bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspirin Resistance in Patients with Hemodynamic Cerebral Ischemia Undergoing Extracranial-Intracranial Bypass Surgery
Authors: Jussen Daniel , Horn Peter , Vajkoczy Peter
Published: April 2013

Background: Aspirin (acetylsalicylic acid, ASA) is the treatment of choice for prevention of vascular events in symptomatic steno-occlusive cerebrovascular disease (CVD). Cerebral revascularization using standard extracranial-intracranial (EC-IC) bypass surgery may be used to revert hemodynamic compromise. Aspirin is prescribed as standard medication in order to avoid bypass failure. Accumulating evidence of an increased risk of major adverse clinical events led to this study, in which we aimed to assess the prevalence of aspirin resistance and prothrombotic disorders among patients scheduled for EC-IC bypass surgery, and the effectiveness of aspirin dose escalation. Methods: We prospectively screened patients with circumscribed high-grade stenosis or occlusion of brain-supplying vessels fulfilling the hemodynamic criteria for EC-IC bypass surgery for aspirin resistance using a platelet function analyzer (PFA-100®) test. We also determined their smoking habits and screened for prothrombotic disorders and comorbidities. The patients were divided into 2 major groups: group A had atherosclerotic steno-occlusive CVD and group B consisted of patients with nonatherosclerotic steno-occlusive CVD (moyamoya disease) and a subgroup of pediatric moyamoya patients (pediatric subgroup). Bypass patency was documented via digital subtraction angiography. Standard initial ASA dose applied was 100 mg/day. In cases of aspirin resistance, doses were increased and the PFA-100 test was repeated. Results: A total of 56 patients were included over a time period of 6 months. In group A (n = 25), we found a ratio of 40% of patients with primary resistance to aspirin 100 mg/day. In contrast, in group B (n = 25), only 20% of the patients were resistant to aspirin 100 mg/day; in the pediatric population (n = 6), there was no primary aspirin resistance. After a dose escalation to 300 mg/day, the ratio of aspirin resistance was reduced to 20% in group A and to 0% in group B. Altogether 5 patients with atherosclerotic steno-occlusive CVD remained aspirin-resistant despite the dose escalation; 2 of them suffered an early bypass failure. Smoking habits and diabetes mellitus were positively correlated with aspirin resistance. Moreover, 25% of all patients had laboratory signs of a prothrombotic disorder, but this had no influence on aspirin response or bypass patency. Conclusions: Aspirin resistance is common in the population of patients with hemodynamic cerebral ischemia scheduled for cerebral revascularization. It may have an adverse impact on the outcome of surgery. Screening and treatment via dose escalation of aspirin is a straightforward and sensible routine for patients undergoing EC-IC bypass surgery.
Promotion of Physical Activity for Children and Adults With Congenital Heart Disease
Authors: Longmuir Patricia E. , Brothers Julie A. , de Ferranti Sarah D. , Hayman Laura L. , Van Hare George F. , Matherne G. Paul , Davis Christopher K. , Joy Elizabeth A. , McCrindle Brian W.
Published: April 2013

The American Heart Association recognizes the importance of physically active lifestyles to the health and well-being of children and adults with congenital heart defects. Counseling of patients with congenital heart defects should emphasize the importance of daily physical activity and decreasing sedentary behavior as appropriate for the patient’s clinical status. The suggested practices are based on relevant research regarding the benefits of physical activity for healthy children and adults, because research on physical activity among patients with congenital heart defects is lacking. There is no evidence regarding whether or not there is a need to restrict recreational physical activity among patients with congenital heart defects, apart from those with rhythm disorders. It is important to recognize that most patients with congenital heart defects are relatively sedentary and that the physical and psychosocial health benefits of physical activity are important for this population, which is at risk for exercise intolerance, obesity, and psychosocial morbidities. Therefore, counseling to encourage daily participation in appropriate physical activity should be a core component of every patient encounter.
Lactobacillus GG and Tributyrin Supplementation Reduce Antibiotic‐Induced Intestinal Injury
Authors: Cresci Gail , Nagy Laura E. , Ganapathy Vadivel
Published: April 2013

Background: Antibiotic therapy negatively alters the gut microbiota. Lactobacillus GG (LGG) decreases antibiotic‐associated diarrhea (AAD) symptoms, but the mechanisms are unknown. Butyrate has beneficial effects on gut health. Altered intestinal gene expression occurs in the absence of gut microbiota. We hypothesized that antibiotic‐induced changes in gut microbiota reduce butyrate production, varying genes involved with gut barrier integrity and water and electrolyte absorption, lending to AAD, and that simultaneous supplementation with LGG and/or tributyrin would prevent these changes. Methods: C57BL/6 mice aged 6–8 weeks received a chow diet while divided into 8 treatment groups (± saline, ± LGG, ± tributyrin, or both). Mice received treatments orally for 7 days with ± broad‐spectrum antibiotics. Water intake was recorded daily and body weight was measured. Intestine tissue samples were obtained and analyzed for expression of genes and proteins involved with water and electrolyte absorption, butyrate transport, and gut integrity via polymerase chain reaction and immunohistochemistry. Results: Antibiotics decreased messenger RNA (mRNA) expression (butyrate transporter and receptor, Na+/H+ exchanger, Cl–/HCO3–, and a water channel) and protein expression (butyrate transporter, Na+/H+ exchanger, and tight junction proteins) in the intestinal tract. LGG and/or tributyrin supplementation maintained intestinal mRNA expression to that of the control animals, and tributyrin maintained intestinal protein intensity expression to that of control animals. Conclusion: Broad‐spectrum antibiotics decrease expression of anion exchangers, butyrate transporter and receptor, and tight junction proteins in mouse intestine. Simultaneous oral supplementation with LGG and/or tributyrin minimizes these losses. Optimizing intestinal health with LGG and/or tributyrin may offer a preventative therapy for AAD.
Identification of Lens culinaris defense genes responsive to the anthracnose pathogen Colletotrichum truncatum
Authors: Bhadauria Vijai , Bett Kirstin E , Zhou Tengsheng , Vandenberg Albert , Wei Yangdou , Banniza Sabine
Published: April 2013

