bluuebunny/crossref_metadata_2025 huggingface dataset:
Society of Toxicologic Pathology Position Paper: Review Series: Assessment of Circulating Hormones in Nonclinical Toxicity Studies: General Concepts and Considerations
Authors: Stanislaus Dinesh , Andersson Håkan , Chapin Robert , Creasy Dianne , Ferguson Duncan , Gilbert Mary , Rosol Thomas J. , Boyce Rogely Waite , Wood Charles E.
Published: May 2012

This is an introductory paper to a series of papers intended to provide the basis for understanding the contribution of endocrine axis disruption or dysfunction to the pathogenesis of morphological findings and to aid in the interpretation of study outcomes. This is the first in this series of guidance papers prepared by the Working Group and outlines general concepts of study design and assay conduct and validation for hormone studies in general.
Practice Patterns for Arthroscopy of Osteoarthritis of the Knee in the United States
Authors: Potts Aaron , Harrast John J. , Harner Christopher D. , Miniaci Anthony , Jones Morgan H.
Published: May 2012

Background: Knee arthroscopy is one of the most common orthopaedic procedures performed in the United States. The publication of a randomized controlled trial of arthroscopy versus sham surgery by Moseley et al in 2002 showed no efficacy and challenged the role of arthroscopy for the treatment of osteoarthritis.

Hypothesis: (1) Knee arthroscopy for osteoarthritis has decreased after the publication of the study by Moseley et al, (2) arthroscopy as a percentage of orthopaedic cases has decreased, and (3) the average age of patients undergoing arthroscopy has decreased.

Study Design: Descriptive epidemiology study.

Methods: The authors examined the American Board of Orthopaedic Surgery (ABOS) database that includes 6-month case logs for each examinee sitting for the Part II board examination for 1999 to 2009. Knee arthroscopy cases were identified by CPT ( Current Procedural Terminology) code and knee osteoarthritis diagnosis was defined by ICD-9 ( International Classification of Diseases, 9th Revision) code. Piecewise linear regression was used to evaluate knee arthroscopy before and after the publication of the Moseley et al article in 2002.

Results: The number of knee arthroscopy cases for patients with osteoarthritis had greatly decreased by 2009 after peaking in 2001 (1621 vs 966 total cases, 2.36 vs 1.40 cases per surgeon). Cases classified as chondroplasty also decreased from 10.0% to 5.8% of knee arthroscopies ( P < .0001). In addition, the total number of knee arthroscopy cases per surgeon decreased from a high of 11.9 in 2003 to a low of 8.6 in 2009. As expected, knee arthroscopy as a percentage of total orthopaedic cases decreased from a high of 9.9% in 2003 to 6.6% in 2009 ( P < .0001).

Conclusion: Knee arthroscopy for patients with osteoarthritis among orthopaedic surgeons during their ABOS examination case collection period has decreased after the publication of a highly publicized article demonstrating a lack of efficacy of this procedure. Further study is needed to determine if this change occurred in the orthopaedic community at large or if practice patterns only changed for surgeons during their board collection periods.

Clinical Relevance: Randomized controlled trials can be effective in changing orthopaedic surgeon practice.
Mortality Among Marathon Runners in the United States, 2000-2009
Authors: Mathews Simon C. , Narotsky David L. , Bernholt David L. , Vogt Matthew , Hsieh Yu-Hsiang , Pronovost Peter J. , Pham Julius Cuong
Published: May 2012

Background:

As participation in marathon running has increased, there has also been concern regarding its safety.

Purpose:

To determine if the increase in marathon participation from 2000 to 2009 has affected mortality and overall performance.

Study Design:

Descriptive epidemiology study.

Methods:

We used publicly available racing and news databases to analyze the number of marathon races, finishing race times, and deaths from 2000 to 2009 in marathons in the United States.

Results:

The total number of marathon finishers has increased over this decade from 299,018 in 2000 to 473,354 in 2009. The average overall marathon finishing time has remained unchanged from 2000 to 2009 (4:34:47 vs 4:35:28; P = .85). Of 3,718,336 total marathon participants over the 10-year study period, we identified 28 people (6 women and 22 men) who died during the marathon race and up to 24 hours after finishing. The overall, male, and female death rates for the 10-year period were 0.75 (95% confidence interval [CI], 0.38-1.13), 0.98 (95% CI, 0.48-1.36), and 0.41 (95% CI, 0.21-0.79) deaths per 100,000 finishers, respectively. There was no change in the death rate during this time period for overall, male, or female groups ( P = .860, .533, and .238, respectively). The median age among deaths was 41.5 years (interquartile range, 25.5 years). Fifty percent (14/28) of deaths occurred in participants less than 45 years old. Myocardial infarction/atherosclerotic heart disease caused 93% (13/14) of deaths in those 45 years and older. A variety of conditions caused death in younger racers, the most common being cardiac arrest not otherwise specified (21%, n = 3).

Conclusion:

Participation in marathons has increased without any change in mortality or average overall performance from 2000 to 2009.
Correlation of Coracoid Thickness and Glenoid Width
Authors: Bueno Rogerio Serpone , Ikemoto Roberto Yukio , Nascimento Luis Gustavo Prata , Almeida Luiz Henrique de Oliveira , Strose Eric , Murachovsky Joel
Published: May 2012

Background:

The coracoid has been widely used as a graft to reconstruct anterior glenoid bone defects, as described by the Latarjet and Bristow procedures, with successful results. Nevertheless, at the present, there are no studies correlating the size of the coracoid graft and its relation to the glenoid.

