bluuebunny/crossref_metadata_2025 huggingface dataset:
BCL-2 Hypermethylation Is a Potential Biomarker of Sensitivity to Antimitotic Chemotherapy in Endocrine-Resistant Breast Cancer
Authors: Stone Andrew , Cowley Mark J. , Valdes-Mora Fatima , McCloy Rachael A. , Sergio C. Marcelo , Gallego-Ortega David , Caldon C. Elizabeth , Ormandy Christopher J. , Biankin Andrew V. , Gee Julia M.W. , Nicholson Robert I. , Print Cristin G. , Clark Susan J. , Musgrove Elizabeth A.
Published: July 2013

Overexpression of the antiapoptotic factor BCL-2 is a frequent feature of malignant disease and is commonly associated with poor prognosis and resistance to conventional chemotherapy. In breast cancer, however, high BCL-2 expression is associated with favorable prognosis, estrogen receptor (ER) positivity, and low tumor grade, whereas low expression is included in several molecular signatures associated with resistance to endocrine therapy. In the present study, we correlate BCL-2 expression and DNA methylation profiles in human breast cancer and in multiple cell models of acquired endocrine resistance to determine whether BCL-2 hypermethylation could provide a useful biomarker of response to cytotoxic therapy. In human disease, diminished expression of BCL-2 was associated with hypermethylation of the second exon, in a region that overlapped a CpG island and an ER-binding site. Hypermethylation of this region, which occurred in 10% of primary tumors, provided a stronger predictor of patient survival (P = 0.019) when compared with gene expression (n = 522). In multiple cell models of acquired endocrine resistance, BCL-2 expression was significantly reduced in parallel with increased DNA methylation of the exon 2 region. The reduction of BCL-2 expression in endocrine-resistant cells lowered their apoptotic threshold to antimitotic agents: nocodazole, paclitaxel, and the PLK1 inhibitor BI2536. This phenomenon could be reversed with ectopic expression of BCL-2, and rescued with the BCL-2 inhibitor ABT-737. Collectively, these data imply that BCL-2 hypermethylation provides a robust biomarker of response to current and next-generation cytotoxic agents in endocrine-resistant breast cancer, which may prove beneficial in directing therapeutic strategy for patients with nonresectable, metastatic disease. Mol Cancer Ther; 12(9); 1874–85. ©2013 AACR.
SF3B1 Mutations Are Associated with Alternative Splicing in Uveal Melanoma
Authors: Furney Simon J. , Pedersen Malin , Gentien David , Dumont Amaury G. , Rapinat Audrey , Desjardins Laurence , Turajlic Samra , Piperno-Neumann Sophie , de la Grange Pierre , Roman-Roman Sergio , Stern Marc-Henri , Marais Richard
Published: July 2013

Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas. We observed only approximately 2,000 predicted somatic single-nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations. SF3B1 encodes a component of the spliceosome, and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes, including ABCC5 and UQCC, and of the long noncoding RNA CRNDE.

Significance: Our data show that despite its dismal prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains and a low mutational burden. We show that SF3B1 is recurrently mutated in uveal melanoma, and the mutations are associated with aberrant alternative splicing. Cancer Discov; 3(10); 1122–9. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1083
Modeling of Oxidized PTH (oxPTH) and Non-oxidized PTH (n-oxPTH) Receptor Binding and Relationship of Oxidized to Non-Oxidized PTH in Children with Chronic Renal Failure, Adult Patients on Hemodialysis and Kidney Transplant Recipients
Authors: Hocher Berthold , Oberthür Dominik , Slowinski Torsten , Querfeld Uwe , Schaefer Franz , Doyon Anke , Tepel Martin , Roth Heinz J. , Grön Hans J. , Reichetzeder Christoph , Betzel Christian , Armbruster Franz P.
Published: July 2013

Background: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970s and 80s. However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. Results: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. Conclusion: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies.
The Association Between Peritoneal Charge Barrier Dysfunction and Protein Lost During Continuous Ambulatory Peritoneal Dialysis
Authors: Yu Guo-Qing , Chen Jian , Li Jun-Xia
Published: July 2013