Background

Anthracnose of lentil, caused by the hemibiotrophic fungal pathogenColletotrichum truncatumis a serious threat to lentil production in western Canada.Colletotrichum truncatumemploys a bi-phasic infection strategy characterized by initial symptomless biotrophic and subsequent destructive necrotrophic colonization of its host. The transition from biotrophy to necrotrophy (known as the biotrophy-necrotrophy switch [BNS]) is critical in anthracnose development. Understanding plant responses during the BNS is the key to designing a strategy for incorporating resistance against hemibiotrophic pathogens either via introgression of resistance genes or quantitative trait loci contributing to host defense into elite cultivars, or via incorporation of resistance by biotechnological means.

Results

Thein plantaBNS ofC. truncatumwas determined by histochemical analysis of infected lentil leaf tissues in time-course experiments. A total of 2852 lentil expressed sequence tags (ESTs) derived fromC. truncatum-infected leaf tissues were analyzed to catalogue defense related genes. These ESTs could be assembled into 1682 unigenes. Of these, 101 unigenes encoded membrane and transport associated proteins, 159 encoded proteins implicated in signal transduction and 387 were predicted to be stress and defense related proteins (GenBank accessions: JG293480 to JG293479). The most abundant class of defense related proteins contained pathogenesis related proteins (encoded by 125 ESTs) followed by heat shock proteins, glutathione S-transferase, protein kinases, protein phosphatase, zinc finger proteins, peroxidase, GTP binding proteins, resistance proteins and syringolide-induced proteins. Quantitative RT-PCR was conducted to compare the expression of two resistance genes of the NBS-LRR class in susceptible and partially resistant genotypes. One (contig186) was induced 6 days post-inoculation (dpi) in a susceptible host genotype (Eston) whereas the mRNA level of another (LT21-1990) peaked 4 dpi in a partially resistant host genotype (Robin), suggesting roles in conditioning the susceptibility and conferring tolerance to the pathogen, respectively.

Conclusions

Data obtained in this study suggest that lentil cells recognizeC. truncatumat the BNS and in response, mount an inducible defense as evident by a high number of transcripts (23% of the total pathogen-responsive lentil transcriptome) encoding defense related proteins. Temporal expression polymorphism of defense related genes could be used to distinguish the response of a lentil genotype as susceptible or resistant.
ContigScape: a Cytoscape plugin facilitating microbial genome gap closing
Authors: Tang Biao , Wang Qi , Yang Minjun , Xie Feng , Zhu Yongqiang , Zhuo Ying , Wang Shengyue , Gao Hong , Ding Xiaoming , Zhang Lixin , Zhao Guoping , Zheng Huajun
Published: April 2013

Background

With the emergence of next-generation sequencing, the availability of prokaryotic genome sequences is expanding rapidly. A total of 5,276 genomes have been released since 2008, yet only 1,692 genomes were complete. The final phase of microbial genome sequencing, particularly gap closing, is frequently the rate-limiting step either because of complex genomic structures that cause sequence bias even with high genomic coverage, or the presence of repeat sequences that may cause gaps in assembly.

Results

We have developed a Cytoscape plugin to facilitate gap closing for high-throughput sequencing data from microbial genomes. This plugin is capable of interactively displaying the relationships among genomic contigs derived from various sequencing formats. The sequence contigs of plasmids and special repeats (IS elements, ribosomal RNAs, terminal repeats, etc.) can be displayed as well.

Conclusions

Displaying relationships between contigs using graphs in Cytoscape rather than tables provides a more straightforward visual representation. This will facilitate a faster and more precise determination of the linkages among contigs and greatly improve the efficiency of gap closing.
Effects of insulin and IGF-I on growth hormone- induced STAT5 activation in 3T3-F442A adipocytes
Authors: Zhang Yuchao , Liu Yuantao , Li Xia , Gao Weina , Zhang Wenjie , Guan Qingbo , Jiang Jing , Frank Stuart J , Wang Xiangdong
Published: April 2013

Background

Growth hormone (GH) and insulin signaling pathways are known important regulators of adipose homeostasis. The cross-talk between GH and insulin signaling pathways in mature adipocytes is poorly understood.

Methods

In the present study, the impact of insulin on GH-mediated signaling in differentiated 3T3-F442A adipocytes and primary mice adipocytes was examined.