Purpose:

To assess the mediolateral (M-L) and anteroposterior (A-P) thickness of the coracoid process as well as the widest anterior-to-posterior glenoid distance (glenoid width) and to analyze the correlation between these measurements, while comparing these with the A-P coracoid process thickness.

Study Design:

Descriptive laboratory study.

Methods:

Sixty-one unpaired, adult human cadaveric scapulae were evaluated. Three examiners performed 3 independent measurements of the largest M-L thickness of the coracoid process and also the widest anterior-to-posterior distance of the glenoid. The A-P coracoid process thickness was also measured to compare for correlations with M-L coracoid thickness.

Results:

The glenoid width was 26.38 ± 2.69 mm (range, 20.03-32.35 mm), and the M-L coracoid thickness was 14.51 ± 1.90 mm (range, 9.60-19.31 mm). Calculating the ratio between the M-L thickness of the coracoid and glenoid width, we observed that the coracoid represented 43% to 70% of the glenoid width (54% on average). The A-P coracoid process thickness was 8.37 ± 0.93 mm (range, 6.61-9.76 mm), representing 31% of the glenoid width on average.

Conclusion:

A strong positive and statistically significant relationship between the coracoid process M-L thickness and the anterior-to-posterior glenoid width exists; the coracoid represents, on average, 54% of the glenoid width.

Clinical Relevance:

Most cases of glenoid bone loss in recurrent shoulder dislocation can be reconstructed with the coracoid process to re-establish its anatomy.
Incidence and Outcome After Revision Anterior Cruciate Ligament Reconstruction
Authors: Lind Martin , Menhert Frank , Pedersen Alma B.
Published: May 2012

Background:

Revision anterior cruciate ligament (ACL) reconstruction is poorly described because of its rare incidence and mainly small case series presented in the literature. The Danish ACL reconstruction registry has monitored the development in revision ACL reconstruction since 2005.

Hypothesis:

We hypothesized that younger patients had a higher risk of revision ACL reconstruction than older patients and that subjective clinical outcome was worse after revision ACL reconstruction than after primary ACL reconstruction.

Study Design:

Cohort study; Level of evidence, 2.

Methods:

All clinics performing ACL reconstructions in Denmark report to the national ACL reconstruction registry. The revision rate after primary ACL reconstruction (n = 12,193 procedures) and re-revision rate after revision ACL reconstruction (n = 1099 procedures) were calculated for the period of 2005 to 2010. Outcome at 1-year follow-up for the revision cohort was reported using the Knee Injury and Osteoarthritis Outcome Score (KOOS), Tegner function score, and objective knee stability measurement.

Results:

The rate of revision ACL reconstruction was 4.1% after 5 years. Revision occurred most frequently after 1 to 2 years. Patients below 20 years of age at the time of primary ACL reconstruction had a higher risk of revision (8.7%) than did patients older than 20 years of age (2.8%) (adjusted relative risk, 2.58; 95% confidence interval, 2.02-3.30). The KOOS scores 1 year after revision ACL reconstruction (mean ± standard deviation) were 73 ± 18 for symptoms, 78 ± 17 for pain, 84 ± 16 for activities of daily living, 52 ± 28 for sports, and 48 ± 21 for quality of life. All these scores were significantly lower than for primary ACL reconstruction: 77 ± 17 for symptoms, 84 ± 15 for pain, 89 ± 13 for activities of daily living, 62 ± 25 for sports, and 59 ± 21 for quality of life. Side-to-side difference in knee laxity improved from 5.8 mm before revision ACL reconstruction to 1.9 mm 1 year after revision ACL surgery. The use of allograft tissue for the revision procedure resulted in a higher risk of re-revision than did autograft tissue (relative risk, 2.05; 95% confidence interval, 1.5-2.4) ( P < .01). The rate of re-revision after 5 years was 5.4%.

Conclusion:

In this observational population-based study, the 5-year revision ACL reconstruction rate was 4.1%. Despite achieving acceptable knee stability after revision ACL reconstruction, subjective outcome is less favorable than after primary ACL reconstruction.
Polyaspartamide spin probes containing isoindoline nitroxide and porphyrin groups
Authors: Yan Guo-Ping , Liu Fan , Ai Chao-Wu , Zou Tou-Jun , Li Liang , Guo Qing-Zhong , Yu Xiang-Hua , Li Qian
Published: May 2012