Background/Aims: The main purpose of the present study was to determine the effect of peritoneal charge barrier dysfunction on hypoalbuminemia during CAPD. Methods: We measured the association of dialysis dose, peritoneal equilibration test (PET) results (ratio of dialysate and plasma creatinine), and peritoneal charge barrier index (ratio of pancreatic and salivary α-amylase clearance) on protein loss in 33 patients on maintenance CAPD. All patients were from a single institution and were diagnosed with chronic nephritis (n = 18 cases), diabetic nephropathy (n = 8), hypertension (n = 5), and hepatitis B virus-associated glomerulonephritis (n = 2). Results: The mean (± SD) dialysate protein loss was 4.04 g (± 1.97) per day. Protein loss was positively correlated with dialysis dose (r = 0.438, p = 0.01) but was not significantly correlated with PET results. The mean (± SD) peritoneal charge barrier index was 6.12 (± 21.20) and was inversely correlated with protein loss into the peritoneal dialysate (r = -0.532, p < 0.01). Conclusions: Taken together, our study of CAPD patients indicates that protein loss into the peritoneal dialysate increases with peritoneal dialysis dose and with disruption of the peritoneal charge barrier.
Lymph Node Dissection in Resectable Advanced Gastric Cancer
Authors: de Steur Wobbe O. , Dikken Johan L. , Hartgrink Henk H.
Published: July 2013

The extent of surgery for gastric cancer has been debated since Billroth performed his first gastrectomy in 1881. This review gives an overview of the available literature on the extent of gastrectomy and lymphadenectomy for advanced resectable gastric cancer. Subtotal gastrectomy is associated with lower morbidity and mortality compared with total gastrectomy, without compromising long-term survival. However, a positive resection margin decreases the chance of curation. Frozen section examination may prevent this. For poorly differentiated singlet ring cell tumors, there may be an argument to perform a total gastrectomy in all cases. In 1981, the Japanese Research Society for the Study of Gastric Cancer provided guidelines for the standardization of surgical treatment and pathological evaluation of gastric cancer. Since then, D2 lymph node dissections have become the standard of care in Japan. Because of the superior stage-specific survival rates in Japan, a D2 dissection was evaluated in several Western randomized controlled trials, but no survival benefit was found for a D2 over a D1 dissection. This might be explained by the increased mortality in the D2 dissection groups which might be the result of a standard pancreaticosplenectomy and low experience with D2 dissections. Adding the removal of the para-aortic nodes to a D2 dissection does not further improve survival. The removal of lymph node stations 10 and 11 by splenectomy showed an increased morbidity, no survival benefit, and a very poor prognosis if lymph nodes were affected. Therefore, pancreaticosplenectomy should only be performed in cases of tumor invasion into these organs. A D2 dissection without routine splenectomy and pancreatic tail resection in experienced hands should be considered standard of care for advanced resectable gastric cancer, both in Asian and in Western patients. Centralization and auditing may further improve outcomes after gastrectomy.
Sentinel Node Navigation Surgery in Patients with Early Gastric Cancer
Authors: Takeuchi Hiroya , Kitagawa Yuko
Published: July 2013

Clinical application of sentinel node (SN) mapping in patients with early gastric cancer has been a controversial issue for years. However, a recent meta-analysis and a prospective multicenter trial of SN mapping for early gastric cancer have shown acceptable SN detection rates and accuracy of determination of lymph node status. A dual-tracer method that utilizes radioactive colloids and blue dyes is currently considered the most reliable method for the stable detection of SNs in patients with early gastric cancer. However, new technologies such as indocyanine green infrared or fluorescence imaging might revolutionize the SN mapping procedures in gastric cancer. For early-stage gastric cancer such as cT1N0, for which a better prognosis can be potentially achieved through conventional surgical approaches, the establishment of individualized, minimally invasive treatments that may retain the patients' quality of life should be the next surgical challenge. Although there are many unresolved technical issues, laparoscopic SN biopsy with laparoscopic minimized gastrectomy or endoscopic mucosal resection/endoscopic submucosal dissection could be a promising strategy to achieve this goal.
Gastric Cancer Pathology and Underlying Molecular Mechanisms
Authors: Grabsch Heike I. , Tan Patrick
Published: July 2013

The development of gastric adenocarcinoma is a complex multistep process involving multiple genetic alterations. Based on pathology, four different macroscopic types and at least two major histological types, intestinal and diffuse, have been described. Most gastric cancer (GC) show genetic instability, either microsatellite instability or chromosomal instability, which is considered an early event in gastric carcinogenesis. Molecular studies of alterations of single genes have provided evidence that intestinal and diffuse type GC evolve via different genetic pathways. Recent results from high-throughput whole-genome expression or copy number studies have demonstrated extensive genetic diversity between cases and within individual GC. Sets of commonly up- or downregulated microRNAs have been identified in GC and might be useful in the near future to identify pathways of GC progression. Results from detailed molecular and/or pathological GC studies, although promising, still have limited clinical utility in predicting survival and stratifying GC patients for appropriate treatment.
Laparoscopic Gastrectomy for Gastric Cancer
Authors: Lee Hyuk-Joon , Yang Han-Kwang
Published: July 2013