Results

Insulin alone did not induce STAT5 tyrosine phosphorylation, but enhanced GH-induced STAT5 activation. This effect was more pronounced when insulin was added 20 min prior to GH treatment. The above results were further confirmed by in vivo study, showing that insulin pretreatment potentiated GH- induced STAT5 tyrosine phosphorylation in visceral adipose tissues of C57/BL6 mice. In addition, our in vitro results showed that IGF-I had similar potentiating effect as insulin on GH-induced STAT5 activation. In vitro, insulin and IGF-I had an additive effect on GH- induced MAPK activation.

Conclusion

These results indicate that both insulin and IGF-I specifically potentiated GH mediated STAT5 activation in mature adipose cells. These findings suggest that insulin and GH, usually with antagonistic functions, might act synergistically to regulate some specific functions in mature adipocytes.
Ancient origin of somatic and visceral neurons
Authors: Nomaksteinsky Marc , Kassabov Stefan , Chettouh Zoubida , Stoeklé Henri-Corto , Bonnaud Laure , Fortin Gilles , Kandel Eric R , Brunet Jean-François
Published: April 2013

Background

A key to understanding the evolution of the nervous system on a large phylogenetic scale is the identification of homologous neuronal types. Here, we focus this search on the sensory and motor neurons of bilaterians, exploiting their well-defined molecular signatures in vertebrates. Sensorimotor circuits in vertebrates are of two types: somatic (that sense the environment and respond by shaping bodily motions) and visceral (that sense the interior milieu and respond by regulating vital functions). These circuits differ by a small set of largely dedicated transcriptional determinants: Brn3 is expressed in many somatic sensory neurons, first and second order (among which mechanoreceptors are uniquely marked by the Brn3+/Islet1+/Drgx+ signature), somatic motoneurons uniquely co-express Lhx3/4 and Mnx1, while the vast majority of neurons, sensory and motor, involved in respiration, blood circulation or digestion are molecularly defined by their expression and dependence on the pan-visceral determinant Phox2b.

Results

We explore the status of the sensorimotor transcriptional code of vertebrates in mollusks, a lophotrochozoa clade that provides a rich repertoire of physiologically identified neurons. In the gastropods Lymnaea stagnalis and Aplysia californica, we show that homologues of Brn3, Drgx, Islet1, Mnx1, Lhx3/4 and Phox2b differentially mark neurons with mechanoreceptive, locomotory and cardiorespiratory functions. Moreover, in the cephalopod Sepia officinalis, we show that Phox2 marks the stellate ganglion (in line with the respiratory — that is, visceral— ancestral role of the mantle, its target organ), while the anterior pedal ganglion, which controls the prehensile and locomotory arms, expresses Mnx.

Conclusions

Despite considerable divergence in overall neural architecture, a molecular underpinning for the functional allocation of neurons to interactions with the environment or to homeostasis was inherited from the urbilaterian ancestor by contemporary protostomes and deuterostomes.
Comparative expression of Toll-like receptors and inflammatory cytokines in pigs infected with different virulent porcine reproductive and respiratory syndrome virus isolates
Authors: Zhang Lili , Liu Jie , Bai Juan , Wang Xiaoye , Li Yufeng , Jiang Ping
Published: April 2013

Background

Porcine reproductive and respiratory syndrome virus (PRRSV) is largely responsible for heavy economic losses in the swine industry worldwide because of its high mutation rate and subsequent emergence of virulent strains. However, the immunological and pathological responses of pigs to PRRSV strains with different virulence have not been completely elucidated.

Methods

Twenty-four piglets were divided into 4 groups (n = 6 each) and inoculated with highly pathogenic PRRSV isolate BB0907 (HP), low pathogenic PRRSV NT0801 (LP), LP derivative strain NT0801-F70 (LP-der), and DMEM medium (control), respectively. The changes in TLR2, 3, 7, and 8 gene expression and TNF-α, IL-1β, IL-6, IFN-γ, and IL-10 secretion were evaluated using real-time PCR and ELISA at 6, 9, and 15 days post inoculation (d.p.i.). The cytokine levels were evaluated in the supernatants of porcine alveolar macrophages (PAMs) and peripheral blood mononuclear cells (PBMCs) following stimulation with LTA, poly(I:C), CL097, and PRRSV individually.

Results

HP caused more severe clinical signs and pathological lesions in swine than LP and LP-der had almost no virulence compared with LP. The serum levels of IL-1β, IL-6, TNF-α, and IFN-γ were increased in HP-infected piglets, which were greater than in those infected with LP or LP-der. The mRNA levels of TLR3, 7, and 8 were significantly up-regulated in PAMs in HP-infected pigs compared to those in groups LP and LP-der. Furthermore, TNF-α and IL-1β secretion in PAMs from group LP was statistically greater than those from the control group after stimulation with either poly(I:C) or CL097. Meanwhile, TNF-α, IL-1β, and IL-6 levels in CL097-stimulated PBMCs from HP-infected pigs were markedly higher than those from the LP- and LP-der-infected groups.

