Timothy , Willacy Michael , Wong Xing-Wei , Lin Jessica , Lotz Thomas , Lee Dominic , Hann Christopher 
Published: April 2008

Abstract
Introduction
Stress-induced hyperglycaemia is prevalent in critical care. Control of blood glucose levels to within a 4.4 to 6.1 mmol/L range or below 7.75 mmol/L can reduce mortality and improve clinical outcomes. The Specialised Relative Insulin Nutrition Tables (SPRINT) protocol is a simple wheel-based system that modulates insulin and nutritional inputs for tight glycaemic control.

Methods
SPRINT was implemented as a clinical practice change in a general intensive care unit (ICU). The objective of this study was to measure the effect of the SPRINT protocol on glycaemic control and mortality compared with previous ICU control methods. Glycaemic control and mortality outcomes for 371 SPRINT patients with a median Acute Physiology And Chronic Health Evaluation (APACHE) II score of 18 (interquartile range [IQR] 15 to 24) are compared with a 413-patient retrospective cohort with a median APACHE II score of 18 (IQR 15 to 23).

Results
Overall, 53.9% of all measurements were in the 4.4 to 6.1 mmol/L band. Blood glucose concentrations were found to be log-normal and thus log-normal statistics are used throughout to describe the data. The average log-normal glycaemia was 6.0 mmol/L (standard deviation 1.5 mmol/L). Only 9.0% of all measurements were below 4.4 mmol/L, with 3.8% below 4 mmol/L and 0.1% of measurements below 2.2 mmol/L. On SPRINT, 80% more measurements were in the 4.4 to 6.1 mmol/L band and standard deviation of blood glucose was 38% lower compared with the retrospective control. The range and peak of blood glucose were not correlated with mortality for SPRINT patients (P >0.30). For ICU length of stay (LoS) of greater than or equal to 3 days, hospital mortality was reduced from 34.1% to 25.4% (-26%) (P = 0.05). For ICU LoS of greater than or equal to 4 days, hospital mortality was reduced from 34.3% to 23.5% (-32%) (P = 0.02). For ICU LoS of greater than or equal to 5 days, hospital mortality was reduced from 31.9% to 20.6% (-35%) (P = 0.02). ICU mortality was also reduced but the P value was less than 0.13 for ICU LoS of greater than or equal to 4 and 5 days.

Conclusion
SPRINT achieved a high level of glycaemic control on a severely ill critical cohort population. Reductions in mortality were observed compared with a retrospective hyperglycaemic cohort. Range and peak blood glucose metrics were no longer correlated with mortality outcome under SPRINT.
Diagnostic Biopsy of Lymph Nodes of the Neck, Axilla and Groin: Rhyme, Reason or Chance?
Authors: Moor James W , Murray Patrick , Inwood Jane , Gouldesbrough David , Bem Chris 
Published: April 2008

INTRODUCTION Improving patient pathways of care is becoming increasingly important in the delivery of timely, appropriate surgical care. With this aim, we analysed the referral and management pathway of patients undergoing diagnostic superficial lymph node biopsy. PATIENTS AND METHODS A retrospective review of case notes of patients undergoing diagnostic superficial lymph node biopsy over 3 years, 1998–2000 at the Bradford Hospitals NHS Trust. Indication for surgical biopsy was based on clinical suspicion following assessment in the out-patient clinic for the majority, and arrangement of investigations as deemed appropriate. There were no clinical algorithms in use during the study period. RESULTS There was no evidence for the use of explicit protocols for referral or management. Biopsy was often delayed. Of 268 patients referred from primary care, referral was made to any of 14 hospital departments with 39% (105 of 268) attending more than one outpatient appointment, and 155 (41 of 268) attending more than one department. Eighteen percent (47 of 268) of patients were informed of their diagnosis within 6 weeks of referral and 42% (113 of 268) within 3 months of referral. Nine percent (24 of 268) underwent pre-operative fine needle aspiration cytology. Of patients with enlarged neck nodes, 29% (52/180) had examination of the upper aero-digestive tract. CONCLUSIONS The study supports the introduction of co-ordinated problem-based referral and management pathways for the management of patients with enlarged superficial lymph nodes supported by regular audits of practice.
Intravenous Human Plasma-Derived Augmentation Therapy in α1-Antitrypsin Deficiency: From Pharmacokinetic Analysis to Individualizing Therapy
Authors: Zamora Nuria Padullés , Pla Rafael Vidal , Rio Pilar Gispert Del , Margaleff Rosendo Jardi , Frias Francisco Rodriguez , Ronsano Jose Bruono Montero 
Published: April 2008

Background: Severs forms of α1-antitrypsin (AAT) deficiency require augmentation therapy by intravenous administration of purified preparations of AAT concentrate. Although standard AAT treatment schedules are widely available, pharmacokinetic studies characterizing AAT serum decay are scarce, and data on the variability of individual patients are almost nonexistent. Objective: To establish individual AAT pharmacokinetics and develop a predictive model based on simple pharmacokinetic characterization that can be used to optimize Individual AAT dosing regimens. Methods: Seven patients with severe hereditary AAT deficiency (PI*ZZ phonotype) with serum AAT levels less than 0.50 g/L Initially received AAT 180 mg/kg every 3 weeks. At 7, 14, and 21 days after AAT administration, serum samples were taken for quantitative AAT analysis and further one-compartment pharmacokinetic analysis. Subsequently, patients were rescheduled (dose and dosing interval) according to their individual responses. The influence of baseline AAT level, age, sex, body weight, and commercial AAT preparation was evaluated. Results: The mean ± SD AAT pharmacokinetic profile was: volume of distribution 127.6 ± 31.9 mL/kg, clearance 10.13 ± 1.84 mL/kg/day, and half-life 8.7 ± 1.0 days. Hence, the mean optimized final AAT dose was 123.1 mg/kg every 2 weeks (range 118.5-125.6). AAT concentrations differed by a mean (geometrical) value of 3.9% (range -4.2% to 6.7%) from the minimum desired AAT serum trough of 0.50 g/L. The impact of baseline AAT levels and commercial AAT preparation used was statistically significant (p = 0.033 and p = 0.035, respectively). Differences between estimated and actual values were slightly lower when baseline AAT levels were taken into consideration, with a mean value ot 3.3% (range -4.2% to 6.1%). Conclusions: AAT augmentation therapy can be effectively individualized on a pharmacokinetic basis with a simple, easily executed method.