Laparoscopic gastrectomy for gastric cancer is rapidly becoming popular because of the technical developments and the accumulated data of laparoscopic surgery in gastric cancer patients. The aim of this review is to present the current body of evidence and to highlight controversial issues of laparoscopic gastrectomy for gastric cancer. Laparoscopic distal gastrectomy (LDG) provides better or comparable outcomes compared to conventional open distal gastrectomy (ODG) in terms of short-term results. The long-term survival of LDG is expected to be comparable to that of ODG in early-stage gastric cancer, and an ongoing Korean multicenter randomized controlled trial (KLASS-01) will provide more clear evidence. Laparoscopic total gastrectomy is still selectively performed compared to LDG, and there is still debate on the safety of the laparoscopic esophagojejunostomy technique. Laparoscopic pylorus-preserving gastrectomy seems to be preferred for early gastric cancer in the middle third of the stomach in terms of functional advantages and comparable oncologic outcome. Evidence for LDG for advanced gastric cancer is still insufficient and the issue of lack of generalization still remains, even after ongoing multicenter randomized controlled trials have revealed clinical evidence. Laparoscopic sentinel node navigation surgery is still experimental and the surgical procedure has yet to be standardized. Robotic gastrectomy is feasible for early gastric cancer in terms of similar outcome, but is much more expensive in comparison to laparoscopic surgery. Its benefit over the conventional laparoscopic gastrectomy has not yet been proven.
Palliative Treatment and the Role of Surgical Resection in Gastric Cancer
Authors: Karpeh Jr. Martin S.
Published: July 2013

Adenocarcinoma of the stomach is often diagnosed in the late stages of the disease. Surgical resection of all gross and microscopic disease is essential for curative treatment. Complete resection is often not achievable when patients present with advanced stage IV cancer. In the absence of symptoms, chemotherapy without resection has been the standard of care in most major centers. With improvements in response to chemotherapy and less invasive surgical approaches, patients with metastatic gastric cancer have had better survival outcomes than in the past. The challenge today when treating these patients is in defining who will benefit from more aggressive interventions. Reviewing the literature for guidance is difficult because the goals of treatment are often not clearly defined. Finding the proper balance of aggressiveness needed to extend survival while preserving and maximizing quality of life is a decision that clinicians have to make with increasing frequency. This review will attempt to provide a framework to aid in determining what role, if any, gastrectomy has in the management of patients with stage IV gastric cancer.
Zoledronic Acid Inhibits Human Osteoblast Activities
Authors: Basso Fernanda G. , Silveira Turrioni Ana Paula , Hebling Josimeri , de Souza Costa Carlos A.
Published: July 2013

Background: Bisphosphonates are potent inhibitors of bone resorption. These kinds of drugs, which are used for the treatment of osteolytic diseases, have been associated with the occurrence of oral osteonecrosis, especially in patients over 60 years old. Current studies have demonstrated that the cytotoxic effects of bisphosphonates on osteoblasts play an important role in oral osteonecrosis development. Objective: The aim of this study was to evaluate the effect of long-term application of a highly potent bisphosphonate - zoledronic acid (ZA) - on human osteoblasts in vitro. Methods: Human osteoblasts (MG63 cell line) were seeded for 72 h in wells of 24-well plates. The Dulbecco's modified Eagle's medium (DMEM) was then replaced by culture medium without fetal bovine serum (FBS), and the cells were incubated for an additional 24 h, after which ZA was added to the DMEM without FBS and incubated in contact with osteoblasts for 7, 14 or 21 days. Cell viability (CV), total protein production (TPP), alkaline phosphatase (ALP) activity, mineral nodule formation (MNF), and gene expression of ALP and osteocalcin (OCN), as well as cell morphology by scanning electronic microscopy, were evaluated. Data were statistically analyzed by Kruskal-Wallis and Mann-Whitney tests, with a significance level of 5%. Results: The cytotoxic effects of ZA on osteoblasts were characterized by reduction of CV, TPP, ALP and MNF production. In addition, ZA MNF caused a decrease in gene expression of ALP and OCN, as well as intense cell morphology alterations. All these negative effects of ZA were concentration and period dependent. Conclusion: Both concentrations of ZA (1 and 5 μM) caused cytotoxic effects to osteoblasts which reduced the production and expression of proteins that play an important role in bone matrix synthesis and mineralization.
The Role of Matrix Metalloproteinase-2 in the Treatment of Atrial Fibrillation Recurrence after a Radiofrequency Modified Maze Procedure
Authors: Wang Xin , Li Yuan , Liu Lei , Hu Sheng-Shou , Song Yun-Hu , Wang Wei
Published: July 2013

