bluuebunny/crossref_metadata_2025 huggingface dataset:
MULTI-TIME-SCALE SYSTEMS MODEL ORDER REDUCTION VIA GENETIC ALGORITHMS WITH EIGENVALUE PRESERVATION
Authors: ABO-HAMMOUR ZÁER. S. , ALSMADI OTHMAN M. K. , AL-SMADI ADNAN M.
Published: December 2011

A novel substructure (dominant eigenvalue) preserving genetic algorithm approach for model order reduction (MOR) of multi-time-scale systems is presented in this paper. The new technique is formulated based on genetic algorithms (GAs), sub-optimization and estimation. The GA predicts the elements of an upper triangular matrix form of the system state matrix A, defined in state space representation along with the elements of B, C, and D matrices. The GA procedure is based on maximizing the fitness function corresponding to the reciprocal response deviation between the full order model and the reduced order model. The proposed GA model order reduction method is compared to well-known reduction techniques such as the Balanced Schur Decomposition (BSD), proper orthogonal decomposition (POD), and state elimination through balanced realization. Simulation results validate the robustness of the new technique for MOR with eigenvalue preservation.
QUESTION-ORIENTED ANSWER SUMMARIZATION VIA TERM HIERARCHICAL STRUCTURE
Authors: LI SHASHA , LI ZHOUJUN
Published: December 2011

In the research area of community-based question and answering (cQA) services such as Yahoo! Answers, reuse of the answers has attracted more and more interest. Most researchers focus on the correctness of answers and pay little attention to the completeness of answers. In this paper, we try to address the answer completeness problem for "survey questions" for which answer completeness is crucial. We propose to generate a more complete answer from replies in cQA services through a term hierarchical structure based question-oriented extractive summarization which is different from traditional query-based extractive summarization. The experimental results are very promising in terms of recall, precision and conciseness.
COST-COGNIZANT COMBINATORIAL TEST CASE PRIORITIZATION
Authors: WANG ZIYUAN , CHEN LIN , XU BAOWEN , HUANG YAN
Published: December 2011

Combinatorial testing has been widely used in practice. People usually assume all test cases in combinatorial test suite will run completely. However, in many scenarios where combinatorial testing is needed, for example the regression testing, the entire combinatorial test suite is not run completely as a result of test resource constraints. To improve the efficiency of testing, combinatorial test case prioritization technique is required. For the scenario of regression testing, this paper proposes a new cost-cognizant combinatorial test case prioritization technique, which takes both combination weights and test costs into account. Here we propose a series of metrics with physical meaning, which assess the combinatorial coverage efficiency of test suite, to guide the prioritization of combinatorial test cases. And two heuristic test case prioritization algorithms, which are based on total and additional techniques respectively, are utilized in our technique. Simulation experimental results illustrate some properties and advantages of proposed technique.
ENTANGLEMENT AND SUPERDENSE CODING WITH LINEAR OPTICS
Authors: PAVIČIĆ MLADEN
Published: December 2011

We discuss a scheme for a full superdense coding of entangled photon states employing only linear optics elements. By using the mixed basis consisting of four states that are unambiguously distinguishable by a standard and polarizing beam splitters we can deterministically transfer four messages by manipulating just one of the two entangled photons. The sender achieves the determinism of the transfer either by giving up the control over 50% of sent messages (although known to her) or by discarding 33% of incoming photons.
MAXIMUM NONLOCAL EFFECTS OF QUANTUM STATES
Authors: FU SHUANGSHUANG , LUO SHUNLONG
Published: December 2011

A fundamental feature of quantum mechanics radically different from classical theory lies in the role and consequence of quantum measurements, which usually cause disturbance to quantum states. For a bipartite state, the minimum disturbance caused by local measurements has been used to define quantum correlations from a measurement perspective. In contrast to this minimum approach, we investigate the maximum disturbance of local measurements, and define the nonlocal effect of a bipartite state as the maximum discrepancy between the global and local disturbances caused by local quantum measurements. Some analytical results are obtained and the significance of the maximum nonlocal effect is briefly discussed.
Galectin-3 modulates phagocytosis-induced stellate cell activation and liver fibrosis in vivo
Authors: Jiang Joy X. , Chen Xiangling , Hsu Daniel K. , Baghy Kornelia , Serizawa Nobuko , Scott Fiona , Takada Yoshikazu , Takada Yoko , Fukada Hiroo , Chen Jenny , Devaraj Sridevi , Adamson Roger , Liu Fu-Tong , Török Natalie J.
Published: December 2011

Hepatic stellate cells (HSC), the key fibrogenic cells of the liver, transdifferentiate into myofibroblasts upon phagocytosis of apoptotic hepatocytes. Galectin-3, a β-galactoside-binding lectin, is a regulator of the phagocytic process. In this study, our aim was to study the mechanism by which extracellular galectin-3 modulates HSC phagocytosis and activation. The role of galectin-3 in engulfment was evaluated by phagocytosis and integrin binding assays in primary HSC. Galectin-3 expression was studied by real-time PCR and enzyme-linked immunosorbent assay, and in vivo studies were done in wild-type and galectin-3−/− mice. We found that HSC from galectin-3−/− mice displayed decreased phagocytic activity, expression of transforming growth factor-β1, and procollagen α1(I). Recombinant galectin-3 reversed this defect, suggesting that extracellular galectin-3 is required for HSC activation. Galectin-3 facilitated the αvβ3 heterodimer-dependent binding, indicating that galectin-3 modulates HSC phagocytosis via cross-linking this integrin and enhancing the tethering of apoptotic cells. Blocking integrin αvβ3 resulted in decreased phagocytosis. Galectin-3 expression and release were induced in active HSC engulfing apoptotic cells, and this was mediated by the nuclear factor-κB signaling. The upregulation of galectin-3 in active HSC was further confirmed in vivo in bile duct-ligated (BDL) rats. Galectin-3−/− mice displayed significantly decreased fibrosis, with reduced expression of α-smooth muscle actin and procollagen α1(I) following BDL. In summary, extracellular galectin-3 plays a key role in liver fibrosis by mediating HSC phagocytosis, activation, and subsequent autocrine and paracrine signaling by a feedforward mechanism.
An ex vivo method for studying mucus formation, properties, and thickness in human colonic biopsies and mouse small and large intestinal explants
Authors: Gustafsson Jenny K. , Ermund Anna , Johansson Malin E. V. , Schütte André , Hansson Gunnar C. , Sjövall Henrik
Published: December 2011