Conclusions

We found that HP was a stronger inducer of TLR 3, 7, and 8 expression and IL-1β, IL-6, TNF-α, and IFN-γ production compared to LP and LP-der. HP enhanced production of TNF-α, IL-1β, and IL-6 in PBMCs following CL097-stimulation more than LP and LP-der, whereas LP enhanced the secretion of TNF-α and IL-1β in poly(I:C)- and CL097-stimulated PAMs. Our data regarding cellular reactivity to different isolates should be useful in the development of more efficacious vaccines.
Upregulation of microRNA-224 is associated with aggressive progression and poor prognosis in human cervical cancer
Authors: Shen Shu-na , Wang Ling-feng , Jia Yong-feng , Hao Yu-qing , Zhang Lin , Wang Hui
Published: April 2013

Objective

Accumulating evidence for differential expression of microRNA-224 (miR-224) in various types of human cancer suggests that it may be play a crucial role in tumor biology. The previous microarray detection also shown that miR-224 was one of miRNAs with significant upregulation in cervical cancer tissues relative to adjacent normal tissues. However, little is known about the function of miR-224 in human cervical cancer. The aim of this study was to investigate the clinical significance of miR-224 expression in cervical cancer.

Methods

MiR-224 expression in 126 pairs of fresh human cervical cancer and adjacent normal tissues was measured by real-time quantitative RT-PCR assay.

Results

miR-224 expression was significantly upregulated in cervical cancer tissues when compared with corresponding adjacent normal tissues (P < 0.001). It was also significantly higher in the cancerous tissues of patients with advanced FIGO stage cervical cancer than those with early FIGO stage (P = 0.02). In addition, miR-224 was expressed at significantly higher levels in lymph node metastasis-positive patients than in lymph node metastasis-negative patients (P = 0.008). Moreover, we found that lesser differentiated tumors expressed higher miR-224 (P = 0.03). Finally, there were sufficient evidence to confirm its value in the status of vascular invasion (P = 0.01) and human papillomavirus (HPV) infection (P = 0.02) in cervical cancer. More importantly, Kaplan-Meier analysis showed that cervical cancer patients with high miR-224 expression tend to have shorter overall survival. In multivariate analysis stratified for known prognostic variables, miR-224 was identified as an independent prognostic marker.

Conclusion

Our data indicated that miR-224 upregulation was associated with aggressive progression and poor prognosis in cervical cancer. MiR-224 was identified for the first time as an independent marker for predicting the clinical outcome of cervical cancer patients.

Virtual slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2170449349527493
Abnormal interneuron development in disrupted-in-schizophrenia-1 L100P mutant mice
Authors: Lee Frankie HF , Zai Clement C , Cordes Sabine P , Roder John C , Wong Albert HC
Published: April 2013

Background

Interneuron deficits are one of the most consistent findings in post-mortem studies of schizophrenia patients and are likely important in the cognitive deficits associated with schizophrenia. Disrupted-in-Schizophrenia 1 (DISC1), a strong susceptibility gene for schizophrenia and other mental illnesses, is involved in neurodevelopment, including that of interneurons. However, the mechanism by which DISC1 regulates interneuron development remains unknown. In this study, we analyzed interneuron histology in the Disc1-L100P single point mutation mouse, that was previously shown to have behavioral abnormalities and cortical developmental defects related to schizophrenia.

Results

We sought to determine whether a Disc1-L100P point mutation in the mouse would alter interneuron density and location. First, we examined interneuron position in the developing mouse cortex during embryonic days 14–16 as an indicator of interneuron tangential migration, and found striking migration deficits in Disc1-L100P mutants. Further analysis of adult brains revealed that the Disc1-L100P mutants have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased GAD67/PV co-localization and mis-positioned interneurons across the neocortex when compared to wild-type littermates.

Conclusion

Our results are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models. Future research is required to determine the specific mechanisms underlying these cellular deficits. Overall, these findings provide further evidence that DISC1 participates in interneuron development and add to our understanding of how DISC1 variants can affect susceptibility to psychiatric illness.
A systematic map protocol: which components or attributes of biodiversity affect which dimensions of poverty?
Authors: Roe Dilys , Sandbrook Chris , Fancourt Max , Schulte Bjorn , Munroe Robert , Sibanda Mxolisi
Published: April 2013

Background

The assumption that biodiversity and ecosystem services can help in efforts to tackle poverty is implicit in international targets set for biodiversity conservation (by the Convention on Biological Diversity) and for poverty reduction (enshrined in the Millennium Development Goals). The 2010 United Nations General Assembly further stressed the linkage, claiming: “preserving biodiversity is inseparable from the fight against poverty.” Nevertheless the evidence-base on biodiversity – poverty links is not as robust as one might assume. Studies in the academic and “grey” literature have used diverse methods and metrics, different components of biodiversity and dimensions of poverty have been studied, and the scale of impact has rarely been assessed.