Background and Objective: Our study aimed to elucidate the potential clinical and molecular issues in recurrent atrial fibrillation (AF) following a radiofrequency modified maze procedure in patients with rheumatic valvular disease and persistent AF. Methods and Results: Eighty patients with rheumatic valvular disease and persistent AF (lasting more than 6 months) who had undergone a radiofrequency modified maze procedure and mitral valve replacement were enrolled into this single-center pilot study and were followed up for another 6 months. Their clinical characteristics were analyzed and the expression of matrix metalloproteinase (MMP)-2 including its specific inhibitor and collagen volume fraction (CVF) was also assessed. During the 6-month follow-up, 24 subjects had recurrent AF. Among them, the left atrial diameter was larger compared to that achieved in sinus rhythm (SR). The mRNA and protein expression of MMP-2 was significantly increased in recurrent AF patients, while its specific inhibitor did not show a significant difference (p > 0.05). The CVF of type I collagen increased significantly in the recurrent AF patients compared to SR patients (18.16 ± 3.22 vs. 11.66 ± 3.38, p < 0.001), whereas the CVF of type III collagen showed no significant difference (8.33 ± 3.44 vs. 9.55 ± 3.67, p > 0.05). Conclusion: This study suggests that the overexpression of MMP-2 is associated with CVF-I in the left atrial appendage which potentially leads to the recurrence of AF following a radiofrequency modified maze procedure in patients with rheumatic valve disease.
Evaluation of Factors Related to Late Recurrence - Later than 10 Years after the Initial Treatment - in Primary Breast Cancer
Authors: Nishimura Reiki , Osako Tomofumi , Nishiyama Yasuyuki , Tashima Rumiko , Nakano Masahiro , Fujisue Mamiko , Toyozumi Yasuo , Arima Nobuyuki
Published: July 2013

Background: Breast cancer is associated with a relatively good prognosis. Prognostic factors examined to date are related to early recurrence while those related to late recurrence and their countermeasures remain unclear. Therefore, we examined the factors related to late recurrence. Patients and Methods: From January 1980 to August 2012, 4,774 patients who underwent primary treatment and estrogen (ER) and progesterone receptor (PgR) assessment were enrolled in this study. The patients were divided into two groups, those with a follow-up period <10 years and those without any recurrence at 10 years but who continued follow-up examinations. Recurrence occurred in 711 patients followed up for <10 years and in 51 patients for ≥10 years. Results: The overall 10-year cumulative disease-free survival rate was 79.5%, and the recurrence rate at ≥10 years was 5.8%. A multivariate analysis revealed that the factors related to late recurrence were PgR positivity and positive nodes. This result differed from that for early recurrence in terms of ER/PgR, Ki-67 index and p53 overexpression. Conclusion: PgR positivity and lymph node metastases significantly correlated with late recurrence. Therefore, it is important to evaluate appropriate measures such as treatment period and treatment regimen for hormone-sensitive patients.
Jaspers, the Body, and Schizophrenia: The Bodily Self
Authors: Gallese Vittorio , Ferri Francesca
Published: July 2013

Karl Jaspers laid the foundations of contemporary psychopathology. Among Jaspers' contributions was his powerful vision of psychiatry as a crucial way to shed light on the human condition and existence by integrating the scientific study of psychic diseases with a theoretical approach focused on human experience. This perspective should be revitalized. In the present paper we start from the role Jaspers assigns to the body when discussing the notion of ‘personalization'. We explore the relationship between a minimal notion of the self, the ‘bodily self', and its potentiality for movement - the self's ‘power for action'. Based on recent empirical evidence, we then propose a connection between the implicit bodily self-experience and important psychopathological aspects of schizophrenia by showing that schizophrenic patients exhibit a disruption of implicit bodily self-knowledge. We propose that the bodily nature of the implicitly experiencing self might enable the continuum of experience along which all visions of the world are located - both in healthy and psychotic individuals. The power for action might provide the possibility to give form to the bodily presence characterizing in the first place our being selves.
Epigenetics as the Underlying Mechanism for Monozygotic Twin Discordance
Authors: Hogenson Tara L.
Published: July 2013

Monozygotic twins share an identical DNA sequence but typically display some level of phenotypic discordance. The cause of this discordance is often unknown. Two known contributing factors to phenotype are genetics and environment. While the mechanism for the genetic effect is defined through DNA sequence, the mechanism for expression of the environmental effect is less defined. With the emergence of the field of epigenetics, researchers have begun to consider it an important contributing factor to phenotype. Exposure to various environmental factors has been shown to have an effect on an individual's epigenetic marks and may be the primary mechanism for how the environment induces a change in phenotype. Current research indicates that epigenetic differences between monozygotic twins may be an important contributing factor to phenotypic discordance. Monozygotic twins are an ideal resource for the study of epigenetics since many confounding factors found in the general population, such as variation in DNA sequence, can be eliminated. Uncovering these epigenetic factors will increase our understanding of the molecular mechanisms that may contribute to phenotypic discordance in monozygotic twins and may lead to new theoretical and experimental opportunities in health and disease.
Intussusception Presentingn with Malignant Hypertension and Lethargy
Authors: de Vries Andra , Ashtiani Nilou , Ahmadi Nazanin , Bakx Roel , Walrave-bij de Vaate Annelies , Bökenkamp Arend
Published: July 2013