The colon mucus layers minimize the contact between the luminal flora and the epithelial cells, and defects in this barrier may lead to colonic inflammation. We now describe an ex vivo method for analysis of mucus properties in human colon and mouse small and large intestine. Intestinal explants were mounted in horizontal perfusion chambers. The mucus surface was visualized by adding charcoal particles on the apical side, and mucus thickness was measured using a micropipette. Mucus thickness, adhesion, and growth rate were recorded for 1 h. In mouse and human colon, the ability of the mucus to act as a barrier to beads the size of bacteria was also evaluated. Tissue viability was monitored by transepithelial potential difference. In mouse ileum, the mucus could be removed by gentle aspiration, whereas in colon ∼40 μm of the mucus remained attached to the epithelial surface. Both mouse and human colon had an inner mucus layer that was not penetrated by the fluorescent beads. Spontaneous mucus growth was observed in human (240 μm/h) and mouse (100 μm/h) colon but not in mouse ileum. In contrast, stimulation with carbachol induced a higher mucus secretion in ileum than colon (mouse ileum: Δ200 μm, mouse colon: Δ130 μm, human colon: Δ140 μm). In conclusion, while retaining key properties from the mucus system in vivo, this setup also allows for studies of the highly dynamic mucus system under well-controlled conditions.
Enhanced catabolism to acetaldehyde in rostral ventrolateral medullary neurons accounts for the pressor effect of ethanol in spontaneously hypertensive rats
Authors: El-Mas Mahmoud M. , Abdel-Rahman Abdel A.
Published: December 2011

We have previously shown that ethanol microinjection into the rostral ventrolateral medulla (RVLM) elicits sympathoexcitation and hypertension in conscious spontaneously hypertensive rats (SHRs) but not in Wistar-Kyoto (WKY) rats. In this study, evidence was sought to implicate the oxidative breakdown of ethanol in this strain-dependent hypertensive action of ethanol. Biochemical experiments revealed significantly higher catalase activity and similar aldehyde dehydrogenase (ALDH) activity in the RVLM of SHRs compared with WKY rats. We also investigated the influence of pharmacological inhibition of catalase (3-aminotriazole) or ALDH (cyanamide) on the cardiovascular effects of intra-RVLM ethanol or its metabolic product acetaldehyde in conscious rats. Compared with vehicle, ethanol (10 μg/rat) elicited a significant increase in blood pressure in SHRs that lasted for the 60-min observation period but had no effect on blood pressure in WKY rats. The first oxidation product, acetaldehyde, played a critical role in ethanol-evoked hypertension because 1) catalase inhibition (3-aminotriazole treatment) virtually abolished the ethanol-evoked pressor response in SHRs, 2) intra-RVLM acetaldehyde (2 μg/rat) reproduced the strain-dependent hypertensive effect of intra-RVLM ethanol, and 3) ALDH inhibition (cyanamide treatment) uncovered a pressor response to intra-RVLM acetaldehyde in WKY rats similar to the response observed in SHRs. These findings support the hypothesis that local production of acetaldehyde, due to enhanced catalase activity, in the RVLM mediates the ethanol-evoked pressor response in SHRs.
Prevention of adverse cardiac remodeling to volume overload in female rats is the result of an estrogen-altered mast cell phenotype
Authors: Lu Hong , Meléndez Giselle C. , Levick Scott P. , Janicki Joseph S.
Published: December 2011

Previously, we have reported sex differences in the cardiac remodeling response to ventricular volume overload whereby male and ovariectomized (OVX) female rats develop eccentric hypertrophy, and intact (Int) female rats develop concentric hypertrophy. In males, this adverse remodeling has been attributed to an initial cascade of events involving myocardial mast cell and matrix metalloproteinase activation and extracellular collagen matrix degradation. The objective of this study was to determine the effect of female hormones on this initial cascade. Accordingly, an aortocaval fistula (Fist) was created in 7-wk-old Int and OVX rats, which, together with sham-operated (sham) controls, were studied at 1, 3, and 5 days postsurgery. In Int-Fist rats, myocardial mast cell density, collagen volume fraction, endothelin (ET)-1, stem cell factor (SCF), and TNF-α remained at control levels or were minimally elevated throughout the study period. This was not the case in the OVX-Fist group, where the initial response included significant increases in mast cell density, collagen degradation, ET-1, SCF, and TNF-α. These events in the OVX-Fist group were abolished by prefistula treatment with a mast cell stabilizer nedocromil. Of note was the observation that ET-1, TNF-α, SCF, and collagen volume fraction values for the OVX-sham group were greater than those of the Int-sham group, suggesting that the reduction of female hormones alone results in major myocardial changes. We concluded that female hormone-related cardioprotection to the volume stressed myocardium is the result of an altered mast cell phenotype and/or the prevention of mast cell activation.
Micron-sized intrapulmonary particle deposition in the developing rat lung
Authors: Schulz Holger , Eder Gunter , Bolle Ines , Tsuda Akira , Karrasch Stefan
Published: December 2011