Methods/Design

This systematic map protocol sets out the proposed methodology for exploring the primary question: Which components or attributes of biodiversity affect (positively or negatively) which dimensions of poverty? The overall aim of our review is to unpack the broad claims and assumptions that are made about biodiversity-poverty links such as those above, and provide researchers, policy-makers and practitioners with a methodical overview of the type and quantity of evidence. The online databases SCOPUS and Web of Science will be searched for relevant peer-reviewed literature using search terms and Boolean search operators. Relevant grey literature will be identified through the membership and resources of the Poverty and Conservation Learning Group. The literature searches will be followed by a title and abstract level search using inclusion and exclusion criteria. Data will be extracted from the final list of papers using a questionnaire established through literature review and an expert workshop. A report and online database will be produced based on the results of the review.
Primary Granulocyte Colony-Stimulating Factor Prophylaxis During the First Two Cycles Only or Throughout All Chemotherapy Cycles in Patients With Breast Cancer at Risk for Febrile Neutropenia
Authors: Aarts Maureen J. , Peters Frank P. , Mandigers Caroline M. , Dercksen M. Wouter , Stouthard Jacqueline M. , Nortier Hans J. , van Laarhoven Hanneke W. , van Warmerdam Laurence J. , van de Wouw Agnes J. , Jacobs Esther M. , Mattijssen Vera , van der Rijt Carin C. , Smilde Tineke J. , van der Velden Annette W. , Temizkan Mehmet , Batman Erdogan , Muller Erik W. , van Gastel Saskia M. , Borm George F. , Tjan-Heijnen Vivianne C.G.
Published: April 2013

Purpose

Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy.

Patients and Methods

In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm.

Results

After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis).

Conclusion

In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.
High-Dose Cytarabine Consolidation With or Without Additional Amsacrine and Mitoxantrone in Acute Myeloid Leukemia: Results of the Prospective Randomized AML2003 Trial
Authors: Schaich Markus , Parmentier Stefani , Kramer Michael , Illmer Thomas , Stölzel Friedrich , Röllig Christoph , Thiede Christian , Hänel Mathias , Schäfer-Eckart Kerstin , Aulitzky Walter , Einsele Hermann , Ho Anthony D. , Serve Hubert , Berdel Wolfgang E. , Mayer Jiri , Schmitz Norbert , Krause Stefan W. , Neubauer Andreas , Baldus Claudia D. , Schetelig Johannes , Bornhäuser Martin , Ehninger Gerhard
Published: April 2013

Purpose

To assess the treatment outcome benefit of multiagent consolidation in young adults with acute myeloid leukemia (AML) in a prospective, randomized, multicenter trial.

Patients and Methods

Between December 2003 and November 2009, 1,179 patients (median age, 48 years; range, 16 to 60 years) with untreated AML were randomly assigned at diagnosis to receive either standard high-dose cytarabine consolidation with three cycles of 18 g/m2 (3× HD-AraC) or multiagent consolidation with two cycles of mitoxantrone (30 mg/m2) plus cytarabine (12 g/m2) and one cycle of amsacrine (500 mg/m2) plus cytarabine (10 g/m2; MAC/MAMAC/MAC). Allogeneic and autologous hematopoietic stem-cell transplantations were performed in a risk-adapted and priority-based manner.

Results

After double induction therapy using a 3 + 7 regimen including standard-dose cytarabine and daunorubicin, complete remission was achieved in 65% of patients. In the primary efficacy population of patients evaluable for consolidation outcomes, consolidation with either 3× HD-AraC or MAC/MAMC/MAC did not result in any significant difference in 3-year overall (69% v 64%; P = .18) or disease-free survival (46% v 48%; P = .99) according to the intention-to-treat analysis. Furthermore, MAC/MAMAC/MAC led to additional GI and hepatic toxicity and a higher rate of infection and bleeding, resulting in significantly shorter 3-year overall survival in the per-protocol analysis compared with 3× HD-AraC (63% v 72%; P = .04).

Conclusion

In younger adults with AML, multiagent consolidation using mitoxantrone and amsacrine in combination with high-dose cytarabine does not improve treatment outcome and confers additional toxicity.
Insights From Mixture Cure Modeling of Molecular Markers for Prognosis in Breast Cancer
Authors: Yilmaz Yildiz E. , Lawless Jerald F. , Andrulis Irene L. , Bull Shelley B.
Published: April 2013

With the ultimate aim of improving clinical management of breast cancer, investigators have sought to identify molecular genetic markers that stratify newly diagnosed patients into subtypes differing in short- or long-term prognosis. Conventional survival models can fail to describe adequately the relationship between subtype and disease recurrence, particularly when there is a substantial proportion of long-term disease-free survivors. The observed patterns of disease-free survival in an undifferentiated patient cohort may be explained by an underlying mixture of two subgroups: patients who will remain free of disease in the long term (ie, cured), and those who will experience disease recurrence within their lifetime (ie, susceptible.) In this article, we review the concepts and methods of the mixture cure models and apply them in the analysis of molecular genetic prognostic factors for disease-free survival and time to disease recurrence in a cohort of patients with axillary lymph node–negative breast cancer.
Strategies for Relapsed Peripheral T-Cell Lymphoma: The Tail That Wags the Curve
Authors: Lunning Matthew A. , Moskowitz Alison J. , Horwitz Steven
Published: April 2013

