bluuebunny/crossref_metadata_2025 huggingface dataset:
How to Be Proactive About Interference
Authors: Wright Anthony A. , Katz Jeffrey S. , Ma Wei Ji
Published: April 2012

Processes of proactive interference were explored using the pigeon as a model system of memory. This study shows that proactive interference extends back in time at least 16 trials (and as many minutes), revealing a continuum of interference and providing a framework for studying memory. Pigeons were tested in a delayed same/different task containing trial-unique pictures. On interference trials, sample pictures from previous trials reappeared as test pictures on different trials. Proactive-interference functions showed greatest interference from the most recent trial and with the longer of two delays (10 s vs. 1 s). These interference functions are accounted for by a time-estimation model based on signal detection theory. The model predicts that accuracy at test is determined solely by the ratio of the elapsed time since the offset of the current-trial sample to the elapsed time since the offset of the interfering sample. Implications for comparing memory of different species and different types of memory (e.g., familiarity vs. recollection) are discussed.
Demographics and Burden on Caregivers of Seriously Wounded, Ill, and Injured Service Members
Authors: Christensen Eric W. , Clinton Yvette C.
Published: April 2012

The media is replete with stories about the impact on families when they drastically alter their lives to provide care to a service member who is seriously wounded, ill, or injured (WII), though few studies have systematically examined these impacts. Using a 2008 survey of seriously WII service members, the authors found that 27% of caregivers provided an average of more than 40 hr of care per week, 64% of caregivers have provided care for more than a year, and 50% expected they may need to provide care over the long term. The probit and ordered probit results show that significant others (such as a spouse, fiancée, or girlfriend) bear a greater caregiving burden in both intensity and duration compared to other caregivers. The results also show that duration of caregiving for Reserve Component service members is greater than for Active Component service members.
On fractional variational problems which admit local transformations
Authors: Malinowska Agnieszka B
Published: April 2012

We extend the second Noether theorem to fractional variational problems which are invariant under infinitesimal transformations that depend upon r arbitrary functions and their fractional derivatives in the sense of Caputo. Our main result is illustrated using the fractional Lagrangian density of the electromagnetic field.
Bilateral radial hemimelia and multiple malformations in a kitten
Authors: Pisoni Luciano , Cinti Filippo , Del Magno Sara , Joechler Monika
Published: April 2012

Hemimelia is a congenital disease of complete or partial absence of one or more bones. The most important hypothesis is that radial agenesis is a consequence of neural crest injury. Treatment selection depends on the degree of the deformity and the reduction of limb function. This report describes a case of bilateral radial hemimelia and multiple malformations in a kitten aged 2 months treated conservatively with splint bandage, until bone maturity. The re-evaluation was performed 4 years later.
Low social interactions in eating disorder patients in childhood and adulthood: A multi-centre European case control study
Authors: Krug Isabel , Penelo Eva , Fernandez-Aranda Fernando , Anderluh Marija , Bellodi Laura , Cellini Elena , di Bernardo Milena , Granero Roser , Karwautz Andreas , Nacmias Benedetta , Ricca Valdo , Sorbi Sandro , Tchanturia Kate , Wagner Gudrun , Collier David , Treasure Janet
Published: April 2012

The objective of this article was to examine lifestyle behaviours in eating disorder (ED) patients and healthy controls. A total of 801 ED patients and 727 healthy controls from five European countries completed the questions related to lifestyle behaviours of the Cross-Cultural Questionnaire (CCQ). For children, the ED sample exhibited more solitary activities (rigorously doing homework [p<0.001] and watching TV [p<0.05] and less socializing with friends [p<0.05]) than the healthy control group and this continued in adulthood. There were minimal differences across ED sub-diagnoses and various cross-cultural differences emerged. Reduced social activities may be an important risk and maintaining factor for ED symptomatology.
Bottle-Weaning Intervention Tools
Authors: Hyden Christel , Kahn Richard , Bonuck Karen
Published: April 2012

Objective. This article describes the development of educational materials for a Women, Infants, and Children (WIC)–based randomized controlled trial of an intervention encouraging timely bottle weaning. Method. Following a systematic process to develop of patient education materials, messages were first tested in 4 focus groups with 26 caregivers of WIC toddlers aged 7 to 36 months of age at the 2 study sites. Following review and revision, the materials were retested in one-on-one nutritional counseling sessions with 10 clients at the WIC sites who met the study’s eligibility criteria. Results. Materials development was an iterative process requiring several levels of input, review, and revision. Use of a systematic process guided by steps adapted from the health education literature was crucial in ensuring continuous feedback from stakeholders, experts, and priority populations and to develop an intervention instrument that met the needs and expectations of all groups. Conclusions and implications. The content, theoretical orientation, and format of the materials were influenced at every turn by feedback from frontline WIC nutritionists, WIC policy staff at the state level, and WIC clients. Development of effective, easy to use materials requires constant input from key stakeholders.
Power in Leader–Follower Work Relationships
Authors: Martinez Arthur D. , Kane Rachel E. , Ferris Gerald R. , Brooks C. Darren
Published: April 2012