Little is known about the effects of postnatal developmental changes in lung architecture and breathing patterns on intrapulmonary particle deposition. We measured deposition in the developing Wistar-Kyoto rat, whose lung development largely parallels that of humans. Deposition of 2-μm sebacate particles was determined in anesthetized, intubated, spontaneously breathing rats on postnatal days (P) 7 to 90 by aerosol photometry (Karrasch S, Eder G, Bolle I, Tsuda A, Schulz H. J Appl Physiol 107: 1293–1299, 2009). Respiratory parameters were determined by body plethysmography. Tidal volume increased substantially from P7 (0.19 ml) to P90 (2.1 ml) while respiratory rate declined from 182 to 107/min. Breath-specific deposition was lowest (9%) at P7 and P90 and markedly higher at P35 (almost 16%). Structural changes of the alveolar region include a ninefold increase in surface area (Bolle I, Eder G, Takenaka S, Ganguly K, Karrasch S, Zeller C, Neuner M, Kreyling WG, Tsuda A, Schulz H. J Appl Physiol 104: 1167–1176, 2008). Particle deposition per unit of time and surface area peaked at P35 and showed a minimum at P90. At an inhaled particle number concentration of 105/cm3, there was an estimated 450, 690, and 330 particles/(min × cm2) at P7, P35, and P90, respectively. Multiple regression models showed that deposition depends on the mean linear intercept as structural component and the breathing parameters, tidal volume, and respiratory rate ( r2> 0.9). In conclusion, micron-sized particle deposition was dependent on the stage of postnatal lung development. A maximum was observed during late alveolarization (P35), which corresponds to human lungs of about eight years of age. Children at this age may therefore be more susceptible to micron-sized airborne environmental health hazards.
Differential effects of jump versus running exercise on trabecular architecture during remobilization after suspension-induced osteopenia in growing rats
Authors: Ju Yong-In , Sone Teruki , Ohnaru Kazuhiro , Choi Hak-Jin , Fukunaga Masao
Published: December 2011

High-impact exercise is considered to be very beneficial for bones. We investigated the ability of jump exercise to restore bone mass and structure after the deterioration induced by tail suspension in growing rats and made comparisons with treadmill running exercise. Five-week-old male Wistar rats ( n = 28) were randomly assigned to four body weight-matched groups: a spontaneous recovery group after tail suspension ( n = 7), a jump exercise group after tail suspension ( n = 7), a treadmill running group after tail suspension ( n = 7), and age-matched controls without tail suspension or exercise ( n = 7). Treadmill running was performed at 25 m/min, 1 h/day, 5 days/wk. The jump exercise protocol consisted of 10 jumps/day, 5 days/wk, with a jump height of 40 cm. Bone mineral density (BMD) of the total right femur was measured by dual-energy X-ray absorptiometry. Three-dimensional trabecular bone architecture at the distal femoral metaphysis was evaluated using microcomputed tomography. After 5 wk of free remobilization, right femoral BMD, right hindlimb muscle weight, and body weight returned to age-matched control levels, but trabeculae remained thinner and less connected. Although both jump and running exercises during the remobilization period increased trabecular bone mass, jump exercise increased trabecular thickness, whereas running exercise increased trabecular number. These results indicate that restoration of trabecular bone architecture induced by jump exercise during remobilization is predominantly attributable to increased trabecular thickness, whereas running adds trabecular bone mass through increasing trabecular number, and suggest that jumping and running exercises have different mechanisms of action on structural characteristics of trabecular bone.
Training-induced adaptation in purine metabolism in high-level sprinters vs. triathletes
Authors: Zieliński Jacek , Kusy Krzysztof
Published: December 2011

The aim of this study was to assess the effect of training loads on metabolic response of purine derivatives in highly trained sprinters (10 men, age range 20–29 yr) in a 1-yr cycle, compared with endurance-training mode in triathletes (10 men, age range 21–28 yr). A four-time measurement of respiratory parameters, plasma hypoxanthine (Hx) concentration, and erythrocyte hypoxanthine-guanine phosphoribosyl transferase (HGPRT) activity was administered in four characteristic training phases (general, specific, competition, and transition). A considerably lower postexercise plasma concentration of Hx in sprinters (8.1–18.0 μmol/l) than in triathletes (14.1–24.9 μmol/l) was demonstrated in all training phases. In both groups, a significant decrease in plasma Hx concentration in the competition phase and a considerable increase in the transition phase were observed. It was found that the resting erythrocyte HGPRT activity increased in the competition period and declined in the transition phase. Sprinters showed higher HGPRT activity (58.5–71.8 nmol IMP·mg Hb−1·h−1) than triathletes (55.8–66.6 nmol IMP·mg Hb−1·h−1) in all examinations. The results suggest a more effective use of anaerobic metabolic energy sources induced by sprint training characterized by higher amount of exercise in the anaerobic lactacid and the nonlactacid zone. The changes in plasma Hx concentration and erythrocyte HGPRT activity might serve as sensitive metabolic indicators in the training control, especially in sprint-trained athletes. These parameters may provide information about the energetic status of the muscles in highly trained athletes in which no significant adaptation changes are detected by means of commonly acknowledged biochemical and physiological parameters.
What is the role of the medial olivocochlear system in speech-in-noise processing?
Authors: de Boer Jessica , Thornton A. Roger D. , Krumbholz Katrin
Published: December 2011