Water-soluble polyaspartamide isoindoline nitroxides 5-(4′-aminophenyl)-10,15,20-tris (4′-sulfonatophenyl) porphyrin, trisodium salt–poly[α,β- N-(2-hydroxyethyl)-l-aspartamide]–5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl were synthesized by the incorporation of 5-(4′-aminophenyl)-10,15,20-tris(4′-sulfonatophenyl) porphyrin, trisodium salt, as a tumor-targeting group, and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl into poly[α,β- N-(2-hydroxyethyl)-l-aspartamide]. These compounds were characterized, and the in vitro properties were evaluated. The polyaspartamide isoindoline nitroxides had higher relaxation effectiveness and had greater toxicity to HeLa cells than that of 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl. The polyaspartamide isoindoline nitroxides retained similar electrochemical properties and redox reaction mechanisms as the parent nitroxides. The electron paramagnetic resonance spectra of polyaspartamide isoindoline nitroxides exhibited characteristic hyperfine electron paramagnetic resonance spectra of tetramethyl isoindoline nitroxides, with typical nitroxide g-values and nitrogen isotropic hyperfine coupling constants. Therefore, the water-soluble 5-(4′-aminophenyl)-10,15,20-tris(4′-sulfonatophenyl) porphyrin, trisodium salt–poly[α,β- N-(2-hydroxyethyl)-l-aspartamide]–5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl is considered to be a novel potential spin probe for electron paramagnetic resonance.
Impact of Cold-Calling on Student Voluntary Participation
Authors: Dallimore Elise J. , Hertenstein Julie H. , Platt Marjorie B.
Published: May 2012

Classroom discussion is perhaps the most frequently used “active learning” strategy. However, instructors are often concerned about students who are less inclined to participate voluntarily. They worry that students not involved in the discussion might have lower quality learning experiences. Although instructors might consider whether to call on a student whose hand is not raised (“cold-call”), some instructors resist cold-calling fearing that the student will feel uncomfortable. This study examines the impact of cold-calling on students’ voluntary participation in class discussions and their comfort participating in discussions. The results demonstrate that significantly more students answer questions voluntarily in classes with high cold-calling, and that the number of students voluntarily answering questions in high cold-calling classes increases over time. Furthermore, students in classes with high cold-calling answer more voluntary questions than those in classes with low cold-calling; this also increases over time. Finally, in classes with high cold-calling, students’ comfort participating in class discussions increases while in classes with low cold-calling, students’ comfort participating does not change. Research findings show that cold-calling can be done fairly extensively without making students uncomfortable. Thus, the research reported here provides support for using this instructional strategy to engage more students to participate in discussions.
Model reduction and analysis of a vibrating beam microgyroscope
Authors: Ghommem Mehdi , Nayfeh Ali H , Choura Slim
Published: May 2012

The present work is concerned with the nonlinear dynamic analysis of a vibrating beam microgyroscope composed of a rotating cantilever beam with a tip mass at its end. The rigid mass is coupled to two orthogonal electrodes in the drive and sense directions, which are attached to the rotating base. The microbeam is driven by an AC voltage in the drive direction, which induces vibrations in the orthogonal sense direction due to rotation about the microbeam axis. The electrode placed in the sense direction is used to measure the induced motions and extract the underlying angular speed. A reduced-order model of the gyroscope is developed using the method of multiple scales and used to examine its dynamic behavior.
Predicting Condom Use Attitudes, Norms, and Control Beliefs in Hispanic Problem Behavior Youth
Authors: Malcolm Shandey , Huang Shi , Cordova David , Freitas Derek , Arzon Margaret , Jimenez Giselle Leon , Pantin Hilda , Prado Guillermo
Published: May 2012

Hispanic problem behavior youth are at an increased risk of engaging in HIV risk behaviors, including low condom use. However, relatively little research has examined factors that affect condom use in this population. Although research indicates that family processes, such as higher levels of family functioning and open parent–adolescent communication about sex, and condom use attitudes, norms, and control beliefs as depicted by the theory of planned behavior have an effect on condom use behaviors, the combination of the two factors has received minimal attention. The purpose of this study was to examine the effect of family functioning on condom use intentions and behaviors through communication about sex and condom use attitudes, parental norms, and control beliefs. A cross-sectional study of 171 predominately male (73.1%) sexually active Hispanic problem behavior adolescents (mean age = 14.88 years) was conducted. Structural equation modeling was used to test the study hypothesis. Findings largely support the overall model and suggest that family functioning had an indirect effect on condom use intention and behavior through communication about sex, condom use attitudes, and control beliefs. Family functioning, however, did not have an indirect effect on condom use intention and behavior through communication about sex and parental norms. Implications for prevention science and future research are discussed.
Getting Explicit About the Implicit
Authors: Uhlmann Eric Luis , Leavitt Keith , Menges Jochen I. , Koopman Joel , Howe Michael , Johnson Russell E.
Published: May 2012

Accumulated evidence from social and cognitive psychology suggests that many behaviors are driven by processes operating outside of awareness, and an array of implicit measures to capture such processes have been developed. Despite their potential application, implicit measures have received relatively modest attention within the organizational sciences, due in part to barriers to entry and uncertainty about appropriate use of available measures. The current article is intended to serve as an implicit measurement “toolkit” for organizational scholars, and as such our goals are fourfold. First, we present theory critical to implicit measures, highlighting advantages of capturing implicit processes in organizational research. Second, we present a functional taxonomy of implicit measures (i.e., accessibility-based, association-based, and interpretation-based measures) and explicate assumptions and appropriate use of each. Third, we discuss key criteria to help researchers identify specific implicit measures most appropriate for their own work, including a discussion of principles for the psychometric validation of implicit measures. Fourth, we conclude by identifying avenues for impactful “next-generation” research within the organizational sciences that would benefit from the use of implicit measures.
Intrauterine environment and multiple sclerosis: a population- based case-control study
Authors: Mueller Beth A , Nelson J Lee , Newcomb Polly A
Published: May 2012

Background:

Associations of several autoimmune disorders with intrauterine and early life exposures have been reported.