There is perhaps no more important dyadic relationship than that between a leader and a follower. Nonetheless, few studies examine the implications of both leader and follower power on important work outcomes. Therefore, using resource dependence and role theories, the authors examined the process by which leader power affects important work outcomes, namely, work relationship quality and job tension, through met relationship expectations. Additionally, the authors suggest that the leader power–met expectations relationship is conditional on follower power. A state agency was sampled to obtain and analyze 100 leader–follower work relationship dyads, whereby both dyadic partners were surveyed. Results indicated that leader power affected both leader–follower relationship quality and job tension through followers’ met relationship expectations. However, contrary to our hypothesis, the leader power–met expectations relationship was not conditional on follower power. Contributions of this study, strengths and limitations, and directions for future research are discussed.
The Relation Between Servant Leadership, Organizational Performance, and the High-Performance Organization Framework
Authors: de Waal André , Sivro Mirna
Published: April 2012

Many authors on servant leadership (SL) claim that there exists a direct positive relationship between SL and organizational performance, but empirical evidence for this has thus far been lacking. There are indications, however, that introducing SL in an organization has a positive influence on mediating factors of performance, which in turn lead to better organizational performance. There is empirical evidence that applying the high-performance organization (HPO) framework does lead to increased organizational performance. As SL deals with behaviors and attitudes of managers, it is a reasonable assumption that SL has a certain influence on management quality, one of the factors of high performance included in the HPO framework. In this respect, one or more HPO factors might be mediating factors between SL and organizational performance. This article evaluates empirically the relation between SL, organizational performance, and the HPO framework. A theoretical proposition of these relations was made and, based on a sample of 116 managers and employees of Vrije Universiteit medical center, the levels of SL, HPO, and performance in Vrije Universiteit medical center were measured. This case study showed no evidence of a direct positive relation between SL and organizational performance. There was evidence of SL having an influence on the factors in the HPO framework but this influence was different on various organizational levels. It was concluded that the role of SL in the case organization was inconsistent.
Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia
Authors: Ribeiro Ana Flávia Tibúrcio , Pratcorona Marta , Erpelinck-Verschueren Claudia , Rockova Veronika , Sanders Mathijs , Abbas Saman , Figueroa Maria E. , Zeilemaker Annelieke , Melnick Ari , Löwenberg Bob , Valk Peter J. M. , Delwel Ruud
Published: April 2012

The prevalence, the prognostic effect, and interaction with other molecular markers of DNMT3A mutations was studied in 415 patients with acute myeloid leukemia (AML) younger than 60 years. We show mutations in DNMT3A in 96 of 415 patients with newly diagnosed AML (23.1%). Univariate Cox regression analysis showed that patients with DNMT3Amutant AML show significantly worse overall survival (OS; P = .022; hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.04-1.81), and relapse-free survival (RFS; P = .005; HR, 1.52; 95% CI, 1.13-2.05) than DNMT3Awild-type AMLs. In a multivariable analysis, DNMT3A mutations express independent unfavorable prognostic value for OS (P = .003; HR, 1.82; 95% CI, 1.2-2.7) and RFS (P < .001; HR, 2.2; 95% CI, 1.4-3.3). In a composite genotypic subset of cytogenetic intermediate-risk AML without FLT3-ITD and NPM1 mutations, this association is particularly evident (OS: P = .013; HR, 2.09; 95% CI, 1.16-3.77; RFS: P = .001; HR, 2.65; 95% CI, 1.48-4.89). The effect of DNMT3A mutations in human AML remains elusive, because DNMT3Amutant AMLs did not express a methylation or gene expression signature that discriminates them from patients with DNMT3Awild-type AML. We conclude that DNMT3A mutation status is an important factor to consider for risk stratification of patients with AML.
Genome-wide miRNA profiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis
Authors: Iqbal Javeed , Shen Yulei , Liu Yanyan , Fu Kai , Jaffe Elaine S. , Liu Cuiling , Liu Zhongfeng , Lachel Cynthia M. , Deffenbacher Karen , Greiner Timothy C. , Vose Julie M. , Bhagavathi Sharathkumar , Staudt Louis M. , Rimsza Lisa , Rosenwald Andreas , Ott German , Delabie Jan , Campo Elias , Braziel Rita M. , Cook James R. , Tubbs Raymond R. , Gascoyne Randy D. , Armitage James O. , Weisenburger Dennis D. , McKeithan Timothy W. , Chan Wing C.
Published: April 2012

miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1–positive MCL (n = 30) and cyclin D1–negative MCL (n = 7) and compared them with small lymphocytic leukemia/lymphoma (n = 12), aggressive B-cell lymphomas (n = 138), normal B-cell subsets, and stromal cells. We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNA classifier showed consistent results in formalin-fixed paraffin-embedded tissues and was able to distinguish cyclin D1–negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators.
Comprehensive analysis of unique cases with extraordinary control over HIV replication
Authors: Mendoza Daniel , Johnson Sarah A. , Peterson Bennett A. , Natarajan Ven , Salgado Maria , Dewar Robin L. , Burbelo Peter D. , Doria-Rose Nicole A. , Graf Erin H. , Greenwald Jamieson H. , Hodge Jessica N. , Thompson William L. , Cogliano Nancy A. , Chairez Cheryl L. , Rehm Catherine A. , Jones Sara , Hallahan Claire W. , Kovacs Joseph A. , Sereti Irini , Sued Omar , Peel Sheila A. , O'Connell Robert J. , O'Doherty Una , Chun Tae-Wook , Connors Mark , Migueles Stephen A.
Published: April 2012