A 69-year-old woman was referred for further evaluation and management of relapsed angioimmunoblastic T-cell lymphoma. At diagnosis, she received six cycles of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and achieved a complete response (CR). Her first surveillance computed tomography scan 3 months later demonstrated enlarging cervical lymphadenopathy. A lymph node excision confirmed relapsed angioimmunoblastic T-cell lymphoma with atypical lymphocytes expressing CD3, CD4, CD10, PD-1, and EBER, with loss of CD5 ( Fig 1 ). A clonal T-cell receptor beta and gamma rearrangement by polymerase chain reaction was identical to that in her initial diagnostic biopsy. At our initial consultation, options for standard as well as investigational therapies were discussed, and HLA typing was initiated. The patient was enrolled onto an investigational phase II study; however, she developed progressive disease after two cycles. She was then treated with romidepsin 14 mg/m2 administered intravenously for 3 consecutive weeks with 1 week off. After two cycles, she achieved a partial response, and after four additional cycles, she maintained her response without further improvement. We discussed additional treatment options.
IsoCleft Finder – a web-based tool for the detection and analysis of protein binding-site geometric and chemical similarities
Authors: Kurbatova Natalja , Chartier Matthieu , Zylber María Inés , Najmanovich Rafael
Published: April 2013

IsoCleft Finder is a web-based tool for the detection of local geometric and chemical similarities between potential small-molecule binding cavities and a non-redundant dataset of ligand-bound known small-molecule binding-sites. The non-redundant dataset developed as part of this study is composed of 7339 entries representing unique Pfam/PDB-ligand (hetero group code) combinations with known levels of cognate ligand similarity. The query cavity can be uploaded by the user or detected automatically by the system using existing PDB entries as well as user-provided structures in PDB format. In all cases, the user can refine the definition of the cavity interactively via a browser-based Jmol 3D molecular visualization interface. Furthermore, users can restrict the search to a subset of the dataset using a cognate-similarity threshold. Local structural similarities are detected using the IsoCleft software and ranked according to two criteria (number of atoms in common and Tanimoto score of local structural similarity) and the associated Z-score and p-value measures of statistical significance. The results, including predicted ligands, target proteins, similarity scores, number of atoms in common, etc., are shown in a powerful interactive graphical interface. This interface permits the visualization of target ligands superimposed on the query cavity and additionally provides a table of pairwise ligand topological similarities. Similarities between top scoring ligands serve as an additional tool to judge the quality of the results obtained. We present several examples where IsoCleft Finder provides useful functional information. IsoCleft Finder results are complementary to existing approaches for the prediction of protein function from structure, rational drug design and x-ray crystallography. IsoCleft Finder can be found at: http://bcb.med.usherbrooke.ca/isocleftfinder.
Reconstruction using femoral head allograft in revision total knee replacement
Authors: Wang J-W. , Hsu C-H. , Huang C-C. , Lin P-C. , Chen W-S.
Published: April 2013

Structural allografts may be used to manage uncontained bone defects in revision total knee replacement (TKR). However, the availability of cadaver grafts is limited in some areas of Asia. The aim of this study was to evaluate the mid-term outcome of the use of femoral head allografts for the reconstruction of uncontained defects in revision TKR, focusing on complications related to the graft.

We retrospectively reviewed 28 patients (30 TKRs) with Anderson Orthopaedic Research Institute (AORI) type 3 bone defects, who underwent revision using femoral head allografts and stemmed components. The mean number of femoral heads used was 1.7 (1 to 3). The allograft–host junctions were packed with cancellous autograft.

At a mean follow-up of 76 months (38 to 136) the mean American Knee Society knee score improved from 37.2 (17 to 60) pre-operatively to 90 (83 to 100) (p < 0.001). The mean function score improved from 26.5 (0 to 50) pre-operatively to 81 (60 to 100) (p < 0.001). All the grafts healed to the host bone. The mean time to healing of the graft was 6.6 months (4 to 16). There have been no complications of collapse of the graft, nonunion, infection or implant loosening. No revision surgery was required.

The use of femoral head allografts in conjunction with a stemmed component and autogenous bone graft in revision TKR in patients with uncontained bone defects resulted in a high rate of healing of the graft with minimal complications and a satisfactory outcome. Longer follow-up is needed to observe the evolution of the graft.

Cite this article: Bone Joint J 2013;95-B:643–8.
Anatomical variations of the deltoid artery
Authors: Bunker T. D. , Cosker T. D. A. , Dunkerley S. , Kitson J. , Smith C. D.
Published: April 2013

Despite the expansion of arthroscopic surgery of the shoulder, the open deltopectoral approach to the shoulder is still frequently used, for example in fracture fixation and shoulder replacement. However, it is sometimes accompanied by unexpected bleeding. The cephalic vein is the landmark for the deltopectoral interval, yet its intimate relationship with the deltoid artery, and the anatomical variations in that structure, have not previously been documented.

In this study the vascular anatomy encountered during 100 consecutive elective deltopectoral approaches was recorded and the common variants described. Two common variants of the deltoid artery were encountered. In type I (71%) it crosses the interval and tunnels into the deltoid muscle without encountering the cephalic vein. However, in type II (21%) it crosses the interval, reaches the cephalic vein and then runs down, medial to and behind it, giving off several small arterial branches that return back across the interval to the pectoralis major. Several minor variations were also seen (8%).

These variations in the deltoid artery have not previously been described and may lead to confusion and unexpected bleeding during this standard anterior surgical approach to the shoulder.