Objective:

We used population-based linked hospital discharge-birth records data to explore maternal, prenatal, and infant characteristics in relation to MS-related hospitalization among Washington State residents.

Methods:

272 cases hospitalized for MS during 1988–2008 and 2720 birth record controls were identified from linked hospital discharge-birth certificate data. Exposure information from their birth records were compared in a population-based case-control study to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95%CIs) for associations with MS hospitalization.

Results:

Most factors examined were not associated with MS. Having a mother with 3+ prior live births (OR 0.54, 95%CI 0.31–0.95) or having 3+ older siblings (OR 0.49, 95%CI 0.28–0.85) were negatively associated. Maternal prenatal smoking (OR 3.09, 95%CI 1.22–7.84) was positively associated.

Conclusion:

Transplacental exposure to smoke constituents including chemicals affecting myelin may help explain any association with maternal prenatal smoking; however, we were unable to assess childhood or adult smoke exposures which may also account at least partly for this effect. The negative associations observed with greater maternal parity and number of siblings are consistent with some other studies. Reasons for these associations may involve various pathways.
A phenomenological exploration of the childfree choice in a sample of Australian women
Authors: Doyle Joanne , Pooley Julie Ann , Breen Lauren
Published: May 2012

Choosing not to have children is considered a deviation from cultural norms, particularly the dominant pronatalist discourse; this is especially so for women. However, little research has documented the experience of Australian women who have consciously chosen to remain childless. Ten voluntarily childfree women participated in unstructured interviews about their choice and its ramifications. The data analysis revealed three broad themes – the experiences and processes of making the choice; the ongoing effects of their choice, ranging from support and acceptance to pressure and discrimination; and no regret as the women described engaging in meaningful, generative activities that contributed to society.
Estimation of risk and interaction of single nucleotide polymorphisms at angiotensinogen locus causing susceptibility to essential hypertension: a case control study
Authors: Charita Bh , Padma G , Sushma P , Deepak P , Padma T
Published: May 2012

Introduction:

The risk conferred by the variants and haplotypes of single nucleotide polymorphisms (SNPs) at human angiotensinogen (AGT) gene to essential hypertension (EHT) have been described in several populations with variations in the results attributed to their ethnicity. We attempted to evaluate the risk of -217G>A, -152G>A, -20A>C, -6G>A, T174M, M235T and 15241A>G polymorphisms at AGT locus along with the analyses of haplotype and epistatic interactions in causing susceptibility to EHT.

Method:

Two-hundred and forty-nine hypertensives and 248 controls were genotyped for the selected markers.

Results:

Study of demographic parameters revealed significant association of obesity, positive family history and non-vegetarian diet habit, suggesting elevated risk of the condition when associated with these parameters. Significantly high risk for males with AA genotype of -217G>A polymorphism was observed for developing EHT ( p = .07). Males with -217A ( p = .01) showed a two-fold higher risk for EHT. Markers -217G>A and -6G>A were in strong linkage disequilibrium in patients as compared to controls. Strong epistatic interactions were found between -6G>A, M235T and -217G>A markers, supporting the synergistic effect between them leading to EHT.

Conclusion:

Our findings suggest that -217A variant is significantly associated with the risk for EHT in males. Further studies on the functional role of the marker -217 are recommended for understanding the cause of association with EHT.
The Perils of Great Medical Care—Overuse?
Authors: Kovner Christine Tassone
Published: May 2012

This essay, a personal reflection on the major medical center diagnosis and treatment odyssey, in which it is not clear that more testing and greater interventions achieve the highest value.
Which Cholinesterase Inhibitor is the Safest for the Heart in Elderly Patients With Alzheimer’s Disease?
Authors: Isik Ahmet Turan , Bozoglu Ergun , Yay Adnan , Soysal Pinar , Ateskan Umit
Published: May 2012

Objective: Cholinesterase inhibitors (ChEIs) are widely used for the treatment of Alzheimer’s disease (AD); however, their cholinergic side effects on the cardiovascular system are still unclear. In this study, we aimed to examine the side effects caused by donepezil, rivastigmine, and galantamine on cardiac rhythm and postural blood pressure changes in elderly patients with AD. Methods: Of 204 consecutive elderly patients who were newly diagnosed with AD, 162 were enrolled and underwent comprehensive geriatric assessments. The electrocardiographs (ECGs) and blood pressures were recorded at the baseline and 4 weeks after the dose of 10 mg/d of donepezil, 10 cm2/d of rivastigmine, and 24 mg/d of galantamine. Results: There were no changes relative to the baseline in any of the ECG parameters or arterial blood pressure with any of the administered ChEIs. Conclusion: It was demonstrated that none of the 3 ChEIs were associated with increased negative chronotropic, arrhythmogenic, and hypotensive effects for the elderly patients with AD.
A Clinical Approach to Early-Onset Inheritable Dementia
Authors: Rogers Brian S. , Lippa Carol F.
Published: May 2012