True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8+ T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8+ T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies.
Human extramedullary bone marrow in mice: a novel in vivo model of genetically controlled hematopoietic microenvironment
Authors: Chen Ye , Jacamo Rodrigo , Shi Yue-xi , Wang Rui-yu , Battula Venkata Lokesh , Konoplev Sergej , Strunk Dirk , Hofmann Nicole A. , Reinisch Andreas , Konopleva Marina , Andreeff Michael
Published: April 2012

The interactions between hematopoietic cells and the bone marrow (BM) microenvironment play a critical role in normal and malignant hematopoiesis and drug resistance. These interactions within the BM niche are unique and could be important for developing new therapies. Here, we describe the development of extramedullary bone and bone marrow using human mesenchymal stromal cells and endothelial colony-forming cells implanted subcutaneously into immunodeficient mice. We demonstrate the engraftment of human normal and leukemic cells engraft into the human extramedullary bone marrow. When normal hematopoietic cells are engrafted into the model, only discrete areas of the BM are hypoxic, whereas leukemia engraftment results in widespread severe hypoxia, just as recently reported by us in human leukemias. Importantly, the hematopoietic cell engraftment could be altered by genetical manipulation of the bone marrow microenvironment: Extramedullary bone marrow in which hypoxia-inducible factor 1α was knocked down in mesenchymal stromal cells by lentiviral transfer of short hairpin RNA showed significant reduction (50% ± 6%; P = .0006) in human leukemic cell engraftment. These results highlight the potential of a novel in vivo model of human BM microenvironment that can be genetically modified. The model could be useful for the study of leukemia biology and for the development of novel therapeutic modalities aimed at modifying the hematopoietic microenvironment.
Chirped InGaAs quantum dot molecules for broadband applications
Authors: Patanasemakul Nirat , Panyakeow Somsak , Kanjanachuchai Songphol
Published: April 2012

Lateral InGaAs quantum dot molecules (QDMs) formed by partial-cap and regrowth technique exhibit two ground-state (GS) peaks controllable via the thicknesses of InAs seed quantum dots (x), GaAs cap (y), and InAs regrowth (z). By adjusting x/y/z in a stacked QDM bilayer, the GS peaks from the two layers can be offset to straddle, stagger, or join up with each other, resulting in multi-GS or broadband spectra. A non-optimized QDM bilayer with a 170-meV full-width at half-maximum is demonstrated. The temperature dependencies of the emission peak energies and intensities from the chirped QDM bilayers are well explained by Varshni's equation and thermal activation of carriers out of constituent quantum dots.
Transesophageal echocardiography, more than a diagnostic tool: use during surgical ligation of coronary artery fistulae - a case report
Authors: Chung Ping-Chen , Huang Pai-Ching , Liu Yu-Fang , Chen Kuen-Bao
Published: April 2012

Coronary artery fistulae (CAF) are an infrequent coronary abnormality. Herein, we describe the use of intraoperative transesophageal echocardiography (TEE) in the treatment of CAF. A 61 year-old woman presented with chest pain and symptoms consistent with unstable angina. Subsequent coronary angiography revealed the presence of 2 CAF, one extending from the left anterior descending artery to the pulmonary artery (PA) and the other extending from the proximal right coronary artery to the PA. Surgical ligation of the CAF without coronary bypass was arranged. Intraoperative TEE was successfully employed to localize the CAF, monitor fistula blood flow and heart wall motion, and confirm successful ligation. The patient recovered without complications. This case highlights the utility of intraoperative TEE during ligation of CAF.
Investigation of unexpected serum CA19-9 elevation in Lewis-negative cancer patients
Authors: Hamada Etsuko , Taniguchi Terumi , Baba Satoshi , Maekawa Masato
Published: April 2012

Background

Cancer patients with a Lewis (a−b−) phenotype have no carbohydrate antigen 19-9 (CA19-9) in their serum. However, we found a small but distinct elevation in the serum CA19-9 level in three cancer patients with the Lewis-negative phenotype. Here, we investigated the reason of such phenomena.

Methods

Six cancer patients with a Lewis-negative phenotype were selected by very low CA19-9 concentrations: three showed a small elevation (Group A) and the other three showed no elevation (Group B) in the serum CA19-9. We investigated the difference by analyzing the Lewis/Secretor genotypes.