The medial olivocochlear (MOC) bundle reduces the gain of the cochlear amplifier through reflexive activation by sound. Physiological results indicate that MOC-induced reduction in cochlear gain can enhance the response to signals when presented in masking noise. Some previous studies suggest that this “antimasking” effect of the MOC system plays a role in speech-in-noise perception. The present study set out to reinvestigate this hypothesis by correlating measures of MOC activity and speech-in-noise processing across a group of normal-hearing participants. MOC activity was measured using contralateral suppression of otoacoustic emissions (OAEs), and speech-in-noise processing was measured by measuring the effect of noise masking on performance in a consonant-vowel (CV) discrimination task and on auditory brain stem responses evoked by a CV syllable. Whereas there was a significant correlation between OAE suppression and both measures of speech-in-noise processing, the direction of this correlation was opposite to that predicted by the antimasking hypothesis, in that individuals with stronger OAE suppression tended to show greater noise-masking effects on CV processing. The current results indicate that reflexive MOC activation is not always beneficial to speech-in-noise processing. We propose an alternative to the antimasking hypothesis, whereby the MOC system benefits speech-in-noise processing through dynamic (e.g., attention- and experience-dependent), rather than reflexive, control of cochlear gain.
Parameter extraction and classification of three cortical neuron types reveals two distinct adaptation mechanisms
Authors: Mensi Skander , Naud Richard , Pozzorini Christian , Avermann Michael , Petersen Carl C. H. , Gerstner Wulfram
Published: December 2011

Cortical information processing originates from the exchange of action potentials between many cell types. To capture the essence of these interactions, it is of critical importance to build mathematical models that reflect the characteristic features of spike generation in individual neurons. We propose a framework to automatically extract such features from current-clamp experiments, in particular the passive properties of a neuron (i.e., membrane time constant, reversal potential, and capacitance), the spike-triggered adaptation currents, as well as the dynamics of the action potential threshold. The stochastic model that results from our maximum likelihood approach accurately predicts the spike times, the subthreshold voltage, the firing patterns, and the type of frequency-current curve. Extracting the model parameters for three cortical cell types revealed that cell types show highly significant differences in the time course of the spike-triggered currents and moving threshold, that is, in their adaptation and refractory properties but not in their passive properties. In particular, GABAergic fast-spiking neurons mediate weak adaptation through spike-triggered currents only, whereas regular spiking excitatory neurons mediate adaptation with both moving threshold and spike-triggered currents. GABAergic nonfast-spiking neurons combine the two distinct adaptation mechanisms with reduced strength. Differences between cell types are large enough to enable automatic classification of neurons into three different classes. Parameter extraction is performed for individual neurons so that we find not only the mean parameter values for each neuron type but also the spread of parameters within a group of neurons, which will be useful for future large-scale computer simulations.
Auditory experience refines cortico-basal ganglia inputs to motor cortex via remapping of single axons during vocal learning in zebra finches
Authors: Miller-Sims Vanessa C. , Bottjer Sarah W.
Published: December 2011

Experience-dependent changes in neural connectivity underlie developmental learning and result in life-long changes in behavior. In songbirds axons from the cortical region LMANcore(core region of lateral magnocellular nucleus of anterior nidopallium) convey the output of a basal ganglia circuit necessary for song learning to vocal motor cortex [robust nucleus of the arcopallium (RA)]. This axonal projection undergoes remodeling during the sensitive period for learning to achieve topographic organization. To examine how auditory experience instructs the development of connectivity in this pathway, we compared the morphology of individual LMANcore→RA axon arbors in normal juvenile songbirds to those raised in white noise. The spatial extent of axon arbors decreased during the first week of vocal learning, even in the absence of normal auditory experience. During the second week of vocal learning axon arbors of normal birds showed a loss of branches and varicosities; in contrast, experience-deprived birds showed no reduction in branches or varicosities and maintained some arbors in the wrong topographic location. Thus both experience-independent and experience-dependent processes are necessary to establish topographic organization in juvenile birds, which may allow birds to modify their vocal output in a directed manner and match their vocalizations to a tutor song. Many LMANcoreaxons of juvenile birds, but not adults, extended branches into dorsal arcopallium (Ad), a region adjacent to RA that is part of a parallel basal ganglia pathway also necessary for vocal learning. This transient projection provides a point of integration between the two basal ganglia pathways, suggesting that these branches convey corollary discharge signals as birds are actively engaged in learning.
Morphological Evidence for Direct Interaction between Kisspeptin and Gonadotropin-Releasing Hormone Neurons at the Median Eminence of the Male Goat: An Immunoelectron Microscopic Study
Authors: Matsuyama Shuichi , Ohkura Satoshi , Mogi Kazutaka , Wakabayashi Yoshihiro , Mori Yuji , Tsukamura Hiroko , Maeda Kei-Ichiro , Ichikawa Masumi , Okamura Hiroaki
Published: December 2011