Early-onset dementia, presenting before age 65 years, is increasingly recognized. It is often difficult to diagnose, since non-Alzheimer’s etiologies and unusual dementias are common. These conditions are more commonly genetic, and important potentially inherited causes of early-onset dementia include early-onset Alzheimer’s disease, frontotemporal dementia, Kufs’ disease, and Niemann-Pick disease type C. For each of these diseases, this review provides information on common clinical presentations, etiology, pathophysiology, and current and experimental treatments. A discussion of the diagnosis and workup for early-onset dementia is included with an emphasis on conditions that may have other involved family members.
The Heir and the Cowboy: Social Predisposition, Mediation and Artistic Profession in Marcel Duchamp and Jackson Pollock
Authors: Peist Nuria
Published: May 2012

This article analyses the social conditions that lead up to modes of entry into the field of art, as experienced by two of the most representative artists of the first and second avant-garde: Marcel Duchamp and Jackson Pollock. Differences in the degree to which the two artists possessed social and cultural capital, born of their respective trajectories, influenced the mediating structure each employed. In contrast to Pollock, Duchamp did not have a profuse or organized network of intermediaries. He was able to convert capital he inherited into a distancing of himself from opportunities made easily available to him. Duchamp achieved a high degree of formal experimentation, opting not to expose his work to the demands of the field of modern art. Both artists embody ideal types, between which many avant-garde artists of the first half of the 20th century would fluctuate. While Duchamp was to be considered the great precursor of contemporary art, Pollock would occupy the place of prototypical avant-garde artist.
Long-Term Evaluation of Autologous Chondrocyte Implantation
Authors: Corpus Keith T. , Bajaj Sarvottam , Daley Erika L. , Lee Andrew , Kercher James S. , Salata Michael J. , Verma Nikhil N. , Cole Brian J.
Published: May 2012

Purpose:

The purpose of this study was to report the clinical outcomes of autologous chondrocyte implantation (ACI) procedures performed by a single orthopedic surgeon at a minimum of 7 years follow-up.

Methods:

A retrospective review of prospectively collected data was performed on 29 patients who underwent ACI of the knee between the years of 1998 and 2003. Prospective data were collected to assess changes in standardized outcome measures preoperatively and 2, 4, and 7 years postoperatively. All patients enrolled in the study were also recruited to undergo physical examination when possible.

Results:

The final cohort consisted of 29 patients with a mean final follow-up time of 8.40 years (range = 7.14-10.88 years). Comparing preoperative scores to 7-year postoperative values, the mean International Knee Documentation Committee (IKDC) score improved from 39.80 to 59.24 ( P < 0.001), mean Tegner-Lysholm score increased from 48.07 to 74.17 ( P < 0.001), SF-12 physical score improved from 40.38 to 48.66 ( P < 0.001), and SF-12 mental score improved from 44.14 to 48.98 ( P < 0.05). Significant improvement occurred in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain (56.03 to 80.36), symptoms (54.19 to 74.75), activities of daily living (72.01 to 85.90), sports (23.34 to 55.34), and quality of life (24.56 to 56.03) ( P < 0.001). In addition, 7-year postoperative scores were at or near levels seen at 2 years (mean = 2.16; range = 0.94-4.03 years) and 4 years (mean = 4.43; range = 2.16-5.88 years) postoperatively, reflecting durable improvement. Subjectively, on a scale of 1 to 10 (10 being completely satisfied), the mean postoperative satisfaction rate was 8.14. Additionally, 88.9% of the patients would elect to have this surgery again if the same problem was to occur in the contralateral joint.

Conclusions:

The results of ACI in patients who present with symptomatic, full-thickness chondral defects remain durable at a minimum of 7-year follow-up with persistent, high levels of patient satisfaction.

Level of Evidence:

Case series; Level of evidence, IV.
The Augmentation of a Collagen/Glycosaminoglycan Biphasic Osteochondral Scaffold with Platelet-Rich Plasma and Concentrated Bone Marrow Aspirate for Osteochondral Defect Repair in Sheep
Authors: Getgood Alan , Henson Frances , Skelton Carrie , Herrera Emilio , Brooks Roger , Fortier Lisa A. , Rushton Neil
Published: May 2012

Objective:

This study investigates the combination of platelet-rich plasma (PRP) or concentrated bone marrow aspirate (CBMA) with a biphasic collagen/glycosaminoglycan (GAG) osteochondral scaffold for the treatment of osteochondral defects in sheep.

Design:

Acute osteochondral defects were created in the medial femoral condyle (MFC) and the lateral trochlea sulcus (LTS) of 24 sheep ( n = 6). Defects were left empty or filled with a 6 × 6-mm scaffold, either on its own or in combination with PRP or CBMA. Outcome measures at 6 months included mechanical testing, International Cartilage Repair Society (ICRS) repair score, modified O’Driscoll histology score, qualitative histology, and immunohistochemistry for type I, II, and VI collagen.

Results:

No differences in mechanical properties, ICRS repair score, or modified O’Driscoll score were detected between the 4 groups. However, qualitative assessments of the histological architecture, Safranin O content, and collagen immunohistochemistry indicated that in the PRP/scaffold groups, there was a more hyaline cartilage–like tissue repair. In addition, the addition of CBMA and PRP to the scaffold reduced cyst formation in the subchondral bone of healed lesions.