Results

All of the six patients with a Le (a−b−) phenotype were genuine Le-negative genotypes: four individuals were homozygous for le1 ( le59,508), one patient was compound heterozygous for le1 ( le59,508) and le2 ( le59,1067) and one patient was compound heterozygous for le1 and le202,314. As for the Secretor gene, the three patients in Group B were homozygous for Se2 (one patient) or compound heterozygous for Se2 and sej (two patients), while the patients in Group A were all homozygous for sej genotypes.

Conclusions

Even genuinely Le-negative patients, who genetically lack the Le enzyme and theoretically never produce CA19-9, occasionally show a slight increase in serum CA19-9 level when they are homozygous for Se-negative genotypes and suffer from advanced cancer with overproduction of glycans as precursors of CA19-9. Although such cases are not frequent, we should be acquainted with the correlation between serum CA19-9 values and genotypes of Lewis and Secretor genes.
Comparative analysis of current diagnostic criteria for gestational diabetes mellitus
Authors: Boyadzhieva Mariya V , Atanasova Iliana , Zacharieva Sabina , Tankova Tsvetalina , Dimitrova Violeta
Published: April 2012

Background

To compare current guidelines for diagnosis of gestational diabetes mellitus (GDM) and to identify the ones that are the most relevant for application among pregnant Bulgarian population.

Methods

A total of 800 pregnant women at high risk for GDM underwent 75 g oral glucose tolerance test between 24 and 28 weeks of gestation as antenatal screening. The results were interpreted and classified according to the guidelines of the International Association of Diabetes and Pregnancy Study Groups (IADPSG), American Diabetes Association (ADA), Australasian Diabetes in Pregnancy Society, Canadian Diabetes Association, European Association for the Study of Diabetes, New Zealand Society for the study of Diabetes and World Health Organization.

Results

The application of different diagnostic criteria resulted in prevalences of GDM between 10.8% and 31.6%. Using any two sets of criteria, women who were classified differently varied between 0.1% and 21.1% ( P < 0.001).The IADPSG criteria were the most inclusive criteria and resulted in the highest prevalence of GDM. There was a significant difference in the major metabolic parameters between GDM and control groups, regardless of which of the diagnostic criteria applied. GDM diagnosed according to all criteria resulted in increased proportion of delivery by caesarean section (CS). However, only ADA and IADPSG criteria identified both increased macrosomia (odds ratio, 2.36; 2.29) and CS rate.

Conclusion

The need for GDM screening is indisputable. In our view, the new IADPSG guidelines offer a unique opportunity for a unified national and global approach to GDM.
Simple external manual manoeuvres to pass the radiofrequency catheter through a bending segment of a saphenous vein
Authors: Schuller-Petrović S , Adamič M , Pavlović M D
Published: April 2012

Smooth passage of a catheter through a varicose saphenous vein during radiofrequency ablation may prove a challenging task. Various types of venous bending in the transverse and sagittal planes and their combinations within the saphenous compartment may be pretty well appreciated by ultrasound examination. Several simple manual manoeuvres like stretching, pushing or lifting along with limb re-positioning may often help the surgeon to advance the catheter through the segments by temporarily changing their special configuration. In this way the number of patients otherwise considered unsuitable for endovascular catheter procedures like radiofrequency or laser ablation may be considerably reduced.
Exact Routing in Large Road Networks Using Contraction Hierarchies
Authors: Geisberger Robert , Sanders Peter , Schultes Dominik , Vetter Christian
Published: April 2012

Contraction hierarchies are a simple approach for fast routing in road networks. Our algorithm calculates exact shortest paths and handles road networks of whole continents. During a preprocessing step, we exploit the inherent hierarchical structure of road networks by adding shortcut edges. A subsequent modified bidirectional Dijkstra algorithm can then find a shortest path in a fraction of a millisecond, visiting only a few hundred nodes. This small search space makes it suitable to implement it on a mobile device. We present a mobile implementation that also handles changes in the road network, like traffic jams, and that allows instantaneous routing without noticeable delay for the user. Also, an algorithm to calculate large distance tables is currently the fastest if based on contraction hierarchies.
Change of Scale and Forecasting with the Control-Function Method in Logit Models
Authors: Guevara Cristian Angelo , Ben-Akiva Moshe E.
Published: April 2012

Endogeneity is a model misspecification that precludes the consistent estimation of the model parameters. The control-function method is the most suitable tool to address endogeneity for several discrete choice models that are relevant in transportation research. However, the estimators obtained with the control-function method are consistent only up to a scale. In this paper, we first depict the determinants of this change of scale by adapting an existing result for omitted orthogonal attributes in logit models. Then, we study the problem of forecasting under these circumstances. We show that a procedure proposed in previous literature may lead to significant biases, and we suggest novel alternatives to be used with synthetic populations. We use Monte Carlo experimentation and real data on residential location choice to illustrate these results. The paper finishes by summarizing the findings of this investigation and suggesting future lines of research in this area.
microRNA and the pathogenesis of ovarian cancer – a new horizon for molecular diagnostics and treatment?
Authors: Kuhlmann Jan Dominik , Rasch Jens , Wimberger Pauline , Kasimir-Bauer Sabine
Published: April 2012

Ovarian cancer is the leading cause of death among gynecologic malignancies and despite advances in treatment, more than 50% of all patients will experience recurrence, resulting in worse overall prognosis. Therefore, identification of novel biomarkers for ovarian cancer is of significant interest. microRNA (miRNA) constitute a class of small gene regulatory RNA molecules (18–24 nt) and by sequence complementarity, they negatively regulate messenger RNA (mRNA) translation of target genes. Rising data are available that miRNA are functionally involved in the pathogenesis of ovarian cancer. In this regard, recent advances in profiling studies revealed a variety of miRNA candidates, differently expressed in ovarian carcinomas and in disease-specific conditions like hypoxia or chemo-resistance. This review abstracts recent efforts on establishing miRNA as novel molecular biomarkers for ovarian cancer and depicts the existing preliminary framework for defining peripheral-blood derived miRNA as novel circulating biomarkers. Beside these clinical implications, we highlight the current functional understanding of miRNA alteration and discuss major challenges in miRNA profiling approaches. Finally, we briefly outline methodologies to therapeutically modulate miRNA expression in cancer and try to assess how miRNA can improve our conceptual understanding and the clinical management of ovarian cancer.
Independent validation of the Enhanced Liver Fibrosis (ELF) score in the ANRS HC EP 23 Fibrostar cohort of patients with chronic hepatitis C
Authors: Guéchot Jérôme , Trocmé Candice , Renversez Jean-Charles , Sturm Nathalie , Zarski Jean-Pierre
Published: April 2012

: The Enhanced Liver Fibrosis (ELF) score combining serum hyaluronan, N-terminal peptide of type III procollagen and tissue inhibitor of metalloproteinase-1, was reported as relevant in predicting liver fibrosis in chronic liver disease and proposed as an alternative to liver biopsy.

: We evaluated the ELF score in a cohort of chronic hepatitis C (CHC) patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar) using commercial reagents, different from those developed by the manufacturer of the Siemens ELF™ test.

: In 512 CHC, the ELF score, using ROC curves, showed good predictive performances for severe fibrosis [AUROC=0.82; 95% confidence interval (CI) 0.78–0.86]and for cirrhosis (AUROC=0.85; 95% CI 0.81–0.90), but slightly lower for significant fibrosis (AUROC=0.78; 95% CI 0.74–0.82). The Obuchowski measure (0.81) showed that the ELF score globally performed as a marker of liver fibrosis. The ELF score predicted significant fibrosis (cut-off=9.0) with a sensitivity of 0.86, a specificity of 0.62, a positive predictive value (PPV) of 0.80 and a negative predictive value (NPV) of 0.70. For extensive fibrosis (cut-off=9.33), sensitivity was 0.90, specificity was 0.63, PPV was 0.73 and NPV was 0.85. For cirrhosis (cut-off=9.35), sensitivity was 0.83, specificity was 0.75, PPV was 0.44 and NPV was 0.95.

: This study confirms the ELF score performance as an index to predict liver fibrosis or cirrhosis in CHC. The ELF test, using validated reagents, could be added to the health authorities approved non-invasive tests in assessing fibrosis as surrogate to liver biopsy.
Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests
Authors: Halbmayer Walter-Michael , Weigel Guenter , Quehenberger Peter , Tomasits Josef , Haushofer Alexander C. , Aspoeck Gerold , Loacker Lorin , Schnapka-Koepf Mirjam , Goebel Georg , Griesmacher Andrea
Published: April 2012

Dabigatran etexilate is a new oral anticoagulant for the therapy and prophylaxis of venous thromboembolism and stroke prevention in patients with atrial fibrillation. To investigate the extent of interactions of this new anticoagulant with frequently used coagulation assays, we completed a multicenter in vitro trial with Conformité Européenne(CE)-labeled dabigatran-spiked plasma samples.

Lyophilized plasma samples with dabigatran concentrations ranging from 0.00 to 0.48 μg/mL were sent to the coagulation laboratories of six major Austrian hospitals for evaluation. Coagulation assays were performed under routine conditions using standard reagents and analyzer.

Dabigatran led to a dose-dependent prolongation of the clotting times in coagulometric tests and influenced the majority of the parameters measured. Statistically significant interference could be observed with the prothrombin time (PT), activated partial thromboplastin time (aPTT) and PT/aPTT-based assays (extrinsic/intrinsic factors, APC-resistance test) as well as lupus anticoagulant testing. Even non-clotting tests, such as the colorimetric factor XIII activity assay and to a minor extent the amidolytic antithrombin activity assay (via factor IIa) were affected.

This multicenter trial confirms and also adds to existing data, demonstrating that laboratories should expect to observe strong interferences of coagulation tests with increasing concentrations of dabigatran. This finding might become particularly important in the elderly and in patients with renal impairment as well as patients whose blood is drawn at peak levels of dabigatran.
Validation of a new generation POCT glucose device with emphasis on aspects important for glycemic control in the hospital care
Authors: Kos Snježana , van Meerkerk Arie , van der Linden Joke , Stiphout Theo , Wulkan Remi
Published: April 2012

Point-of-care (POC) glucose devices are widely used for insulin-dosage decision-making although such an application is not always permitted. In this study, we have evaluated a new generation of POC glucose device, the HemoCue

This study was performed according to the CLSI/STARD criteria. The 201DMRT was compared to the laboratory hexokinase glucose method (Siemens Dimension Vista

The 201DMRT showed a good agreement with the laboratory reference method. This was examined using Deming regression analysis, percentage Bland-Altman plot and a modified Clarke-error grid. The total analytical error at the clinically critical glucose concentrations of 5.6, 7.0 and 11.1 mmol/L (101, 126 and 200 mg/dL) was 6.4%, 4.3% and 3.0%, respectively. The total error among the different POC devices and among different cuvette lot numbers was <6.5%. Glucose measurements on the 201DMRT were not affected by changes in partial pressure of oxygen, whereas changes in hematocrit had influence on the results (3.4% for every 0.10 L/L change in hematocrit).

The 201DMRT device can be used for glycemic control based on analytical results presented. However, the clinical applicability for tight glycemic control must be confirmed in a clinical study.
γ′ Fibrinogen as a novel marker of thrombotic disease
Authors: Farrell David H.
Published: April 2012

γ′ Fibrinogen is an isoform of fibrinogen that normally constitutes about 7% of total plasma fibrinogen, and arises from an alternative processing event in the γ chain mRNA. γ′ Fibrinogen is a newly-emerging cardiovascular disease (CVD) risk factor that appears to have an independent association with CVD from that of total fibrinogen, which is itself a well-established CVD risk factor. γ′ Fibrinogen shows a significant association with coronary artery disease and myocardial infarction in at least four case-control studies, including the Stockholm Coronary Artery Risk Factor study and the Framingham Heart Study. γ′ Fibrinogen is also significantly associated with stroke, as shown in the Erasmus Stroke Study and others. The role of genetic polymorphisms in the association between γ′ fibrinogen and CVD is under active investigation. γ′ Fibrinogen increases during inflammation, and is differentially regulated from total fibrinogen under pathologic conditions, as demonstrated in the Periodontitis and Vascular Events study. The association between γ′ fibrinogen and venous thromboembolism remains unclear, however, with some studies showing an inverse association with γ′ fibrinogen levels and other studies showing the opposite.
The role of red blood cell distribution width in cardiovascular and thrombotic disorders
Authors: Montagnana Martina , Cervellin Gianfranco , Meschi Tiziana , Lippi Giuseppe
Published: April 2012

The red blood cell (RBC) distribution width (RDW) is a measurement of the size variation as well as an index of the heterogeneity of the erythrocytes (i.e., anysocytosis), which is typically used in combination with the mean corpuscular volume to troubleshoot the cause of an underlying anemia. Reliable data emerged from a variety of clinical studies have, however, disclosed a new and unpredictable scenario in the clinical usefulness of this measure, supporting the hypothesis that RDW might be a useful parameter for gathering meaningful clinical information, either diagnostic or prognostic, on a variety of cardiovascular and thrombotic disorders. Highly significant associations have been described between RDW value and all-cause, non-cardiac and cardiac mortality in patients with coronary artery disease, acute and chronic heart failure, peripheral artery disease, stroke, pulmonary embolism and pulmonary arterial hypertension. It is however still unclear whether anysocytosis might be the cause, or a simple epiphenomenon of an underlying disease, such as inflammation, impaired renal function, undernutrition, oxidative damage, or perhaps an element of both. Nevertheless, RDW is an easy, inexpensive, routinely reported test, whose assessment might allow the acquisition of significant diagnostic and prognostic information in patients with cardiovascular and thrombotic disorders.
Percentage of hypochromic erythrocytes as a potential marker of iron availability
Authors: Urrechaga Eloísa , Borque Luís , Escanero Jesús F.
Published: April 2012

The percentage of hypochromic red cells (% Hypo-He) is now available on the Sysmex analyzer XE 5000 (Sysmex Corporation, Kobe, Japan). In this study the reliability of % Hypo-He in the assessment of iron status in the presence of inflammation is investigated.

Ninety healthy subjects, 91 patients with iron deficiency anemia (IDA) previous to therapy, 65 patients with chronic kidney disease (CKD), 57 patients with anemia of chronic diseases (ACD) and 28 patients with storage iron deficiency (ACD/IDA) receiving therapy were analyzed. Pearson’s correlation, Independent samples t-test, receiver operating characteristic (ROC) curve analysis and Cohen’s k index were applied.

% Hypo-He values inversely correlated with the blood hemoglobin (Hb) (r=–0.78) and Hb content (MHC, r=–0.75). In patients with IDA and ACD/IDA the values obtained for % Hypo-He showed no statistical difference (p=0.5037). ROC analysis results for % Hypo-He in the detection of iron deficiency defined by a serum transferrin receptor (sTfR) >21 nmol/L. The area under the curve is 0.929; cut-off 3.6%, sensitivity 91.5% and specificity 80.9%. Using the threshold 3.6% the k index obtained in comparison to sTfR was 0.64.

% Hypo-He is a reliable parameter for the detection of iron deficiency in patients with anemia in the presence of inflammation.
Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis
Authors: Brännström Kristoffer , Öhman Anders , von Pawel Rammingen Ulrich , Olofsson Anders , Brattsand Maria
Published: April 2012

SPINK9, a Kazal-type serine protease inhibitor, is almost exclusively expressed in the palmo-plantar epidermis. SPINK9 selectively inhibits kallikrein-related peptidase 5 (KLK5), no other target enzyme is known at present. In this study, we defined the reactive loop to residues 48 and 49 of SPINK9 and characterized the inhibition and binding of different SPINK9 variants towards KLK5, KLK7, KLK8 and KLK14. Substitutions of single amino acids in the reactive loop had a large impact on both inhibitory efficiency and specificity. Binding studies showed that it is mainly the dissociation rate that is affected by the amino acid substitutions. The inhibitory effect of wild-type SPINK9 was clearly pH-dependent with an improved effect at a pH similar to that of the outer layers of the skin. Modeling of the enzyme-inhibitor complexes showed that the reactive loop of SPINK9 fits very well into the deep negatively charged binding pocket of KLK5. A decrease in pH protonates His48 of the wild-type protein resulting in a positively charged residue, thereby explaining the observed decreased dissociation rate. Interestingly, substitution with a positively charged amino acid at position 48 resulted in a more efficient inhibitor at higher pH.
Kallikrein 6 is a novel molecular trigger of reactive astrogliosis
Authors: Scarisbrick Isobel A. , Radulovic Maja , Burda Joshua E. , Larson Nadya , Blaber Sachiko I. , Giannini Caterina , Blaber Michael , Vandell Alexander G.
Published: April 2012

Kallikrein-related peptidase 6 (KLK6) is a trypsin-like serine protease upregulated at sites of central nervous system (CNS) injury, including de novo expression by reactive astrocytes, yet its physiological actions are largely undefined. Taken with recent evidence that KLK6 activates G-protein-coupled protease-activated receptors (PARs), we hypothesized that injury-induced elevations in KLK6 contribute to the development of astrogliosis and that this occurs in a PAR-dependent fashion. Using primary murine astrocytes and the Neu7 astrocyte cell line, we show that KLK6 causes astrocytes to transform from an epitheliod to a stellate morphology and to secrete interleukin 6 (IL-6). By contrast, KLK6 reduced expression of glial fibrillary acidic protein (GFAP). The stellation-promoting activities of KLK6 were shown to be dependent on activation of the thrombin receptor, PAR1, as a PAR1-specific inhibitor, SCH79797, blocked KLK6-induced morphological changes. The ability of KLK6 to promote astrocyte stellation was also shown to be linked to activation of protein kinase C (PKC). These studies indicate that KLK6 is positioned to serve as a molecular trigger of select physiological processes involved in the development of astrogliosis and that this is likely to occur at least in part by activation of the G-protein-coupled receptor, PAR1.
One round of SELEX for the generation of DNA aptamers directed against KLK6
Authors: Arnold Steve , Pampalakis Georgios , Kantiotou Kalliopi , Silva Dilson , Cortez Celia , Missailidis Sotiris , Sotiropoulou Georgia
Published: April 2012

Kallikrein-related peptidase 6 (KLK6) is an active serine protease that has been implicated in common pathologies, including neurodegenerative disorders such as Parkinson and Alzheimer disease and certain types of cancer. Antibodies, either polyclonal or monoclonal, that exhibit specificity for distinct members of the extended kallikrein family, including KLK6, were developed. With the exception of KLK3/PSA, the identification and generation of aptamers, as potential new tools with improved characteristics demanded for therapeutic and diagnostic applications, has not been explored for KLKs. Here, we report for the first time the identification of novel DNA aptamers against KLK6 that were isolated using a modified systemic evolution of ligands by exponential enrichment technique. The identified aptamers were characterized using fluorescence spectroscopy, competition ELISA, and quartz crystal microbalance, and two aptamers (008 and 022) were found to exhibit high affinity (K
d in the low nanomolar range) for KLK6. Aptamers were tested for their ability to bind to serum albumin, to demonstrate their specificity for their target, and the possible involvement of such proteins in the transport of aptamers into the bloodstream. The developed aptamers are expected to assist the development of novel diagnostic, biosensing, and therapeutic strategies.
Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients
Authors: Seiz Lina , Dorn Julia , Kotzsch Matthias , Walch Axel , Grebenchtchikov Nicolai I. , Gkazepis Apostolos , Schmalfeldt Barbara , Kiechle Marion , Bayani Jane , Diamandis Eleftherios P. , Langer Rupert , Sweep Fred C.G.J. , Schmitt Manfred , Magdolen Viktor
Published: April 2012

Several members of the human kallikrein-related peptidase family, including KLK6, are up-regulated in ovarian cancer. High KLK6 mRNA or protein expression, measured by quantitative polymerase chain reaction and enzyme-linked immunoassay, respectively, was previously found to be associated with a shortened overall and progression-free survival (OS and PFS, respectively). In the present study, we aimed at analyzing KLK6 protein expression in ovarian cancer tissue by immunohistochemistry. Using a newly developed monospecific polyclonal antibody, KLK6 immunoexpression was initially evaluated in normal tissues. We observed strong staining in the brain and moderate staining in the kidney, liver, and ovary, whereas the pancreas and the skeletal muscle were unreactive, which is in line with previously published results. Next, both tumor cell- and stromal cell-associated KLK6 immunoexpression were analyzed in tumor tissue specimens of 118 ovarian cancer patients. In multivariate Cox regression analysis, only stromal cell-associated expression, besides the established clinical parameters FIGO stage and residual tumor mass, was found to be statistically significant for OS and PFS [high vs. low KLK6 expression; hazard ratio (HR), 1.92; p=0.017; HR, 1.80; p=0.042, respectively]. These results indicate that KLK6 expressed by stromal cells may considerably contribute to the aggressiveness of ovarian cancer.
The kallikrein 14 gene is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness
Authors: Lose Felicity , Lawrence Mitchell G. , Srinivasan Srilakshmi , O’Mara Tracy , Marquart Louise , Chambers Suzanne , Gardiner Robert A. , Aitken Joanne F. , Spurdle Amanda B. , Batra Jyotsna , Clements Judith A.
Published: April 2012

Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.
Epigenetic regulation of kallikrein-related peptidases: there is a whole new world out there
Authors: Pasic Maria D. , Olkhov Ekaterina , Bapat Bharati , Yousef George M.
Published: April 2012

The human kallikreins are a cluster of 15 kallikreins and kallikrein-related peptidases (KLKs). Evidence shows the involvement of KLKs in a wide range of pathophysiological processes, and underscores their potential contribution to cancer, skin and neurodegenerative disorders. The control of KLK expression is not fully elucidated. Understanding the mechanisms controlling KLK expression is an essential step towards exploring the pathogenesis of several diseases and the use of KLKs as disease biomarkers and/or therapeutic targets. Recently, epigenetic changes (including methylation, histone modification and microRNAs [miRNAs]) have drawn attention as a new dimension for controlling KLK expression. Reports showed the effect of methylation on the expression of KLK genes. This was also shown to have potential utility as a prognostic marker in cancer. miRNAs are small RNAs that control the expression of their targets at the post-transcriptional level. Target prediction showed that KLKs are potential targets of miRNAs that are dysregulated in tumors, including prostate, kidney and ovarian cancers, with downstream effect on tumor proliferation. Experimental validation remains an essential step to confirm the KLK-miRNA interaction. Epigenetic regulation of KLKs holds promise for an array of therapeutic applications in many diseases including cancer.
Tissue-specific selection of stable reference genes for real-time PCR normalization in an obese rat model
Authors: Cabiati Manuela , Raucci Serena , Caselli Chiara , Guzzardi Maria Angela , D'Amico Andrea , Prescimone Tommaso , Giannessi Daniela , Del Ry Silvia
Published: April 2012

Obesity is a complex pathology with interacting and confounding causes due to the environment, hormonal signaling patterns, and genetic predisposition. At present, the Zucker rat is an eligible genetic model for research on obesity and metabolic syndrome, allowing scrutiny of gene expression profiles. Real-time PCR is the benchmark method for measuring mRNA expressions, but the accuracy and reproducibility of its data greatly depend on appropriate normalization strategies. In the Zucker rat model, no specific reference genes have been identified in myocardium, kidney, and lung, the main organs involved in this syndrome. The aim of this study was to select among ten candidates (Actb, Gapdh, Polr2a, Ywhag, Rpl13a, Sdha, Ppia, Tbp, Hprt1andTfrc) a set of reference genes that can be used for the normalization of mRNA expression data obtained by real-time PCR in obese and lean Zucker rats both at fasting and during acute hyperglycemia. The most stable genes in the heart wereSdha, Tbp, andHprt1; in kidney,Tbp,Actb, andGapdhwere chosen, whileActb,Ywhag, andSdhawere selected as the most stably expressed set for pulmonary tissue. The normalization strategy was used to analyze mRNA expression of tumor necrosis factor α, the main inflammatory mediator in obesity, whose variations were more significant when normalized with the appropriately selected reference genes. The findings obtained in this study underline the importance of having three stably expressed reference gene sets for use in the cardiac, renal, and pulmonary tissues of an experimental model of obese and hyperglycemic Zucker rats.