Cite this article: Bone Joint J 2013;95-B:657–9.
Transfer RNA Post-Transcriptional Processing, Turnover, and Subcellular Dynamics in the YeastSaccharomyces cerevisiae
Authors: Hopper Anita K
Published: April 2013

Transfer RNAs (tRNAs) are essential for protein synthesis. In eukaryotes, tRNA biosynthesis employs a specialized RNA polymerase that generates initial transcripts that must be subsequently altered via a multitude of post-transcriptional steps before the tRNAs beome mature molecules that function in protein synthesis. Genetic, genomic, biochemical, and cell biological approaches possible in the powerful Saccharomyces cerevisiae system have led to exciting advances in our understandings of tRNA post-transcriptional processing as well as to novel insights into tRNA turnover and tRNA subcellular dynamics. tRNA processing steps include removal of transcribed leader and trailer sequences, addition of CCA to the 3′ mature sequence and, for tRNAHis, addition of a 5′ G. About 20% of yeast tRNAs are encoded by intron-containing genes. The three-step splicing process to remove the introns surprisingly occurs in the cytoplasm in yeast and each of the splicing enzymes appears to moonlight in functions in addition to tRNA splicing. There are 25 different nucleoside modifications that are added post-transcriptionally, creating tRNAs in which ∼15% of the residues are nucleosides other than A, G, U, or C. These modified nucleosides serve numerous important functions including tRNA discrimination, translation fidelity, and tRNA quality control. Mature tRNAs are very stable, but nevertheless yeast cells possess multiple pathways to degrade inappropriately processed or folded tRNAs. Mature tRNAs are also dynamic in cells, moving from the cytoplasm to the nucleus and back again to the cytoplasm; the mechanism and function of this retrograde process is poorly understood. Here, the state of knowledge for tRNA post-transcriptional processing, turnover, and subcellular dynamics is addressed, highlighting the questions that remain.
Can a Patient Designate His Doctor as His Proxy Decision Maker?
Authors: Black Philip G. , Derse Arthur R. , Derrington Sabrina , Lantos John D.
Published: April 2013

Most lawyers and bioethicists recommend that patients enact a durable power of attorney for health care designating somebody as their proxy decision maker should they become unable to make decisions. Most people choose family members as their agent. But what if a patient wants his or her doctor to be his or her proxy decision maker? Can the doctor be both physician and surrogate decision maker? Or should those roles necessarily be kept separate? We present a case in which those issues arose, and sought comments from Sabrina Derrington, a pediatric palliative care physician; Arthur Derse, an emergency department physician and lawyer; and Phil Black, a pulmonologist.
Linking agricultural practices, mycorrhizal fungi, and traits mediating plant–insect interactions
Authors: Barber Nicholas A. , Kiers E. Toby , Theis Nina , Hazzard Ruth V. , Adler Lynn S.
Published: April 2013

Agricultural management has profound effects on soil communities. Activities such as fertilizer inputs can modify the composition of arbuscular mycorrhizal fungi (AMF) communities, which form important symbioses with the roots of most crop plants. Intensive conventional agricultural management may select for less mutualistic AMF with reduced benefits to host plants compared to organic management, but these differences are poorly understood. AMF are generally evaluated based on their direct growth effects on plants. However, mycorrhizal colonization also may alter plant traits such as tissue nutrients, defensive chemistry, or floral traits, which mediate important plant–insect interactions like herbivory and pollination. To determine the effect of AMF from different farming practices on plant performance and traits that putatively mediate species interactions, we performed a greenhouse study by inoculating Cucumis sativus (cucumber, Cucurbitaceae) with AMF from conventional farms, organic farms, and a commercial AMF inoculum. We measured growth and a suite of plant traits hypothesized to be important predictors of herbivore resistance and pollinator attraction. Several leaf and root traits and flower production were significantly affected by AMF inoculum. Both conventional and organic AMF reduced leaf P content but increased Na content compared to control and commercial AMF. Leaf defenses were unaffected by AMF treatments, but conventional AMF increased root cucurbitacin C, the primary defensive chemical of C. sativus, compared to organic AMF. These effects may have important consequences for herbivore preference and population dynamics. AMF from both organic and conventional farms decreased flower production relative to commercial and control treatments, which may reduce pollinator attraction and plant reproduction. AMF from both farm types also reduced seed germination, but effects on plant growth were limited. Our results suggest that studies only considering AMF effects on growth may overlook changes in plant traits that have the potential to influence interactions, and hence yield, on farms. Given the effects of AMF on plant traits documented here, and the great importance of both herbivores and pollinators to wild and cultivated plants, we advocate for comprehensive assessments of mycorrhizal effects in complex community contexts, with the aim of incorporating multispecies interactions both above and below the soil surface.
The analysis of the connection between plaque morphology of the asymptomatic carotid stenosis and ischemic brain lesions
Authors: Milosevic Djordje , Pasternak Janko , Popovic Vladan , Nikolic Dragan , Milosevic Pavle , Manojlovic Vladimir
Published: April 2013