The most common cause of malignant hypertension in children is renal or renovascular pathology. The combination with lethargy suggests a diagnosis of hypertensive crisis with hypertensive encephalopathy. Here, we present a case of severe hypertension with lethargy as the sole presenting symptoms of ileocecal intussusception. Both normalized following surgical repositioning. We conclude that malignant hypertension and lethargy can be presenting symptoms of intussusception.
National Center for Complementary and Alternative Medicine (NCCAM) Introduction to Acupuncture with Disclaimer
Authors: Kendall Donald E.
Published: July 2013

The United States National Center for Complementary and Alternative Medicine (NCCAM) has yet to confirm the validity of acupuncture. Organizations supporting nonsensical acupuncture ideas posted an article on the NCCAM website in December 2007 and updated on March 24, 2011. A public disclaimer notes that this information is not a substitute for medical advice or therapy and is not endorsed by the NCCAM. The article promotes physiologically incorrect acupuncture concepts created by Georges Soulié de Morant some 80 years ago involving the impossible idea of blood and energy circulating by invisible meridians. Chinese pīnyīn (拼 音) pronunciation guide terms have been adopted as a pretense that Soulié de Morant's bogus ideas were consistent with the original Chinese. These unfortunate misconceptions serve as a basis of almost all Western acupuncture training programs. The cited articles provide a clear challenge and opportunity to start providing correct science-based translations of those Chinese medicine terms that are most often misunderstood. The correct Chinese translation of key concepts noted in the ‘Comments on Translations' section of this article indicates that the ancient Chinese had a keen understanding of the physiological basis of the original Chinese texts. Professional needle therapy/acupuncture training standards need to be upgraded to physiologically-based programs to best serve the public's interest.
MicroRNAs in Stem Cell Function and Regenerative Therapy of the Heart
Authors: Seeger Florian H. , Zeiher Andreas M. , Dimmeler Stefanie
Published: July 2013

MicroRNAs are small noncoding RNAs that posttranscriptionally control gene expression by targeting mRNAs. Distinct microRNAs regulate stem and progenitor cell functions, thereby modulating cell survival and homing or controlling differentiation and maturation. Experimental studies additionally show that microRNAs regulate endogenous repair and might potentially be useful to enhance the regeneration of the heart. This review summarizes the current studies that address the use of microRNAs to either improve cellular therapies or that might be targeted for enhancing endogenous tissue repair and regeneration after myocardial infarction.
Superactivated Platelets
Authors: Mazepa Marshall , Hoffman Maureane , Monroe Dougald
Published: July 2013

Platelets contribute to hemostasis by forming the platelet plug and then contributing to coagulation by providing a catalytic surface where thrombin generation occurs efficiently. This catalytic activity, known as the platelet procoagulant response, is being recognized as a nuanced response. This review examines platelets’ response to strong stimuli, which results in the formation of a platelet subpopulation (superactivated platelets) with several unique properties, including enhanced procoagulant activity. These platelets contribute uniquely to thrombus architecture and seem to have thrombus regulatory activity. Superactivated platelets’ role in diseases of thrombosis and hemostasis, as either potentiating or mitigating factors, is not currently known, but may be an important pharmacological target.
Interpreting Secondary Cardiac Disease Variants in an Exome Cohort
Authors: Ng David , Johnston Jennifer J. , Teer Jamie K. , Singh Larry N. , Peller Lindsey C. , Wynter Jamila S. , Lewis Katie L. , Cooper David N. , Stenson Peter D. , Mullikin James C. , Biesecker Leslie G.
Published: July 2013

Background—

Massively parallel sequencing to identify rare variants is widely practiced in medical research and in the clinic. Genome and exome sequencing can identify the genetic cause of a disease (primary results), but it can also identify pathogenic variants underlying diseases that are not being sought (secondary or incidental results). A major controversy has developed surrounding the return of secondary results to research participants. We have piloted a method to analyze exomes to identify participants at risk for cardiac arrhythmias, cardiomyopathies, or sudden death.

Methods and Results—

Exome sequencing was performed on 870 participants not selected for arrhythmia, cardiomyopathy, or a family history of sudden death. Exome data from 22 cardiac arrhythmia- and 41 cardiomyopathy-associated genes were analyzed using an algorithm that filtered results on genotype quality, frequency, and database information. We identified 1367 variants in the cardiomyopathy genes and 360 variants in the arrhythmia genes. Six participants had pathogenic variants associated with dilated cardiomyopathy (n=1), hypertrophic cardiomyopathy (n=2), left ventricular noncompaction (n=1), or long-QT syndrome (n=2). Two of these participants had evidence of cardiomyopathy and 1 had left ventricular noncompaction on echocardiogram. Three participants with likely pathogenic variants had prolonged QTc. Family history included unexplained sudden death among relatives.