Kisspeptin has been thought to play pivotal roles in the control of both pulse and surge modes of gonadotropin-releasing hormone (GnRH) secretion. To clarify loci of kisspeptin action on GnRH neurons, the present study examined the morphology of the kisspeptin system and the associations between kisspeptin and GnRH systems in gonadally intact and castrated male goats. Kisspeptin-immunoreactive (ir) and Kiss1-positive neurons were found in the medial preoptic area of intact but not castrated goats. Kisspeptin-ir cell bodies and fibers in the arcuate nucleus (ARC) and median eminence (ME) were fewer in intact male goats compared with castrated animals. Apposition of kisspeptin-ir fibers on GnRH-ir cell bodies was very rare in both intact and castrated goats, whereas the intimate association of kisspeptin-ir fibers with GnRH-ir nerve terminals was observed in the ME of castrated animals. Neurokinin B immunoreactivity colocalized not only in kisspeptin-ir cell bodies in the ARC but also in kisspeptin-ir fibers in the ME, suggesting that a majority of kisspeptin-ir fibers projecting to the ME originates from the ARC. A dual immunoelectron microscopic examination revealed that nerve terminals containing kisspeptin-ir vesicles made direct contact with GnRH-ir nerve terminals at the ME of castrated goats. There was no evidence for the existence of the typical synaptic structure between kisspeptin- and GnRH-ir fibers. The present results suggest that the ARC kisspeptin neurons act on GnRH neurons at the ME to control (possibly the pulse mode of) GnRH secretion in males.
Spectrum of Risk of Malignancy in Subcategories of ‘Atypia of Undetermined Significance’
Authors: Olson Matthew T. , Clark Douglas P. , Erozan Yener S. , Ali Syed Z.
Published: December 2011

Objective: To determine if focal ‘nuclear atypia’ or ‘microfollicular architecture’ portends a higher risk of malignancy than other subcategories of atypia of undetermined significance (AUS) in thyroid fine-needle aspirations (FNAs). Study Design: The frequencies of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) categories were calculated from 3,956 thyroid FNAs interpreted over a 26-month period at The Johns Hopkins Hospital after adoption of TBSRTC. TBSRTC criteria were applied strictly. The risk of malignancy, specifically for AUS subcategories, was analyzed by cyto-histo correlation. Results: Of the 133 cases diagnosed as AUS, 32% were found to have stageable carcinoma (not incidental microcarcinoma) on resection. When the subset of AUS with ‘nuclear atypia’ (AUS-N) was separated from other AUS cases, 48% (30/62) of them had stageable carcinoma on resection; of the AUS subset with ‘microfollicular architecture’ (AUS-F), 27% (8/30) were malignant on resection. The ‘suspicious for papillary thyroid carcinoma’ (SPTC) group maintained a higher risk of malignancy versus AUS-N (relative risk, RR 1.57; 95% CI 1.23–1.81). Conclusion: The subcategory of ‘nuclear atypia’ within AUS indicates a higher risk of malignancy than other subcategories of AUS but has a lower risk of malignancy than SPTC does. Thus, it is an important distinction with potential clinical implications.
The UK Royal College of Pathologists Thyroid Fine-Needle Aspiration Diagnostic Classification Is a Robust Tool for the Clinical Management of Abnormal Thyroid Nodules
Authors: Lobo Claudia , McQueen Andrew , Beale Tim , Kocjan Gabrijela
Published: December 2011

Objective: To compare the outcomes and evaluate the relative risk of thyroid cancer by using the UK thyroid fine-needle aspiration (FNA) cytological diagnostic categories, with the main objective being the clarity of patient management. Study Design: Results of thyroid FNA reported as Thy3a, Thy3f, Thy4, and Thy5 were correlated with histological outcomes. The specificity and positive predictive value (PPV; risk of malignancy) for each reporting category was assessed. Results: Of a total of 873 thyroid FNAs, 237 (27%) were reported as ‘abnormal’: 40 (4.6%) as Thy3a, 119 (13.6%) as Thy3f, 20 (2.2%) as Thy4, and 58 (6.6%) as Thy 5. The final outcomes were available in 136 (57%) cases which underwent surgical resection (25, 60, 55, and 74% of Thy3a, Thy3f, Thy4, and Thy5, respectively). The known outcomes of the Thy3a category were too low to be statistically significant. The specificity and PPV of the Thy3f, Thy4, and Thy5 (equivalent to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) IV, V, and VI) categories were 50, 50, and 100% and 28, 64, and 100%, respectively. The PPV of Thy3f for diagnosis of ‘neoplasms’ (benign and malignant) was 63%. Conclusion: The current thyroid FNA classification system used in the UK, which is comparable to TBSRTC, offers a sound basis for clear communication on which the management of patients with abnormal thyroid FNA findings can be based. Categories Thy3f, Thy4, and Thy5 carry a progressively rising risk of malignancy, justifying their continuing use. Diagnostic category Thy5 ‘malignant’ is robust and can be used as a sure indication of a definitive surgical management.
Application of Magnetic-Resonance-Spectroscopy- Based Metabolomics to the Fine-Needle Aspiration Diagnosis of Papillary Thyroid Carcinoma
Authors: Jordan Kate W. , Adkins Christen B. , Cheng Leo L. , Faquin William C.
Published: December 2011