Conclusion:

There was more hyaline cartilage–like tissue formed in the PRP/scaffold group and less subchondral cystic lesion formation in the CBMA and PRP/scaffold groups, although there were no quantitative differences in the repair tissue formed.
Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management
Authors: Yazdanbakhsh Karina , Ware Russell E. , Noizat-Pirenne France
Published: May 2012

Red blood cell transfusions have reduced morbidity and mortality for patients with sickle cell disease. Transfusions can lead to erythrocyte alloimmunization, however, with serious complications for the patient including life-threatening delayed hemolytic transfusion reactions and difficulty in finding compatible units, which can cause transfusion delays. In this review, we discuss the risk factors associated with alloimmunization with emphasis on possible mechanisms that can trigger delayed hemolytic transfusion reactions in sickle cell disease, and we describe the challenges in transfusion management of these patients, including opportunities and emerging approaches for minimizing this life-threatening complication.
Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids
Authors: Shibeko Alexey M. , Woodle Samuel A. , Lee Timothy K. , Ovanesov Mikhail V.
Published: May 2012

Recombinant factor VIIa (rFVIIa) is used for treatment of hemophilia patients with inhibitors, as well for off-label treatment of severe bleeding in trauma and surgery. Effective bleeding control requires supraphysiological doses of rFVIIa, posing both high expense and uncertain thrombotic risk. Two major competing theories offer different explanations for the supraphysiological rFVIIa dosing requirement: (1) the need to overcome competition between FVIIa and FVII zymogen for tissue factor (TF) binding, and (2) a high-dose–requiring phospholipid-related pathway of FVIIa action. In the present study, we found experimental conditions in which both mechanisms contribute simultaneously and independently to rFVIIa-driven thrombin generation in FVII-deficient human plasma. From mathematical simulations of our model of FX activation, which were confirmed by thrombin-generation experiments, we conclude that the action of rFVIIa at pharmacologic doses is dominated by the TF-dependent pathway with a minor contribution from a phospholipid-dependent mechanism. We established a dose-response curve for rFVIIa that is useful to explain dosing strategies. In the present study, we present a pathway to reconcile the 2 major mechanisms of rFVIIa action, a necessary step to understanding future dose optimization and evaluation of new rFVIIa analogs currently under development.
Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model
Authors: Hilden Ida , Lauritzen Brian , Sørensen Brit Binow , Clausen Jes Thorn , Jespersgaard Christina , Krogh Berit Olsen , Bowler Andrew Neil , Breinholt Jens , Gruhler Albrecht , Svensson L. Anders , Petersen Helle Heibroch , Petersen Lars Christian , Balling Kristoffer W. , Hansen Lene , Hermit Mette Brunsgaard , Egebjerg Thomas , Friederichsen Birgitte , Ezban Mirella , Bjørn Søren Erik
Published: May 2012

Hemophilia is treated by IV replacement therapy with Factor VIII (FVIII) or Factor IX (FIX), either on demand to resolve bleeding, or as prophylaxis. Improved treatment may be provided by drugs designed for subcutaneous and less frequent administration with a reduced risk of inhibitor formation. Tissue factor pathway inhibitor (TFPI) down-regulates the initiation of coagulation by inhibition of Factor VIIa (FVIIa)/tissue factor/Factor Xa (FVIIa/TF/FXa). Blockage of TFPI inhibition may facilitate thrombin generation in a hemophilic setting. A high-affinity (KD = 25pM) mAb, mAb 2021, against TFPI was investigated. Binding of mAb 2021 to TFPI effectively prevented inhibition of FVIIa/TF/FXa and improved clot formation in hemophilia blood and plasma. The binding epitope on the Kunitz-type protease inhibitor domain 2 of TFPI was mapped by crystallography, and showed an extensive overlap with the FXa contact region highlighting a structural basis for its mechanism of action. In a rabbit hemophilia model, an intravenous or subcutaneous dose significantly reduced cuticle bleeding. mAb 2021 showed an effect comparable with that of rFVIIa. Cuticle bleeding in the model was reduced for at least 7 days by a single intravenous dose of mAb 2021. This study suggests that neutralization of TFPI by mAb 2021 may constitute a novel treatment option in hemophilia.
Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds
Authors: Shen Yue , Guo Yongzhi , Mikus Peter , Sulniute Rima , Wilczynska Malgorzata , Ny Tor , Li Jinan
Published: May 2012

Despite decades of research on wound healing, effective biologic agents for the treatment of chronic wounds, especially diabetic wounds, are still lacking. In the present study, we report that the inert plasma protein plasminogen (plg) acts as a key regulatory molecule that potentiates wound healing in mice. Early in the healing process, plg bound to inflammatory cells is transported to the wound area, where the level of plg is increased locally, leading to the induction of cytokines and intracellular signaling events and to a potentiation of the early inflammatory response. Systemic administration of additional plg not only accelerates the healing of acute burn wounds in wild-type mice, but also improves the healing of chronic diabetic wounds in a mouse model of diabetes. Our results suggest that the administration of plg may be a novel therapeutic strategy to treat many different types of wounds, especially chronic wounds such as those caused by diabetes.
Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention
Authors: Norde Wieger J. , Hobo Willemijn , van der Voort Robbert , Dolstra Harry
Published: May 2012