Conclusions—

Approximately 0.5% of participants in this study had pathogenic variants in known cardiomyopathy or arrhythmia genes. This high frequency may be due to self-selection, false positives, or underestimation of the prevalence of these conditions. We conclude that clinically important cardiomyopathy and dysrhythmia secondary variants can be identified in unselected exomes.
Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation
Authors: Steinberg Benjamin A. , Kim Sunghee , Piccini Jonathan P. , Fonarow Gregg C. , Lopes Renato D. , Thomas Laine , Ezekowitz Michael D. , Ansell Jack , Kowey Peter , Singer Daniel E. , Gersh Bernard , Mahaffey Kenneth W. , Hylek Elaine , Go Alan S. , Chang Paul , Peterson Eric D.
Published: July 2013

Background—

The role of concomitant aspirin (ASA) therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant ASA use and its association with clinical outcomes among AF patients treated with OAC.

Methods and Results—

The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry enrolled 10 126 AF patients from 176 US practices from June 2010 through August 2011. The study population was limited to those on OAC (n=7347). Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant ASA therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% of AF patients (n=2543) on OAC also received ASA (OAC+ASA). Patients receiving OAC+ASA were more likely to be male (66% versus 53%;
P
<0.0001) and had more comorbid illness than those on OAC alone. More than one third of patients (39%) receiving OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding risk scores (≥5). Major bleeding (adjusted hazard ratio, 1.53; 95% confidence interval, 1.20–1.96) and bleeding hospitalizations (adjusted hazard ratio, 1.52; 95% confidence interval, 1.17–1.97) were significantly higher in those on OAC+ASA compared with those on OAC alone. Rates of ischemic events were low.

Conclusions—

Patients with AF receiving OAC are often treated with concomitant ASA, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant ASA outweigh the risks in AF patients already on OAC.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01165710.
Japanese Foreign Direct investment in Indian Automobile Sector Evolution and Practices
Authors: Kumar Kanungo Anil , Mahajan Kreeti
Published: July 2013

The paper aimed to examine whether the Japanese automakers find India an ‘Investment Friendly Nation’ based upon their experience in India so far. It analyses the ‘Japanese Management Style’ and observed the advantages and disadvantages it offers through a comparative analysis with the management style prevalent in the Indian auto companies especially in two major auto companies in India such as Maruti Suzuki and Honda. It sought to identify the major challenges faced by the Japanese car makers while investing in India and the steps taken in form of policies and practices to tackle such challenges. The findings included that Japanese companies would emphasise on long term vision and planning. Quality and customer satisfaction are key to their growth and market penetration. Japanese auto majors values ‘trust’ especially in joint ventures like Maruti Suzuki. Skilling workers especially at lower end is important for success in auto sectors.
Why Are Paintings Painted as They Are? The Place of Children’s Drawings in Vision and Art
Authors: Pinna Baingio
Published: July 2013

This work explores phenomenologically a new research perspective, whose purpose is to answer the question ‘why are paintings painted as they are?’. This perspective is based on the pictorial reproduction task aimed to reveal how subjects of different ages copy/paint what they perceived and how they organize the visual raw material. The results demonstrated the emergence of visual singularities organized in at least four stages going from 4 to 18 years of age reflecting different artistic styles and accomplishments appeared during the history of art. These outcomes entail that the answer to the previous basic question is: ‘we paint what and the way we paint because we perceive what and the way we perceive’ (painting–perception coupling). On the basis of these results, it is suggested that children’s drawings can significantly contribute to the comprehension and explanation of the painting–perception coupling.
A new species of Metrodorea (Rutaceae) from Brazil: morphology, molecular phylogenetics, and distribution
Authors: DIAS PEDRO , UDULUTSCH RENATA GIASSI , PIRANI JOSÉ RUBENS
Published: July 2013

A new species of Metrodorea (Rutaceae), M. concinna, is described and illustrated, and morphological, molecular phylogenetic, and distributional support for the new taxon and its relationships with morphologically similar species, as well as with sympatric ones, are explored. The new species is endemic to semideciduous forests of southeastern Bahia, eastern Brazil. It is distinct from other species of the genus mainly by the combination of shrubby to treelet habit, (sub)sessile leaves, sessile leaflets without conspicuous, dark glands on the abaxial surface, and by each carpel bearing one dorsal apophysis. In addition to the diagnostic morphological features, molecular data provide further support to the new taxon.
Euphorbia otjipembana subsp. okakoraensis (Euphorbiaceae), a new subspecies from the Kaokoveld, Namibia, with an amplified description of Euphorbia otjipembana
Authors: SWANEPOEL WESSEL
Published: July 2013