Background/Aim. A certain percentage of patients with asymptomatic carotid
stenosis have an unstable carotid plaque. For these patients it is possible
to register by modern imaging methods the existence of lesions of the brain
parenchyma - the silent brain infarction. These patients have a greater risk
of ischemic stroke. The aim of this study was to analyze the connection
between the morphology of atherosclerotic carotid plaque in patients with
asymptomatic carotid stenosis and the manifestation of silent brain
infarction, and to analyze the influence of risk factors for cardiovascular
diseases on the occurrence of silent brain infarction and the morphology of
carotid plaque. Methods. This retrospective study included patients who had
been operated for high grade (> 70%) extracranial atherosclerotic carotid
stenosis at the Clinic for Vascular and Transplantation Surgery of the
Clinical Center of Vojvodina over a period of 5 years. The patients analyzed
had no clinical manifestation of cerebrovascular insufficiency of the carotid
artery territory up to the time of operation. The classification of carotid
plaque morphology was carried out according to the Gray-Weale
classification, after which all the types were subcategorized into two
groups: stable and unstable. Brain lesions were verified using preoperative
imaging of the brain parenchyma by magnetic resonance. We analyzed
ipsilateral lesions of the size > or = 3 mm. Results. Out of a 201 patients
78% had stable plaque and 22% unstable one. Unstable plaque was prevalent in
the male patients (male/female ratio = 24.8% : 17.8%), but without a
statistically significant difference (p > 0.05). The risk factors
(hypertension, nicotinism, hyperlipoproteinemia, and diabetes mellitus)
showed no statistically significant impact on carotid plaque morphology and
the occurrence of silent brain infarction. Silent brain infarction was
detected in 30.8% of the patients. Unstable carotid plaque was found in a
larger percentage of patients with silent brain infarction (36.4% : 29.3%)
but without a significant statistical difference (p > 0.05). Conclusions.
Even though silent brain infarction is more frequent in patients with
unstable plaque of carotid bifurication, the difference is of no statistical
significance. The effects of the number and type of risk factors bear no
statistical significance on the incidence of morphological asymptomatic
carotid plaque.
La nouvelle-métropole (l’église Saint-Stephane) à Nessébar: Résultats d’une recherche
Authors: Gerov Georgi
Published: April 2013

This paper presents the most important conclusions regarding the architecture
and wall paintings of the New Metropolis (Church of St. Stephen) in Nesebar,
adopted during the recent restoration works in this church, which were
financed by the Leventis Foundation.
Development of the Human Pancreas From Foregut to Endocrine Commitment
Authors: Jennings Rachel E. , Berry Andrew A. , Kirkwood-Wilson Rebecca , Roberts Neil A. , Hearn Thomas , Salisbury Rachel J. , Blaylock Jennifer , Piper Hanley Karen , Hanley Neil A.
Published: April 2013

Knowledge of human pancreas development underpins our interpretation and exploitation of human pluripotent stem cell (PSC) differentiation toward a β-cell fate. However, almost no information exists on the early events of human pancreatic specification in the distal foregut, bud formation, and early development. Here, we have studied the expression profiles of key lineage-specific markers to understand differentiation and morphogenetic events during human pancreas development. The notochord was adjacent to the dorsal foregut endoderm during the fourth week of development before pancreatic duodenal homeobox-1 detection. In contrast to the published data from mouse embryos, during human pancreas development, we detected only a single-phase of Neurogenin 3 (NEUROG3) expression and endocrine differentiation from approximately 8 weeks, before which Nirenberg and Kim homeobox 2.2 (NKX2.2) was not observed in the pancreatic progenitor cell population. In addition to revealing a number of disparities in timing between human and mouse development, these data, directly assembled from human tissue, allow combinations of transcription factors to define sequential stages and differentiating pancreatic cell types. The data are anticipated to provide a useful reference point for stem cell researchers looking to differentiate human PSCs in vitro toward the pancreatic β-cell so as to model human development or enable drug discovery and potential cell therapy.
Cord Serum Lipidome in Prediction of Islet Autoimmunity and Type 1 Diabetes
Authors: Orešič Matej , Gopalacharyulu Peddinti , Mykkänen Juha , Lietzen Niina , Mäkinen Marjaana , Nygren Heli , Simell Satu , Simell Ville , Hyöty Heikki , Veijola Riitta , Ilonen Jorma , Sysi-Aho Marko , Knip Mikael , Hyötyläinen Tuulia , Simell Olli
Published: April 2013

Previous studies show that children who later progress to type 1 diabetes (T1D) have decreased preautoimmune concentrations of multiple phospholipids as compared with nonprogressors. It is still unclear whether these changes associate with development of β-cell autoimmunity or specifically with clinical T1D. Here, we studied umbilical cord serum lipidome in infants who later developed T1D (N = 33); infants who developed three or four (N = 31) islet autoantibodies, two (N = 31) islet autoantibodies, or one (N = 48) islet autoantibody during the follow-up; and controls (N = 143) matched for sex, HLA-DQB1 genotype, city of birth, and period of birth. The analyses of serum molecular lipids were performed using the established lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry. We found that T1D progressors are characterized by a distinct cord blood lipidomic profile that includes reduced major choline-containing phospholipids, including sphingomyelins and phosphatidylcholines. A molecular signature was developed comprising seven lipids that predicted high risk for progression to T1D with an odds ratio of 5.94 (95% CI, 1.07–17.50). Reduction in choline-containing phospholipids in cord blood therefore is specifically associated with progression to T1D but not with development of β-cell autoimmunity in general.