The adaptive immune system can be a potent defense mechanism against cancer; however, it is often hampered by immune suppressive mechanisms in the tumor microenvironment. Coinhibitory molecules expressed by tumor cells, immune cells, and stromal cells in the tumor milieu can dominantly attenuate T-cell responses against cancer cells. Today, a variety of coinhibitory molecules, including cytotoxic T lymphocyte–associated antigen-4, programmed death-1, B and T lymphocyte attenuator, LAG3, T-cell immunoglobulin and mucin domain 3, and CD200 receptor, have been implicated in immune escape of cancer cells. Sustained signaling via these coinhibitory molecules results in functional exhaustion of T cells, during which the ability to proliferate, secrete cytokines, and mediate lysis of tumor cells is sequentially lost. In this review, we discuss the influence of coinhibitory pathways in suppressing autologous and allogeneic T cell–mediated immunity against hematologic malignancies. In addition, promising preclinical and clinical data of immunotherapeutic approaches interfering with negative cosignaling, either as monotherapy or in conjunction with vaccination strategies, are reviewed. Numerous studies indicate that coinhibitory signaling hampers the clinical benefit of current immunotherapies. Therefore, manipulation of coinhibitory networks is an attractive adjuvant immunotherapeutic intervention for hematologic cancers after standard treatment with chemotherapy and hematopoietic stem cell transplantation.
Genomic characterization of the conditionally dispensable chromosome in Alternaria arborescens provides evidence for horizontal gene transfer
Authors: Hu Jinnan , Chen Chenxi , Peever Tobin , Dang Ha , Lawrence Christopher , Mitchell Thomas
Published: May 2012

Background

Fungal plant pathogens cause serious agricultural losses worldwide. Alternaria arborescens is a major pathogen of tomato, with its virulence determined by the presence of a conditionally dispensable chromosome (CDC) carrying host-specific toxin genes. Genes encoding these toxins are well-studied, however the genomic content and organization of the CDC is not known.

Results

To gain a richer understanding of the molecular determinants of virulence and the evolution of pathogenicity, we performed whole genome sequencing of A. arborescens. Here we present the de-novo assembly of the CDC and its predicted gene content. Also presented is hybridization data validating the CDC assembly. Predicted genes were functionally annotated through BLAST. Gene ontology terms were assigned, and conserved domains were identified. Differences in nucleotide usage were found between CDC genes and those on the essential chromosome (EC), including GC3-content, codon usage bias, and repeat region load. Genes carrying PKS and NRPS domains were identified in clusters on the CDC and evidence supporting the origin of the CDC through horizontal transfer from an unrelated fungus was found.

Conclusions

We provide evidence supporting the hypothesis that the CDC in A. arborescens was acquired through horizontal transfer, likely from an unrelated fungus. We also identified several predicted CDC genes under positive selection that may serve as candidate virulence factors.
Expansion of CORE-SINEs in the genome of the Tasmanian devil
Authors: Nilsson Maria A , Janke Axel , Murchison Elizabeth P , Ning Zemin , Hallström Björn M
Published: May 2012

Background

The genome of the carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii, Order: Dasyuromorphia), was sequenced in the hopes of finding a cure for or gaining a better understanding of the contagious devil facial tumor disease that is threatening the species’ survival. To better understand the Tasmanian devil genome, we screened it for transposable elements and investigated the dynamics of short interspersedelement (SINE) retroposons.

Results

The temporal history of Tasmanian devil SINEs, elucidated using a transposition in transposition analysis, indicates that WSINE1, a CORE-SINE present in around 200,000 copies, is the most recently active element. Moreover, we discovered a new subtype of WSINE1 (WSINE1b) that comprises at least 90% of all Tasmanian devil WSINE1s. The frequencies of WSINE1 subtypes differ in the genomes of two of the other Australian marsupial orders. A co-segregation analysis indicated that at least 66 subfamilies of WSINE1 evolved during the evolution of Dasyuromorphia. Using a substitution rate derived from WSINE1 insertions, the ages of the subfamilies were estimated and correlated with a newly established phylogeny of Dasyuromorphia. Phylogenetic analyses and divergence time estimates of mitochondrial genome data indicate a rapid radiation of the Tasmanian devil and the closest relative the quolls (Dasyurus) around 14 million years ago.

Conclusions

The radiation and abundance of CORE-SINEs in marsupial genomes indicates that they may be a major player in the evolution of marsupials. It is evident that the early phases of evolution of the carnivorous marsupial order Dasyuromorphia was characterized by a burst of SINE activity. A correlation between a speciation event and a major burst of retroposon activity is for the first time shown in a marsupial genome.
Genome-wide expression profiling shows transcriptional reprogramming in Fusarium graminearum by Fusarium graminearum virus 1-DK21 infection
Authors: Cho Won Kyong , Yu Jisuk , Lee Kyung-Mi , Son Moonil , Min Kyunghun , Lee Yin-Won , Kim Kook-Hyung
Published: May 2012

Background

Fusarium graminearum virus 1 strain-DK21 (FgV1-DK21) is a mycovirus that confers hypovirulence toF. graminearum, which is the primary phytopathogenic fungus that causes Fusarium head blight (FHB) disease in many cereals. Understanding the interaction between mycoviruses and plant pathogenic fungi is necessary for preventing damage caused byF. graminearum. Therefore, we investigated important cellular regulatory processes in a host containing FgV1-DK21 as compared to an uninfected parent using a transcriptional approach.