Euphorbia otjipembana was hitherto only known from the type locality within the Kaokoveld Centre of Endemism, northwestern Namibia. Subsequently several additional populations were discovered, allowing for an amplified description of the species and the recognition of two subspecies. Euphorbia otjipembana subsp. okakoraensis, here described as a new subspecies, is only known from a small area within the Kaokoveld Centre. Diagnostic characters for subsp. okakoraensis include a shrubby habit and medium (up to 1 m) height, 5–7-angled, scarcely constricted branches with two pairs of spines per node and single cymes comprising of three horizontally arranged cyathia. A key as well as a comparative table with diagnostic morphological characters to distinguish between the two subspecies of E. otjipembana is provided.
New records of deep-water Scleractinia off Argentina and the Falkland Islands
Authors: CAIRNS STEPHEN D. , POLONIO VIRGINIA
Published: July 2013

The twenty species of Scleractinia (all azooxanthellate) known to occur off Argentina and the Falkland Islands (the Atlantic component of the cold temperate Magellan Province) are discussed, 15 of which are documented by new records. Five new species are described: Caryophyllia kellerae, C. coronula, Solenosmilia australis, Flabellum cinctutum, and Javania cristata. Five geographic and nine bathymetric range extensions are also documented. A brief history of species discovery in this region is given, and a key to the species is provided.
Description of Notoglanidium pembetadi new species (Siluriformes: Claroteidae) from the Kouilou-Niari River, Republic of the Congo
Authors: VREVEN EMMANUEL , ZAMBA ARMEL IBALA , MAMONEKENE VICTOR , GEERINCKX TOM
Published: July 2013

A new claroteid catfish, Notoglanidium pembetadi, is described from the Kouilou-Niari River basin (Republic of the Congo). This species can be distinguished from all other currently known Notoglanidium species as well as from the very similar Anaspidoglanis boutchangai, to which two specimens have erroneously been attributed in the past, by the following combination of characters: II, 10–13 dorsal-fin rays; long dorsal-fin base (21.1–24.4% SL); short predorsal distance (30.1–33.5% SL); and short prepelvic distance (40.1–45.4% SL).
Finding the Balance
Authors: Whalen Kevin
Published: July 2013

Since mid-1990s, scholars of Indian education have placed increasing emphasis on indigenous approaches to federal Indian boarding schools during the early 20th century. Where earlier studies emphasized the design and operation of boarding schools, more recent literature often examines how Native students, families, and communities sometimes used the schools to access employment, offset financial hardship, and gain new skills and perspectives. To some, scholarly emphasis on “the brighter side of boarding schools” covers over the hardship and loss brought about by institutions created to eradicate Native American cultures and identities. In this article, I address a central question: How can scholars of Indian education illuminate Native approaches to boarding schools without underplaying the tremendous cultural loss they inflicted on indigenous communities? Drawing on the expansive secondary literature on federal Indian education and primary source documents from Sherman Institute, a federal Indian boarding school in Riverside, California, I argue that studies of Indian education can benefit from deeper consideration of the concept of “cultural genocide” and careful attention to Native voices of the past and present.
If the Truth Be Told
Authors: Norton Jack
Published: July 2013

It has been argued that the United States did not receive California from Mexico by “right of conquest” or by the Treaty of Guadalupe Hidalgo because the majority of California was not under the control of the Mexican government. In eastern portions of Southern and Central California, few or no Spanish occupants were present. Northward from Santa Rosa to what would become the Oregon border, no Mexican governmental institutions were to be seen. This area was the aboriginal homelands of the Pomo, Wiyot, Yurok, Hupa, Karuk, Modoc peoples, just to name a few. They had lived there for thousands of years, and their aboriginal rights and supreme entitlement to their land and natural resources were undeniable. Therefore, the settlement of California must be reviewed and reevaluated.
Structural analysis of composites with porosity defects based on X-ray computed tomography
Authors: Nikishkov Yuri , Seon Guillaume , Makeev Andrew
Published: July 2013

Advanced structural analysis methods that account for manufacturing defects in composite parts are needed to enable accurate assessment of their capability and useful life and to enhance current design and maintenance practices. In particular, porosity/voids are typical defects in carbon/epoxy and glass/epoxy composite aircraft flight-critical components. High-fidelity nondestructive evaluation by X-ray computed tomography allows accurate defect measurement and automatic conversion to structural models to assess the effects of defects on structural properties. This study presents a comprehensive structural analysis methodology, which includes nondestructive detection and finite element modeling of the defects in composites. Effects of porosity/voids on interlaminar tensile and shear strength of unidirectional carbon/epoxy composite specimens are investigated. Failure predictions and subsequent test correlations are presented.
Skeletal muscle metastases from lung cancer
Authors: Kwas Hamida H , Zendah Ines , Ghedira Habib
Published: July 2013