Objective: This study explores the potential use of high-resolution magic angle spinning proton magnetic resonance spectroscopy as an ancillary diagnostic technique for papillary thyroid carcinoma in thyroid fine-needle aspiration biopsies. The method has already been shown to be effective in the classification of various other nonthyroid cancers. Study Design: Twenty-six samples (13 paired cytologic and histologic samples) from patients being evaluated for thyroid abnormalities at the Massachusetts General Hospital were spectroscopically analyzed, and included: papillary thyroid carcinomas (n = 4), follicular adenomas (n = 4), and normal thyroid samples (n = 5). Metabolic profiles were statistically generated based on the spectroscopy results, which were then correlated with the final cytologic and histologic diagnoses from the same samples to determine the diagnostic capacity of the profiles. Results: Principal component analysis of the tissue samples revealed statistically significant correlations among principal components and various cytologic and histologic features. Canonical score 1, calculated with principal components in correlation with analyzed pathologies, revealed the ability of the metabolic profile to differentiate all three examined histologic tissue groups (ANOVA, p < 0.0001). Applying coefficients of principal components and canonical scores obtained with tissue samples directly onto spectral results of cytology samples, the calculated canonical score 1 also revealed similar trends among the three fine-needle aspiration biopsy groups. In particular, the papillary thyroid carcinoma group exhibited significant differences from both the adenomatous and normal cytology groups (p < 0.0170). Conclusions: The results indicate the potential of high-resolution magic angle spinning proton magnetic resonance spectroscopy as an ancillary marker for papillary thyroid carcinoma in fine-needle aspiration biopsy specimens.
BRAF Mutation Analysis of Fine-Needle Aspiration Biopsies of Papillary Thyroid Carcinoma: Impact on Diagnosis and Prognosis
Authors: Colanta Agnes , Lin Oscar , Tafe Laura , Ghossein Ronald , Nafa Khedoudja , Mitchell Talia , Ladanyi Marc , Arcila Maria
Published: December 2011

Objective: The BRAF V600E mutation has been associated with aggressive disease in papillary thyroid carcinoma (PTC). Molecular testing has been proposed as a useful adjunct to cytology in the diagnosis of malignancy and for tailoring clinical management. The aims of our study were to evaluate the BRAF mutational status using archived fine-needle aspiration biopsy (FNAB) material from patients with long-term follow-up and to correlate it with the original cytology diagnosis, clinicopathological stage at surgery, and prognosis. Study Design: FNAB material from 52 cases of PTC, with a mean follow-up of 8.4 years, was used in this study. DNA was extracted from archival cytology slides. Mutation analysis was performed by standard sequencing and locked nucleic acid-PCR/sequencing. Results: The BRAF V600E mutation was present in 46% of cases, but it was absent in all FNABs diagnosed originally as atypical and in 14 of 17 suspicious cases. Recurrence was significantly more frequent (p = 0.006) in cases with BRAF mutations and 54% of these cases presented with stage 2 or higher. Conclusion: The BRAF V600E mutation is associated with a higher pathological stage at surgery and a higher rate of recurrence. BRAF mutation analysis did not provide a significant increase in the accuracy of thyroid FNABs diagnosed as suspicious or atypical in our institution.
Allele-Specific PCR with Competitive Probe Blocking for Sensitive and Specific Detection of BRAF V600E in Thyroid Fine-Needle Aspiration Specimens
Authors: Smith G. Denice , Zhou Luming , Rowe Leslie R. , Jarboe Elke A. , Collins Brian T. , Bentz Joel S. , Wittwer Carl T. , Chadwick Barbara E.
Published: December 2011

Objective: To detect BRAF V600E mutation in thyroid fine-needle aspiration (FNA) slides and needle rinses (NR). Study Design: Tumor-enriched DNA was extracted from FNA smears, formalin-fixed paraffin-embedded (FFPE) sections, or NR specimens from 37 patients with confirmed papillary thyroid carcinoma or benign findings. An allele-specific primer selectively amplified the 1799 T>A BRAF mutation while simultaneously blocking amplification of wild-type (WT) BRAF with an unlabeled probe during PCR. Mutation detection was accomplished by melting analysis of the probe. Results: Allele-specific/blocking probe PCR confirmed the BRAF mutation status for 20 of 24 paired FNA/FFPE samples previously tested by fluorescent probe real-time PCR. For the other 4 cases, the sensitive PCR method detected the BRAF mutation in all paired FNA/FFPE samples. Previously, the mutation had been detected in only the FFPE samples. The BRAF mutation was also detected in some NR specimens. Conclusion: Treatment of patients with thyroid nodules is guided by FNA biopsy, which can be scantly cellular, necessitating a sensitive test that can detect low levels of BRAF V600E mutation in a WT background. We report increased detection of BRAF V600E in FNA specimens using allele-specific/blocking probe PCR, which has an analytical sensitivity of 0.01%.
Long-Term Risk of Leukaemia or Cardiomyopathy after Mitoxantrone Therapy for Multiple Sclerosis
Authors: Mulroy Eoin , Joyce Emer , Scott Jaqueline , Melling Jane , Goggin Carole , Mahon Niall , O’Rourke Killian , Lynch Timothy
Published: December 2011

Background: Mitoxantrone has been extensively used as a disease-modifying therapy for multiple sclerosis. However, estimates of the associated risk of therapy-related acute leukaemia and cardiomyopathy have been derived from short-term studies. This study aimed to ascertain the long-term risk of therapy-related acute leukaemia or cardiomyopathy after mitoxantrone therapy for multiple sclerosis. Methods: Between 2002 and 2010, 50 patients were treated with mitoxantrone at a single centre using a standard protocol (12 mg/m2 body surface area monthly for 6 months as tolerated to a maximum of 72 mg/m2 body surface area). Follow-up haematologic and echocardiographic data were collected in March 2011. Results: Fifteen patients (30%) were excluded from analysis either because of lack of follow-up data, death due to non-cardiac and non-haematologic causes, or comorbid cardiovascular disease. The remaining 35 patients (70%) were followed for a median of 75 months (range: 9–103). The median cumulative mitoxantrone dose given was 72 mg/m2 body surface area (range: 24–123). At the end of follow-up, no patients had developed therapy-related acute leukaemia. One patient suffered an asymptomatic drop in left ventricular ejection fraction from 55 to 47%. Conclusion: This series of patients followed for up to 8.5 years suggests that the risk of either therapy-related acute leukaemia or cardiomyopathy after mitoxantrone therapy for multiple sclerosis is low when patients are treated within standard protocol.
Timing of Repeat Thyroid Fine-Needle Aspiration in the Management of Thyroid Nodules
Authors: Singh Remmi S. , Wang Helen H.
Published: December 2011