Results

Using a 3′-tiling microarray covering all knownF. graminearumgenes, we carried out genome-wide expression analyses ofF. graminearumat two different time points. At the early point of growth of an infected strain as compared to an uninfected strain, genes associated with protein synthesis, including ribosome assembly, nucleolus, and ribosomal RNA processing, were significantly up-regulated. In addition, genes required for transcription and signal transduction, including fungal-specific transcription factors and cAMP signaling, respectively, were actively up-regulated. In contrast, genes involved in various metabolic pathways, particularly in producing carboxylic acids, aromatic amino acids, nitrogen compounds, and polyamines, showed dramatic down-regulation at the early time point. Moreover, genes associated with transport systems localizing to transmembranes were down-regulated at both time points.

Conclusion

This is the first report of global change in the prominent cellular pathways in theFusariumhost containing FgV1-DK21. The significant increase in transcripts for transcription and translation machinery in fungal host cells seems to be related to virus replication. In addition, significant down-regulation of genes required for metabolism and transporting systems in a fungal host containing the virus appears to be related to the host defense mechanism and fungal virulence. Taken together, our data aid in the understanding of how FgV1-DK21 regulates the transcriptional reprogramming ofF. graminearum.
The nucleotide excision repair (NER) system of Helicobacter pylori: Role in mutation prevention and chromosomal import patterns after natural transformation
Authors: Moccia Claudia , Krebes Juliane , Kulick Stefan , Didelot Xavier , Kraft Christian , Bahlawane Christelle , Suerbaum Sebastian
Published: May 2012

Background

Extensive genetic diversity and rapid allelic diversification are characteristics of the human gastric pathogen Helicobacter pylori, and are believed to contribute to its ability to cause chronic infections. Both a high mutation rate and frequent imports of short fragments of exogenous DNA during mixed infections play important roles in generating this allelic diversity. In this study, we used a genetic approach to investigate the roles of nucleotide excision repair (NER) pathway components in H. pylori mutation and recombination.

Results

Inactivation of any of the four uvr genes strongly increased the susceptibility of H. pylori to DNA damage by ultraviolet light. Inactivation of uvrA and uvrB significantly decreased mutation frequencies whereas only the uvrA deficient mutant exhibited a significant decrease of the recombination frequency after natural transformation. A uvrC mutant did not show significant changes in mutation or recombination rates; however, inactivation of uvrC promoted the incorporation of significantly longer fragments of donor DNA (2.2-fold increase) into the recipient chromosome. A deletion of uvrD induced a hyper-recombinational phenotype.

Conclusions

Our data suggest that the NER system has multiple functions in the genetic diversification of H. pylori, by contributing to its high mutation rate, and by controlling the incorporation of imported DNA fragments after natural transformation.
Standardized collection of MNase-seq experiments enables unbiased dataset comparisons
Authors: Rizzo Jason M , Bard Jonathan E , Buck Michael J
Published: May 2012

Background

The organization of eukaryotic DNA into chromatin has a strong influence on the accessibility and regulation of genetic information. The locations and occupancies of a principle component of chromatin, nucleosomes, are typically assayed through use of enzymatic digestion with micrococcal nuclease (MNase). MNase is an endo-exo nuclease that preferentially digests naked DNA and the DNA in linkers between nucleosomes, thus enriching for nucleosome-associated DNA. To determine nucleosome organization genome-wide, DNA remaining from MNase digestion is sequenced using high-throughput sequencing technologies (MNase-seq). Unfortunately, the results of MNase-seq can vary dramatically due to technical differences and this confounds comparisons between MNase-seq experiments, such as examining condition-dependent chromatin organizations.

Results

In this study we use MNase digestion simulations to demonstrate how MNase-seq signals can vary for different nucleosome configuration when experiments are performed with different extents of MNase digestion. Signal variation in these simulations reveals an important DNA sampling bias that results from a neighborhood effect of MNase digestion techniques. The presence of this neighborhood effect ultimately confounds comparisons between different MNase-seq experiments. To address this issue we present a standardized chromatin preparation which controls for technical variance between MNase-based chromatin preparations and enables the collection of similarly sampled (matched) chromatin populations. Standardized preparation of chromatin includes a normalization step for DNA input into MNase digestions and close matching of the extent of digestion between each chromatin preparation using gel densitometry analysis. The protocol also includes directions for successful pairing with multiplex sequencing reactions.

Conclusions

We validated our method by comparing the experiment-to-experiment variation between biological replicates of chromatin preparations from S. cerevisiae. Results from our matched preparation consistently produced MNase-seq datasets that were more closely correlated than other unstandardized approaches. Additionally, we validated the ability of our approach at enabling accurate downstream comparisons of chromatin structures, by comparing the specificity of detecting Tup1-dependent chromatin remodeling events in comparisons between matched and un-matched wild-type and tup1 Δ MNase-seq datasets. Our matched MNase-seq datasets demonstrated a significant reduction in non-specific (technical) differences between experiments and were able to maximize the detection of biologically-relevant (Tup1-dependent) changes in chromatin structure.