Lung cancers are diagnosed at a metastatic stage in 40% to 50% of cases. Skeletal muscle metastases are rare and usually discovered at autopsy. We report 3 cases of skeletal muscle metastasis. Muscular metastasis revealed the cancer in one patient. The metastases were asymptomatic in all patients. The diagnosis was confirmed histologically in one case and by radiography in the other 2. The evolution was characterized by tumor progression and death after 1–7 months.
Recombinant activated factor VII in cardiac surgery: single-center experience
Authors: Singh Sarvesh Pal , Chauhan Sandeep , Choudhury Minati , Malik Vishwas , Choudhary Shiv Kumar
Published: July 2013

Background

the widespread off-label use of recombinant activated factor VII for the control of refractory postoperative hemorrhage continues despite a warning from the Food and Drug Administration. Although effective in reducing the need for transfusion of blood and blood products, safety concerns still prevail.

Objective

to compare the dosing and efficacy of recombinant activated factor VII between pediatric and adult patients, and in the operating room and intensive care unit.

Methods

the records of 69 patients (33 children and 36 adults) who underwent cardiovascular surgery and received recombinant activated factor VII were reviewed retrospectively. The dose of recombinant activated factor VII, mediastinal drainage, use of blood and blood products, incidence of thrombosis, and 28-day mortality were studied.

Results

the efficacy of recombinant activated factor VII was comparable in adults and children, despite the lower dose in adults. Prophylactic use of recombinant activated factor VII decreased the incidence of mediastinal exploration and the duration of intensive care unit stay. A 4.3% incidence of thrombotic complications was observed in this study.

Conclusion

the efficacious dose of recombinant activated factor VII is much less in adults compared to children. Prophylactic use of recombinant activated factor VII decreases the dose required, the incidence of mediastinal exploration, and intensive care unit stay, with no survival benefit.
Second relapse of solitary fibrous tumor within 20 years of initial resection
Authors: Okabe Ryo , Omasa Mitsugu , Kurosawa Manabu , Tokuno Junko , Cho Hiroyuki , Huang Cheng-long
Published: July 2013

A 64-year-old woman presented with a sessile solitary fibrous tumor in the right thoracic cavity. She had undergone 2 solitary fibrous tumor resections 7 and 20 years previously. The latest histological findings were identical to the previous, and pathologically benign. However, we clinically classified the tumors as malignant because of repeated relapse. The tumor and extrapulmonary structures should be resected at the time of recurrence.
The Polish Underground Resistance During the Second World War: A Study in Political Disunity During Occupation
Authors: Pra ż mowska Anita
Published: July 2013

The armed resistance movement which emerged in Poland during the Second World War is usually portrayed as united and representing all sections of society. In reality, this was very far from the case and the underground resistance was divided on several lines, of which that separating the Home Army (AK) from the peasant armed units was most pronounced. Conflicts between the two related to the army’s role in the destruction of democracy before the war. As the end of the war appeared in sight, so these divisions multiplied as the peasant movement became anxious about the AK reconstructing the pre-war state of affairs.
Validation of quality indicators for the organization of palliative care: A modified RAND Delphi study in seven European countries (the Europall project)
Authors: Woitha Kathrin , Van Beek Karen , Ahmed Nisar , Jaspers Birgit , Mollard Jean M , Ahmedzai Sam H , Hasselaar Jeroen , Menten Johan , Vissers Kris , Engels Yvonne
Published: July 2013

Background:

Validated quality indicators can help health-care professionals to evaluate their medical practices in a comparative manner to deliver optimal clinical care. No international set of quality indicators to measure the organizational aspects of palliative care settings exists.

Aim:

To develop and validate a set of structure and process indicators for palliative care settings in Europe.

Design:

A two-round modified RAND Delphi process was conducted to rate clarity and usefulness of a previously developed set of 110 quality indicators.

Setting/participants:

In total, 20 multi-professional palliative care teams of centers of excellence from seven European countries.

Results:

In total, 56 quality indicators were rated as useful. These valid quality indicators concerned the following domains: the definition of a palliative care service (2 quality indicators), accessibility to palliative care (16 quality indicators), specific infrastructure to deliver palliative care (8 quality indicators), symptom assessment tools (1 quality indicator), specific personnel in palliative care services (9 quality indicators), documentation methodology of clinical data (14 quality indicators), evaluation of quality and safety procedures (1 quality indicator), reporting of clinical activities (1 quality indicator), and education in palliative care (4 quality indicator).

Conclusion:

The modified RAND Delphi process resulted in 56 international face-validated quality indicators to measure and compare organizational aspects of palliative care. These quality indicators, aimed to assess and improve the organization of palliative care, will be pilot tested in palliative care settings all over Europe and be used in the EU FP7 funded IMPACT project.