Objective: The Bethesda System for reporting thyroid fine-needle aspirations (FNAs) recommends repeat aspirations be done at least 3 months following the initial aspiration to prevent false-positive misinterpretations due to reactive/reparative changes. Because limited data exists, we reviewed our own data to ascertain the recommendation. Study Design: We retrospectively reviewed thyroid FNAs accessioned in the Cytology Laboratory at Beth Israel Deaconess Medical Center in Boston, Mass., USA, from January 2006 to December 2008. We identified patients with repeat aspirates of a single lesion and those with thyroidectomy specimens. Cytologic and surgical diagnoses along with time between FNAs were recorded. Results: No statistically significant difference was detected in the distribution among nondiagnostic, suboptimal, and adequate categories with respect to the timing of repeat FNA (p = 0.25). Forty-six percent of the lesions that were nondiagnostic/suboptimal initially yielded the same results on repeat. Twenty-eight percent of initially adequate specimens were nondiagnostic/suboptimal on repeat (p = 0.04). Nine percent of those with an initial atypical diagnosis had the same diagnosis on repeat, while 2.6% of those who did not have an initial atypical diagnosis had an atypical diagnosis on repeat (p = 0.29). False positives between early (16%) and late (12%) repeats were not statistically significant (p = 0.74). Conclusion: The diagnostic yield and accuracy of repeat FNA is independent of the time interval between procedures but may be related to the original FNA diagnosis.
Haemostatic variables during normal menstrual cycle
Authors: Kemperman Ramses F. J. , Kluin-Nelemans Hanneke C. , Mulder André B. , Meijer Karina , Knol H.
Published: December 2011

For a number of haemostatic factors menstrual cycle variation has been studied. Such variation could have clinical implications for the timing of haemostatic testing in women. It was our objective to systematically review the literature about evidence for timing of haemostatic testing during menstrual cycle.We searched MEDLINE, EMBASE and the Cochrane library to identify studies that measured haemostatic variables [platelet function, von Willebrand factor (VWF), factor VIII (FVIII), factor IX (FIX), factor XI (FXI), factor XIII (FXIII), D-dimer, plasminogen activator inhibitor-I (PAI-I), tissue plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), α2-antiplasmin and fibrinogen] during normal menstrual cycle without hormonal contraceptives. Two investigators independently selected studies, and abstracted data in duplicate. We identified 1,046 studies of which we included 30 studies (25 longitudinal and 5 cross-sectional studies). All studies reported on haemostatic variables during menstrual cycle. Overall, most of the studies found no cyclic variation in VWF, FVIII, FXI, FXIII, fibrinolytic factors (PAI, t-PA, uPA, D-dimer and α2-antiplasmin) and fibrinogen. However, in studies where these variables showed any variation, they reached the lowest levels during menstrual and early follicular phase, especially for VWF, FVIII and platelet function tests. In conclusion, the optimal timing for haemostatic testing during menstrual cycle seems to be menstrual and early follicular phase.
Platelet Glycoprotein VI Dimerization, an Active Process Inducing Receptor Competence, Is an Indicator of Platelet Reactivity
Authors: Loyau Stéphane , Dumont Bénédicte , Ollivier Véronique , Boulaftali Yacine , Feldman Laurent , Ajzenberg Nadine , Jandrot-Perrus Martine
Published: December 2011

Objective—

The immune receptor homologue glycoprotein VI (GPVI)/FcR receptor γ chain complex is primarily responsible for platelet activation by collagen. There is growing evidence that optimal binding of GPVI to collagen depends on the assembly of GPVI dimers. The valence of GPVI on resting platelets needs to be clearly established because platelet avidity for collagen would be greater if GPVI is constitutively expressed as a dimer than as a monomer.

Methods and Results—

Using a monoclonal antibody (9E18) that preferentially binds to GPVI dimers, we found that GPVI was maintained in a monomeric form on human resting platelets under the control of intraplatelet cAMP concentration. Activation by soluble agonists or von Willebrand factor induced a shift toward GPVI dimerization related to increased platelet adhesion to collagen. A correlation between platelet binding of 9E18 and P-selectin exposure was observed in patients experiencing coronary artery disease, and antagonists of the ADP receptor P2Y
12
limited ADP-induced GPVI dimerization.

Conclusion—

The rapid assembly of highly competent dimers of GPVI at sites of vascular lesion represents an important step in the sequence of events leading to platelet activation by collagen. GPVI dimers could represent a new marker to analyze platelet reactivity.
Atrial Fibrillation After Pulmonary Transplantation
Authors: Henri Christine , Giraldeau Geneviève , Dorais Marc , Cloutier Alexis-Simon , Girard François , Noiseux Nicolas , Ferraro Pasquale , Rinfret Stéphane
Published: December 2011

Background—

Atrial fibrillation (AF) is common after thoracic surgery. Limited data exist concerning the incidence of AF, its impact on mortality, the effectiveness of therapy, and the risk factors of AF after pulmonary transplantation.

Methods and Results—

We reviewed the medical files of 224 consecutive lung transplant recipients who underwent surgery over a 10-year period at a large Canadian center. We collected patient characteristics, in-hospital treatments, and outcomes. Time-to-event analysis was used to account for in-hospital follow-up and models generated to assess the impact of AF on mortality and independent risk factors of AF after transplantation. Postoperative AF occurred in 65 patients (29%). AF was more likely to occur with complications such as pneumonia, mediastinitis, and bronchial dehiscence and was not an independent risk factor of mortality (hazard ratio=1.56; 95% confidence interval, 0.52–4.63). Pharmacological or electric therapy for rhythm or rate control of AF was administered to 97% of patients. Intravenous amiodarone was used in 46%, electric cardioversion in 28%, and heparin in 26%. Only 1 patient remained in AF at discharge. Age (hazard ratio=1.08 by year; 95% confidence interval, 1.05–1.12), bilateral transplantation (hazard ratio=1.87; 95% confidence interval, 1.03–3.42), and a history of AF before the transplantation (hazard ratio=4.48; 95% confidence interval, 1.05–19.11) were found to be independently associated with an increased incidence of postoperative AF.

Conclusions—

AF is fairly common after pulmonary transplantation, transient, and relatively benign. It is not independently associated with increased in-hospital mortality. Most patients return to sinus rhythm before discharge. Age, prior AF, and bilateral transplantation increase the risk of postoperative AF.
Thymosin Beta 4 Is Dispensable for Murine Cardiac Development and Function
Authors: Banerjee Indroneal , Zhang Jianlin , Moore-Morris Thomas , Lange Stephan , Shen Tao , Dalton Nancy D. , Gu Yusu , Peterson Kirk L. , Evans Sylvia M. , Chen Ju
Published: December 2011

Rationale:

Thymosin beta 4 (Tβ4) is a 43–amino acid factor encoded by an X-linked gene. Recent studies have suggested that Tβ4 is a key factor in cardiac development, growth, disease, epicardial integrity, and blood vessel formation. Cardiac-specific short hairpin (sh)RNA knockdown of
tβ4
has been reported to result in embryonic lethality at E14.5–16.5, with severe cardiac and angiogenic defects. However, this shRNA
tβ4
-knockdown model did not completely abrogate Tβ4 expression. To completely ablate Tβ4 and to rule out the possibility of off-target effects associated with shRNA gene silencing, further studies of global or cardiac-specific knockouts are critical.

Objective:

We examined the role of Tβ4 in developing and adult heart through global and cardiac specific
t
β4-knockout mouse models.

Methods and Results:

Global
t
β
4
-knockout mice were born at mendelian ratios and exhibited normal heart and blood vessel formation. Furthermore, in adult global
t
β
4
-knockout mice, cardiac function, capillary density, expression of key cardiac fetal and angiogenic genes, epicardial marker expression, and extracellular matrix deposition were indistinguishable from that of controls. Tissue-specific
t
β
4
-deficient mice, generated by crossing
t
β
4
-floxed mice to
Nkx2.5-Cre
and α
MHC-Cre
, were also found to have no phenotype.

Conclusions:

We conclude that Tβ4 is dispensable for embryonic viability, heart development, coronary vessel development, and adult myocardial function.
Delay of Stroke Onset by Milk Proteins in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Chiba Tsuyoshi , Itoh Tatsuki , Tabuchi Masaki , Ooshima Kana , Satou Takao , Ezaki Osamu
Published: December 2011

Background and Purpose—

There is an inverse association between dairy food consumption and the incidence of stroke in observational studies. However, it is unknown whether the relationship is causal or, if so, what components in milk are responsible for reducing the incidence of stroke.

Methods—

Stroke-prone spontaneously hypertensive rats were fed diets comprising amino acids, proteins from different sources (casein, whey, soybean, or egg white), or fats from different sources (butter, beef tallow, or cocoa butter) and the onset of stroke and lifespan were examined.

Results—

Increasing the amount of dietary casein (5% to 55% of caloric intake) markedly delayed the onset of stroke. However, when stroke-prone spontaneously hypertensive rats were fed diets containing 55% of caloric intake as protein, rats fed casein or whey protein, a major component of milk, displayed a delayed onset of stroke compared with rats fed soybean or egg white protein. Rats fed an amino acids diet containing the same amino acids composition as casein did not have a delay in the onset of stroke. Increasing dietary fats, including butter as well as beef tallow and cocoa butter, did not affect the onset of stroke. All diets did not affect blood pressure in the early stage.

Conclusions—

These data suggest that the inverse association between dairy food consumption and incidence of stroke in epidemiological studies is causal and that peptides in milk protein, but not fat, might be responsible for this effect.
Vessel Wall MRI to Differentiate Between Reversible Cerebral Vasoconstriction Syndrome and Central Nervous System Vasculitis
Authors: Mandell Daniel M. , Matouk Charles C. , Farb Richard I. , Krings Timo , Agid Ronit , terBrugge Karel , Willinsky Robert A. , Swartz Richard H. , Silver Frank L. , Mikulis David J.
Published: December 2011

Background and Purpose—

Prospective differentiation between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis can be challenging. We hypothesized that high-resolution vessel wall MRI would demonstrate arterial wall enhancement in central nervous system vasculitis but not in reversible cerebral vasoconstriction syndrome.

Methods—

We identified all patients with multifocal segmental narrowing of large intracranial arteries who had high-resolution vessel wall MRI and follow-up angiography at our institute over a 4-year period and performed a detailed chart review.

Results—

Three patients lacked arterial wall enhancement, and these all had reversal of arterial narrowing within 3 months. Four patients demonstrated arterial wall enhancement, and these had persistent or progressive arterial narrowing at a median follow-up of 17 months (range, 6–36 months) with final diagnoses of central nervous system vasculitis (3) and cocaine vasculopathy (1).

Conclusions—

Preliminary results suggest that high-resolution contrast-enhanced vessel wall MRI may enable differentiation between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis.