bluuebunny/crossref_metadata_2025 huggingface dataset:
Coactivation of different neurons within an isofrequency lamina of the inferior colliculus elicits enhanced auditory cortical activation
Authors: Calixto Roger , Lenarz Minoo , Neuheiser Anke , Scheper Verena , Lenarz Thomas , Lim Hubert H.
Published: May 2012

The phenomenal success of the cochlear implant (CI) is attributed to its ability to provide sufficient temporal and spectral cues for speech understanding. Unfortunately, the CI is ineffective for those without a functional auditory nerve or an implantable cochlea required for CI implementation. As an alternative, our group developed and implanted in deaf patients a new auditory midbrain implant (AMI) to stimulate the central nucleus of the inferior colliculus (ICC). Although the AMI can provide frequency cues, it appears to insufficiently transmit temporal cues for speech understanding. The three-dimensional ICC consists of two-dimensional isofrequency laminae. The single-shank AMI only stimulates one site in any given ICC lamina and does not exhibit enhanced activity (i.e., louder percepts or lower thresholds) for repeated pulses on the same site with intervals <2–5 ms, as occurs for CI pulse or acoustic click stimulation. This enhanced activation, related to short-term temporal integration, is important for tracking the rapid temporal fluctuations of a speech signal. Therefore, we investigated the effects of coactivation of different regions within an ICC lamina on primary auditory cortex activity in ketamine-anesthetized guinea pigs. Interestingly, our findings reveal an enhancement mechanism for integrating converging inputs from an ICC lamina on a fast scale (<6-ms window) that is compromised when stimulating just a single ICC location. Coactivation of two ICC regions also reduces the strong and long-term (>100 ms) suppressive effects induced by repeated stimulation of just a single location. Improving AMI performance may require at least two shanks implanted along the tonotopic gradient of the ICC that enables coactivation of multiple regions along an ICC lamina with the appropriate interstimulus delays.
Presynaptic modulation by somatostatin in the rat neostriatum is altered in a model of parkinsonism
Authors: López-Huerta Violeta G. , Blanco-Hernández Eduardo , Bargas José , Galarraga Elvira
Published: May 2012

Somatostatin (SST) is a peptide synthesized and released by a class of neostriatal local GABAergic interneurons, which, to some extent, are in charge of the feedforward inhibitory circuit. Spiny projection neurons (SPNs) make synapses with each other via their local axon collaterals, shaping the feedback inhibitory circuit. Both inhibitory circuits, feedforward and feedback, are related through SST, which, being released by interneurons, presynaptically inhibits connections among SPNs. Here, we studied SST presynaptic modulation of synapses among SPNs in the 6-hydroxydopamine (6-OHDA) rodent model of parkinsonism. We performed antidromic field stimulation from the external globus pallidus and whole cell voltage-clamp recordings of antidromically evoked inhibitory postsynaptic currents (IPSCs) among SPNs. SST presynaptically reduced IPSCs by ∼34% in all control synapses tested. However, after striatal dopamine deprivation, three changes became evident. First, it was harder to evoke feedback inhibition. Second, presynaptic inhibition of some SPNs connections was larger than in controls: 57% reduction in ∼53% of evoked IPSCs. Presynaptic inhibition was recorded from direct pathway neurons (direct SPNs). Finally, SST also induced presynaptic facilitation in some SPNs connections, with 82% enhancement in ∼43% of evoked IPSCs. Presynaptic facilitation was recorded from indirect pathway neurons (indirect SPNs). Both inhibition and facilitation were accompanied by corresponding changes in the paired pulse ratio. It was demonstrated that after dopamine deprivation, SST modulation is altered in surviving feedback inhibitory synapses. It may underlie a homeostatic mechanism trying to compensate for the excitability imbalance between direct and indirect basal ganglia pathways found during parkinsonism.
Sensory reweighting of proprioceptive information of the left and right leg during human balance control
Authors: Pasma J. H. , Boonstra T. A. , Campfens S. F. , Schouten A. C. , Van der Kooij H.
Published: May 2012

To keep balance, information from different sensory systems is integrated to generate corrective torques. Current literature suggests that this information is combined according to the sensory reweighting hypothesis, i.e., more reliable information is weighted more strongly than less reliable information. In this approach, no distinction has been made between the contributions of both legs. In this study, we investigated how proprioceptive information from both legs is combined to maintain upright stance. Healthy subjects maintained balance with eyes closed while proprioceptive information of each leg was perturbed independently by continuous rotations of the support surfaces (SS) and the human body by platform translation. Two conditions were tested: perturbation amplitude of one SS was increased over trials while the other SS 1) did not move or 2) was perturbed with constant amplitude. With the use of system identification techniques, the response of the ankle torques to the perturbation amplitudes (i.e., the torque sensitivity functions) was determined and how much each leg contributed to stabilize stance (i.e., stabilizing mechanisms) was estimated. Increased amplitude of one SS resulted in a decreased torque sensitivity. The torque sensitivity to the constant perturbed SS showed no significant differences. The properties of the stabilizing mechanisms remained constant during perturbations of each SS. This study demonstrates that proprioceptive information from each leg is weighted independently and that the weight decreases with perturbation amplitude. Weighting of proprioceptive information of one leg has no influence on the weight of the proprioceptive information of the other leg. According to the sensory reweighting hypothesis, vestibular information must be up-weighted, because closing the eyes eliminates visual information.
Serum Insulin-Like Growth Factor-1 Levels Predict Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy
Authors: Shao Yu-Yun , Huang Chien-Chung , Lin Shiou-Der , Hsu Chih-Hung , Cheng Ann-Lii
Published: May 2012

Purpose: Patients with liver cirrhosis or hepatocellular carcinoma (HCC) have decreased serum insulin-like growth factor (IGF)-1 levels. We evaluated whether IGF-1 levels were associated with the outcomes of patients with advanced HCC treated with systemic antiangiogenic therapy.

Experimental Design: The study was based on patients with advanced HCC who were enrolled in two clinical trials evaluating first-line combination antiangiogenic therapy. Serum samples were collected before treatment and four to six weeks after the start of treatment. The levels of IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP3) were analyzed for their associations with treatment outcomes.

Results: A total of 83 patients were included in the study. Patients who had high (≥the median level) baseline IGF-1 levels had significantly higher disease control rate (DCR) than patients who had low (<the median level) levels (71% vs. 39%, P = 0.003). The levels of posttreatment IGF-1, and pre- or posttreatment IGF-2 and IGFBP3 were not associated with DCR. Patients with high baseline IGF-1 levels, compared with patients with low levels, had significantly longer progression-free survival (PFS; median, 4.3 vs. 1.9 months, P = 0.014) and overall survival (OS; median, 10.7 vs. 3.9 months, P = 0.009). The high baseline IGF-1 level remains an independent factor associated with favorable PFS and OS in multivariate analysis.

Conclusions: High pretreatment IGF-1 levels were associated with better DCR, PFS, and OS of patients who received antiangiogenic therapy for advanced HCC. This finding warrants validation in large studies. Clin Cancer Res; 18(14); 3992–7. ©2012 AACR.
Molecular Mechanisms Involved in the Synergistic Interaction of the EZH2 Inhibitor 3-Deazaneplanocin A with Gemcitabine in Pancreatic Cancer Cells
Authors: Avan Amir , Crea Francesco , Paolicchi Elisa , Funel Niccola , Galvani Elena , Marquez Victor E , Honeywell Richard J. , Danesi Romano , Peters Godefridus J. , Giovannetti Elisa
Published: May 2012

Pancreatic ductal adenocarcinoma (PDAC) is characterized by overexpression of enhancer of Zeste homolog-2 (EZH2), which plays a pivotal role in cancer stem cell (CSC) self-renewal through methylation of histone H3 lysine-27 (H3K27me3). Against this background, EZH2 was identified as an attractive target, and we investigated the interaction of the EZH2 inhibitor DZNeP with gemcitabine. EZH2 expression was detected by quantitative PCR in 15 PDAC cells, including seven primary cell cultures, showing that expression values correlated with their originator tumors (Spearman R2 = 0.89, P = 0.01). EZH2 expression in cancer cells was significantly higher than in normal ductal pancreatic cells and fibroblasts. The 3-deazaneplanocin A (DZNeP; 5 μmol/L, 72-hour exposure) modulated EZH2 and H3K27me3 protein expression and synergistically enhanced the antiproliferative activity of gemcitabine, with combination index values of 0.2 (PANC-1), 0.3 (MIA-PaCa-2), and 0.7 (LPC006). The drug combination reduced the percentages of cells in G2–M phase (e.g., from 27% to 19% in PANC-1, P < 0.05) and significantly increased apoptosis compared with gemcitabine alone. Moreover, DZNeP enhanced the mRNA and protein expression of the nucleoside transporters hENT1/hCNT1, possibly because of the significant reduction of deoxynucleotide content (e.g., 25% reduction of deoxycytidine nucleotides in PANC-1), as detected by liquid chromatography/tandem mass spectrometry. DZNeP decreased cell migration, which was additionally reduced by DZNeP/gemcitabine combination (–20% in LPC006, after 8-hour exposure, P < 0.05) and associated with increased E-cadherin mRNA and protein expression. Furthermore, DZNeP and DZNeP/gemcitabine combination significantly reduced the volume of PDAC spheroids growing in CSC-selective medium and decreased the proportion of CD133+ cells. All these molecular mechanisms underlying the synergism of DZNeP/gemcitabine combination support further studies on this novel therapeutic approach for treatment of PDACs. Mol Cancer Ther; 11(8); 1735–46. ©2012 AACR.
Human ESC Self-renewal Promoting microRNAs Induce Epithelial–Mesenchymal Transition in Hepatocytes by Controlling the PTEN and TGFβ Tumor Suppressor Signaling Pathways
Authors: Jung Christine J. , Iyengar Sushma , Blahnik Kimberly R. , Jiang Joy X. , Tahimic Candice , Torok Natalie J. , de vere White Ralph W. , Farnham Peggy J. , Zern Mark
Published: May 2012

The self-renewal capacity ascribed to embryonic stem cells (ESC) is reminiscent of cancer cell proliferation, raising speculation that a common network of genes may regulate these traits. A search for general regulators of these traits yielded a set of microRNAs for which expression is highly enriched in human ESCs and liver cancer cells (HCC) but attenuated in differentiated quiescent hepatocytes. Here, we show that these microRNAs promote hESC self-renewal, as well as HCC proliferation, and when overexpressed in normally quiescent hepatocytes, induce proliferation and activate cancer signaling pathways. Proliferation in hepatocytes is mediated through translational repression of Pten, Tgfbr2, Klf11, and Cdkn1a, which collectively dysregulates the PI3K/AKT/mTOR and TGFβ tumor suppressor signaling pathways. Furthermore, aberrant expression of these miRNAs is observed in human liver tumor tissues and induces epithelial–mesenchymal transition in hepatocytes. These findings suggest that microRNAs that are essential in normal development as promoters of ESC self-renewal are frequently upregulated in human liver tumors and harbor neoplastic transformation potential when they escape silencing in quiescent human hepatocytes. Mol Cancer Res; 10(7); 979–91. ©2012 AACR.
Insight and Awareness as Related to Psychopathology and Cognition
Authors: Trevisi Manuela , Talamo Alessandra , Bandinelli Pier Luca , Ducci Giuseppe , Kotzalidis Giorgio D. , Santucci Chiara , Manfredi Giovanni , Girardi Nicoletta , Tatarelli Roberto
Published: May 2012

Background: Insight affects adherence and treatment outcome and relates to cognitive impairment and psychopathology. We investigated the relationship of insight with cognition in patients with major depression, schizophrenia and bipolar disorder in acute psychiatric care, long-term inpatient, and outpatient settings. Methods: Eighty-one patients (women, 59.5%; age, 45.9 ± 13.5 years; 27 in each setting group; 33.3% with DSM-IV bipolar disorder, 39.5% with unipolar major depression, and 27.2% with schizophrenia) underwent the Wisconsin Card Sorting Test (WCST) to test flexibility, clinician-rated Scale to Assess Unawareness of Mental Disorder (SUMD), and self-rated Insight Scale (IS) to assess insight/awareness. Results: Poor performance on the WCST correlated with higher SUMD scores such as current psychiatric illness unawareness, impaired symptom attribution, unawareness of medication effect, or of social consequences, but not with IS scores. The latter correlated with days on continuous treatment. Patients receiving psycho-education showed greater symptom awareness compared to patients treated with drugs alone. Cognitive flexibility and diagnostic category did not correlate. Poor insight corresponded with severe mental illness, particularly acute psychosis. Conclusions: Treatment setting specificity reflects psychopathology and severity. Insight is inversely proportional to illness severity and cognitive flexibility, which is also affected by psychopathology. Limitations comprise group heterogeneity, cross-sectional design, and limited sample size.
Are Names of Children with Attention Deficit Hyperactivity Disorder More ‘Hyperactive’?
Authors: Shoval Gal , Manor Iris , Nahshoni Eitan , Weizman Abraham , Zalsman Gil
Published: May 2012

Background: The role of the meaning of given names has been noted in psychotherapy as well as in everyday life. This study aimed to investigate the possible association between the nature of given names of children and attention deficit hyperactivity disorder (ADHD) diagnosis. Sampling and Methods: A total of 134 given names of children and adolescent patients diagnosed as having ADHD were compared with those of an age- and gender-matched randomly chosen control group from the general population. The first names of the two cohorts were compared with regard to the following: the literal meaning of their names, whether the name constitutes a verb, the prevalence of each name and their length (number of syllables). Results: The meaning of first names of children and adolescents with ADHD combined type were rated by referees as expressing significantly more activity and containing less syllables than the names of controls. In addition, the prevalence of their names was significantly lower than that of names used in the general population. All findings remained significant following Bonferroni adjustment. Conclusions: Our findings demonstrate an intriguing relationship between children’s given names and ADHD diagnosis. Given names may serve as a possible predictor of later diagnosis of ADHD. Clinicians should be more attentive to given names in the context of child psychiatric evaluation and therapy.
Depression and Suicidal Ideation in College Students
Authors: Farabaugh Amy , Bitran Stella , Nyer Maren , Holt Daphne J. , Pedrelli Paola , Shyu Irene , Hollon Steven D. , Zisook Sidney , Baer Lee , Busse Wilma , Petersen Timothy J. , Pender Maribeth , Tucker Dorothy D. , Fava Maurizio
Published: May 2012

Background/Aims: Suicide is one of the leading causes of death in college students and is often associated with depression. The aim of this study was to assess the rates of suicidal ideation (SI) on college campuses and to identify its correlates. Methods: On-campus depression screening sessions were conducted at 3 universities (n = 898; 55% female; mean age 20.07 ± 1.85 years). Participants completed the Beck Depression Inventory (BDI; mean ± SD of total score = 6.27 ± 6.31) and other measures. Eighty-four students endorsed a ‘1’ on the BDI suicidality item, suggesting thoughts of suicide. Results: Results showed that students with greater depression severity, higher levels of hopelessness, and poorer quality of life were more likely to endorse SI. Conclusion: Factors associated with SI highlighted in this study may aid in the identification of college students at risk for suicide.
Epistemology of Psychiatry
Authors: Marková Ivana S. , Berrios German E.
Published: May 2012

In historical and epistemological terms, psychiatry is a new discipline born during the 19th century. Rooted in both the natural and social sciences, psychiatric objects of inquiry, namely mental symptoms and mental disorders, are hybrid, constituted by the blending of components arising from disparate sources of knowledge ranging from the biological to the semantic in its widest sense. This poses problems for psychiatric research and therapy. Whilst conventional pluralism may be a convenient approach to manage aspects of psychiatric practice, it lacks the capacity to analyse psychiatric objects in their entirety. For the latter, psychiatry demands a new, tailored regional epistemology. This paper outlines the main features of an epistemology specific to the needs of psychiatry. It highlights the relational approach that needs to be taken and illustrates the usefulness of this approach by analysing the structure of psychiatric objects, exploring the manner in which they may be inscribed in the brain, and identifying the need to periodically recalibrate the language of psychiatry.
Chemotherapy-Related Thrombocytosis: Does It Increase the Risk of Thromboembolism?
Authors: Ahmed S. , Shahid R.K. , Bhatt H. , Lee-Ying R. , Lim J.
Published: May 2012

Objectives: Chemotherapy increases the risk of thromboembolism in patients with cancer. Although thrombocytopenia is a known side effect of chemotherapy, reactive thrombocytosis related to chemotherapy is uncommonly reported. The present study aimed to determine the incidence of gemcitabine-related thrombocytosis and the associated risk of thromboembolism. Methods: Medical records of 250 consecutive patients with a malignant disease who received gemcitabine-based therapy were reviewed. A multivariate analysis was done to determine factors associated with thromboembolism. Results: A total of 220 eligible patients with a median age of 63 years (range 26–83) were identified. Of these 220 patients, 95% had advanced malignancy and 59% had received prior chemotherapy. A total of 69% of patients received a platinum combination. In all, 46% patients experienced thrombocytosis following chemotherapy, with a median platelet count of 632 × 109/l (range 457–1,385). Twenty-three of the 220 patients experienced a vascular event within 6 weeks of treatment. Eleven patients with thrombocytosis experienced a vascular event compared with 10 patients without thrombocytosis (not significant). On multivariate analysis, leukocytosis (odds ratio 5.8, 95% confidence interval 2.1–15.8) and comorbid illnesses (odds ratio 4.1, 95% confidence interval 1.4–12.6) were correlated with thromboembolism. Conclusions: Although gemcitabine-based therapy has been associated with an increased incidence of thrombocytosis, it does not increase the risk of thromboembolism in cancer patients. Leukocytosis and comorbid illnesses do increase the risk of thromboembolism.
Impaired Performance of Female APP/PS1 Mice in the Morris Water Maze Is Coupled with Increased Aβ Accumulation and Microglial Activation
Authors: Gallagher J.J. , Minogue A.M. , Lynch M.A.
Published: May 2012

Background: Alzheimer’s disease (AD) is characterized by progressive neuronal loss and cognitive decline. Epidemiological studies suggest that the risk of AD is higher in women even when data are adjusted for age. Objective: We set out to compare changes in 9-month-old male and female mice which overexpress amyloid precursor protein (APP) with presenilin (PS1; APP/PS1 mice) and to evaluate whether any changes were coupled with deficits in spatial learning. Methods: APP/PS1 mice were assessed for their ability to learn in the Morris water maze and Aβ burden assessed by Congo Red and Aβ triple ultrasensitive assay. Neuroinflammatory changes were examined in brain tissue along with expression of Aβ-generating and Aβ-degrading enzymes. Results: A deficit in reversal phase learning in the Morris water maze was observed in female mice and was paralleled by evidence of increased accumulation of Aβ, microglial activation and expression of IL-1β. Accumulation of Aβ was coupled with an increase in expression of BACE-1 and a decrease in insulin-degrading enzyme (IDE). Conclusion: The results indicate that the observed impairment in spatial memory in female APP/PS1 mice correlated with increased Aβ burden and the changes in Aβ may have occurred as a result of enhanced BACE-1 and decreased IDE expression.
The Most Negatively Charged Low-Density Lipoprotein L5 Induces Stress Pathways in Vascular Endothelial Cells
Authors: Chen Ching-Yi , Hsu Hsiu-Ching , Lee An-Sheng , Tang Daming , Chow Lu-Ping , Yang Chao-Yuh , Chen Han , Lee Yuan-Teh , Chen Chu-Huang
Published: May 2012

Background/Aims: L5, the most negatively charged species of low-density lipoprotein (LDL), has been implicated in atherogenesis by inducing apoptosis of endothelial cells (ECs) and inhibiting the differentiation of endothelial progenitor cells. In this study, we compared the effects of LDL charge on cellular stress pathways leading to atherogenesis. Methods: We isolated L5 and L1 (the least negatively charged LDL) from the plasma of patients with familial hypercholesterolemia and used JC-1 staining to examine the effects of L5 and L1 on the mitochondrial membrane potential (DCm) in human umbilical vein ECs (HUVECs). Additionally, we characterized the gene expression profiles of 7 proteins involved in various types of cellular stress. Results: The DCm was severely compromised in HUVECs treated with L5. Furthermore, compared with L1, L5 induced a decrease in mRNA and protein expression of the endoplasmic reticulum (ER) chaperone proteins ORP150, Grp94, and Grp58, mitochondrial proteins Prdx3 and ATP synthase, and an increase in the expression of the pro-inflammatory protein hnRNP C1/C2. Conclusions: Our work suggests that L5, but not L1, may promote the destruction of ECs that occurs during atherogenesis by causing mitochondrial dysfunction and modulating the expression of key proteins to promote inflammation, ER dysfunction, oxidative stress, and apoptosis.
Primary Mixed Glial Cultures from Fetal Ovine Forebrain Are a Valid Model of Inflammation-Mediated White Matter Injury
Authors: Weaver-Mikaere Luke , Gibbons Hannah M. , De Silva Devaki , Fraser Mhoyra
Published: May 2012

Astrocytes, microglial cells and oligodendrocytes (OLs) have been employed separately in vitro to assess cellular pathways following a variety of stimuli. Mixed glial cell cultures, however, have not been utilized to the same extent, despite the observed discrepancy in outcomes resulting from cell-to-cell contact of different glia in culture. Our objective was to standardize and morphologically characterize a primary culture of preterm ovine glial cells in order to attain a relevant in vitro model to assess the intracellular effects of infection and inflammation. This would provide a high-throughput model necessary for in-depth studies on the various pathophysiological mechanisms of white matter injury (WMI), which may occur in the preterm infant as a consequence of maternal infection or the fetal inflammatory response. Glial cells from the forebrains of 0.65-gestation ovine fetuses (comparable to 24- to 26-week human fetal brain development) were mechanically and enzymatically isolated and plated at a final density of 250,000 cells per well. When reaching confluence at 5 days after plating, the cultures contained astrocytes, microglial cells, as well as progenitor, precursor and immature OLs. Glial cell morphology and phenotypic immunoreactivity were characteristic of and consistent with previous observations of separately cultured cell types. To determine the effects of infection or inflammation in our in vitro model, we then treated mixed glial cultures with tumour necrosis factor-α (TNF-α; 50 or 100 ng/ml) or lipopolysaccharide (LPS; 1 µg/ml) for a period of 48 h. Cytokine levels were measured by ELISA and cell numbers for specific glial cell types were determined along with OL proliferation and apoptosis by Ki67 and caspase-3 immunocytochemistry, respectively. Our results showed that exposure to TNF-α or LPS resulted in a characteristic inflammatory response entailed by up-regulation of pro-inflammatory cytokines, a lack of astrogliosis and a marked reduction in OLs attributable to increased apoptosis. In LPS-treated cultures, there was a marked increase in the pro-inflammatory cytokine TNF-α at both 24 and 48 h. In conclusion, this is the first report of the immunocytochemical description and characterization of fetal ovine-derived mixed glial cell primary cultures. This in vitro model provides a novel and efficient system to explore the mechanisms of infection/inflammation-mediated WMI at the cellular level and for screening candidate therapeutic strategies.
Renal Evaluation in Women with Preeclampsia
Authors: Facca T.A. , Mastroianni Kirsztajn G. , Pereira A.R. , Moreira S.R. , Teixeira V.P.C. , Nishida S.K. , Sass N.
Published: May 2012

Background/Aims: Preeclampsia (PE) is a cause of glomerulopathy worldwide. Urinary retinol-binding protein (RBP) is a marker of proximal tubular dysfunction, albuminuria is an endothelial injury marker, urine protein:creatinine ratio (PCR) may have a predictive value for renal disease later in life, and, recently, podocyturia has been proposed as a sensitive tool in pregnancy, but it needs to be tested. The aim of this study was to evaluate renal involvement in PE and healthy pregnancy. Methods: Case-control study with 39 pregnant women assessed after 20 weeks of gestation (25 in the control group, CG, and 14 in the PE group) by performing urinary tests. Results: Mean (±SD) age and gestational age of the CG were 26.9 ± 6.4 years and 37.1 ± 5.0 weeks, and of the PE group 26.4 ± 6.9 years and 30.6 ± 5.6 weeks, respectively (p = 0.001). Mean (±SD) urinary RBP (p = 0.017), albuminuria (p = 0.002), and urinary albumin concentration (UAC) ratio (p = 0.006) of the CG were 0.4 ± 0.7 mg/l, 7.3 ± 6.9 mg/l, and 8.2 ± 6.7 mg/g and of the PE group 2.0 ± 4.4 mg/l, 2,267.4 ± 2,130.8 mg/l (p = 0.002), and 3,778.9 ± 4,296.6 mg/g (p = 0.006), respectively. Mean (±SD) urine PCR in the PE group was 6.7 ± 6.1 g/g (p < 0.001). No statistical differences were found between podocyturia in the CG and PE group (p = 0.258). Conclusions: Urinary RBP, PCR, albuminuria, and UAC ratio were elevated in the PE group in comparison to the CG. Podocyturia did not predict PE.
Predicting Torsade de Pointes in Acquired Long QT Syndrome: Optimal Identification of Critical QT Interval Prolongation
Authors: Chiladakis John , Kalogeropoulos Andreas , Zagkli Fani , Koutsogiannis Nikolaos , Chouchoulis Konstantinos , Alexopoulos Dimitrios
Published: May 2012

Objectives: To determine the optimal method of ventricular repolarization assessment in predicting torsade de pointes (Tdp) in acquired long QT syndrome (LQTS) within the context of the recommended cutoff levels of concern for QT/corrected QT (QTc) interval prolongation. Methods: Twenty-nine patients with LQTS and Tdp (age 66 ± 11 years) and matched controls were studied. Standard 12-lead electrocardiograms were utilized to evaluate ventricular repolarization by using six different QT/JT heart rate correction methods. We compared the distribution of QT/QTc and JT/corrected JT intervals of patients who experienced Tdp with (1) the corresponding intervals in the matched controls and (2) the recommended cutoff levels for QT/JT interval prolongation. Results: Patients with Tdp (23 with narrow QRS, 6 with wide QRS) had longer ventricular repolarization intervals than controls (p < 0.001). For patients with narrow QRS, the QTc interval as determined firstly by the method of Hodges (t = 7.56, c = 0.933, p < 0.001), followed by the Nomogram and Fridericia methods, best discriminated Tdp patients from controls and provided the optimal balance between sensitivity and specificity at all three cutoff levels. For patients with wide QRS, the JT interval or, alternatively, the Hodges method seemed most useful. Conclusions: Assessment of ventricular repolarization by the Hodges, Nomogram and Fridericia methods performs best in identifying subsequent Tdp.
Electrode Migration in Cochlear Implant Patients: Not an Exception
Authors: van der Marel Kim S. , Verbist Berit M. , Briaire Jeroen J. , Joemai Raoul M.S. , Frijns Johan H.M.
Published: May 2012

Objective: It was the aim of this study to investigate the occurrence of electrode migration of a cochlear implant in patients with and without complaints. Methods: We performed a retrospective case review in a tertiary referral center. The electrode position was evaluated in 35 cochlear implantees, 16 with a CII HiFocus1 (non-positioner) and 19 with a HiRes90K HiFocus1J, using multiplanar reconstructions of the postoperative CT scans. Of 5 patients, a second scan was obtained to evaluate complaints of performance drop, vertigo, tinnitus, headache or nonauditory stimulation. Displacements of the electrode contacts were calculated and displacements of >1 mm were considered a migration. The possible correlation with implant type, insertion depth or presence of complaints was analyzed. Results: Migrations were detected in 10 patients (29%). There was a significant effect of the implant type in favour of the HiFocus1, but no relation with the original insertion depth of the device. In the 5 patients scanned because of complaints, two migrations were detected. Conclusions: In our patient population, electrode migration was not uncommon and turned out to occur in patients with and without complaints.
Genome Size Evolution: Sizing Mammalian Genomes
Authors: Redi C.A. , Capanna E.
Published: May 2012

The study of genome size (GS) and its variation is so fascinating to the scientific community because it constitutes the link between the present-day analytical and molecular studies of the genome and the old trunk of the holistic and synthetic view of the genome. The GS of several taxa vary over a broad range and do not correlate with the complexity of the organisms (the C-value paradox). However, the biology of transposable elements has let us reach a satisfactory view of the molecular mechanisms that give rise to GS variation and novelties, providing a less perplexing view of the significance of the GS (C-enigma). The knowledge of the composition and structure of a genome is a pre-requisite for trying to understand the evolution of the main genome signature: its size. The radiation of mammals provides an approximately 180-million-year test case for theories of how GS evolves. It has been found from data-mining GS databases that GS is a useful cyto-taxonomical instrument at the level of orders/superorders, providing genomic signatures characterizing Monotremata, Marsupialia, Afrotheria, Xenarthra, Laurasiatheria, and Euarchontoglires. A hypothetical ancestral mammalian-like GS of 2.9–3.7 pg has been suggested. This value appears compatible with the average values calculated for the high systematic levels of the extant Monotremata (∼2.97 pg) and Marsupialia (∼4.07 pg), suggesting invasion of mobile DNA elements concurrently with the separation of the older clades of Afrotheria (∼5.5 pg) and Xenarthra (∼4.5 pg) with larger GS, leaving the Euarchontoglires (∼3.4 pg) and Laurasiatheria (∼2.8 pg) genomes with fewer transposable elements. However, the paucity of GS data (546 mammalian species sized from 5,488 living species) for species, genera, and families calls for caution. Considering that mammalian species may be vanished even before they are known, GS data are sorely needed to phenotype the effects brought about by their variation and to validate any hypotheses on GS evolution in mammals.
Implication of Bony Cochlear Nerve Canal on Hearing in Patients with Congenital Unilateral Sensorineural Hearing Loss
Authors: Jang Jeong Hun , Kim Ji-Hoon , Yoo Jae Chul , Kim Chang-Hee , Kim Min Soo , Chang Sun O , Oh Seung Ha , Lee Jun Ho
Published: May 2012

This study was designed to evaluate the dimensions of the bony cochlear nerve canal (BCNC) in congenital unilateral sensorineural hearing loss (USNHL) patients with normal inner ears, and to analyze the correlation between BCNC and hearing status. Medical records and temporal bone computed tomography (TBCT) findings of 380 patients who visited Seoul National University Hospital between January 1999 and December 2007 were reviewed retrospectively. The length and width of the BCNC at the fundus of the internal auditory canal were measured in millimeters based on the axial view of TBCT for three ear groups: normal inner ears of control group subjects (group A, 179 ears), normal inner ears on the contralateral side of USNHL patients (group B, 201 ears), and the affected inner ears in USNHL (group C, 201 ears). The mean values of length and width in group C (0.79 ± 0.36 and 1.58 ± 0.83 mm, respectively) were significantly smaller than those in group A (1.07 ± 0.10 and 2.38 ± 0.28 mm, respectively; p < 0.001) and group B (1.04 ± 0.23 and 2.33 ± 0.39 mm, respectively; p < 0.001). The receiver operating characteristic curves for BCNC were conducted to estimate the cutoff values from which the proportions of profound hearing loss increased, compared to those of mild to severe hearing loss. The areas under the curve were 0.487 ± 0.044 (p = 0.781) and 0.622 ± 0.041 (p = 0.011) for length and width, respectively. The cutoff value of width with a sensitivity of 90% for profound USNHL was 1.16 mm in otherwise normal inner ears. Clinicians would be recommended to take a close look at BCNC as one of the possible causes of hearing loss in otherwise normal inner ears of USNHL on TBCT.
Pharmacokinetic and Pharmacodynamic Effects of Elinogrel
Authors: Angiolillo Dominick J. , Welsh Robert C. , Trenk Dietmar , Neumann Franz-Josef , Conley Pamela B. , McClure Matthew W. , Stephens Gillian , Kochman Janusz , Jennings Lisa K. , Gurbel Paul A. , Wójcik Jarosław , Dabrowski Marek , Saucedo Jorge F. , Stumpf Juergen , Buerke Michael , Broderick Samuel , Harrington Robert A. , Rao Sunil V.
Published: May 2012

Background—

Elinogrel is the only selective, competitive and reversible platelet P2Y
12
inhibitor available in both intravenous (IV) and oral formulations.

Methods and Results—

This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300–600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens.

Conclusions—

Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00751231.
Noise-Free Visualization of Microscopic Calcium Signaling by Pixel-Wise Fitting
Authors: Tian Qinghai , Kaestner Lars , Lipp Peter
Published: May 2012

Rationale:

Our insights into physiological and pathophysiological cardiac excitation-contraction coupling has greatly benefited from significant advancement in optical technologies such as high-speed confocal microscopy. This has pushed pixel dwell times into the time domain of nanoseconds, resulting in low signal-to-noise ratios, which have limited data analysis and interpretation.

Objective:

Line scan imaging has been and still is dominant in high speed confocal recording. It allows analysis only of a small fraction of a cell's cross section (1.5%), but the appreciation of spatiotemporal fine details of excitation-contraction coupling is instrumental for the further understanding of pathological mechanisms. We aim to provide a novel analysis tool to extract otherwise hidden fine details in cardiac excitation-contraction coupling from high-speed 2-dimensional confocal image series.

Methods and Results:

We demonstrate that high-speed 2-dimensional confocal data (150 frames/s) can be analyzed quantitatively by a pixel-wise fitting approach, using a mathematical formalism to phenomenologically describe local calcium transients. Such an approach produces virtually noise-free fluorescence data originating from minute volumes (0.025 femtoliter) and allows extraction of detailed and most importantly quantitative and mechanistically novel information on microscopic calcium signaling and excitation-contraction coupling in a robust manner.

Conclusions:

Pixel-wise fitting provides novel insights into cardiac excitation-contraction coupling. Specifically, it revealed microscopic calcium alternans on the level of individual coupling sites. Microscopic calcium alternans is an early precursor of cellular alternans and as such will shed more light onto this mechanism leading to cardiac arrhythmia.
Association Between Family History and Coronary Heart Disease Death Across Long-Term Follow-Up in Men
Authors: Bachmann Justin M. , Willis Benjamin L. , Ayers Colby R. , Khera Amit , Berry Jarett D.
Published: May 2012

Background—

Family history of coronary heart disease (CHD) has been well studied as an independent risk factor for CHD events in the short term (<10 years). However, data are sparse on the association between family history and risk for CHD across long-term follow-up.

Methods and Results—

We included 49 255 men from the Cooper Center Longitudinal Study. Premature family history of CHD was defined as the presence of angina, myocardial infarction, angioplasty, or bypass surgery in a relative <50 years of age. Cause-specific mortality was obtained from the National Death Index. The association between premature family history and cardiovascular disease (CVD) or CHD death was compared across 3 unique follow-up periods (0–10, >10–20, and >20 years). Lifetime risk was estimated by use of a modified survival analytic technique adjusted for competing risk with non-CVD death as the competing event. After 811 708 person-years of follow-up, there were 919 CHD deaths and 1456 CVD deaths. After adjustment for traditional risk factors, premature family history was associated with CHD mortality >10 to 20 years (1.59; 95% confidence interval, 1.14–2.22) and >20 years (1.43; 95% confidence interval, 1.05–1.95) with wider confidence intervals at 0 to 10 years (1.32; 95% confidence interval, 0.76–2.31). Similar findings were observed for CVD mortality. Compared with men without a family history of coronary artery disease, premature family history was associated with an ≈50% higher lifetime risk for both CHD and CVD mortality (13.7% versus 8.9% and 21% versus 14.1%, respectively).

Conclusion—

Premature family history was associated with a persistent increase in both CHD and CVD mortality risk across long-term follow-up, resulting in significantly higher lifetime risk estimates.
High-Sensitivity Cardiac Troponin in the Distinction of Acute Myocardial Infarction From Acute Cardiac Noncoronary Artery Disease
Authors: Haaf Philip , Drexler Beatrice , Reichlin Tobias , Twerenbold Raphael , Reiter Miriam , Meissner Julia , Schaub Nora , Stelzig Claudia , Freese Michael , Heinzelmann Amely , Meune Christophe , Balmelli Cathrin , Freidank Heike , Winkler Katrin , Denhaerynck Kris , Hochholzer Willibald , Osswald Stefan , Mueller Christian
Published: May 2012

Background—

We hypothesized that high-sensitivity cardiac troponin (hs-cTn) and its early change are useful in distinguishing acute myocardial infarction (AMI) from acute cardiac noncoronary artery disease.

Methods and Results—

In a prospective, international multicenter study, hs-cTn was measured with 3 assays (hs-cTnT, Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI Siemens) in a blinded fashion at presentation and serially thereafter in 887 unselected patients with acute chest pain. Accuracy of the combination of presentation values with serial changes was compared against a final diagnosis adjudicated by 2 independent cardiologists. AMI was the adjudicated final diagnosis in 127 patients (15%); cardiac noncoronary artery disease, in 124 (14%). Patients with AMI had higher median presentation values of hs-cTnT (0.113 μg/L [interquartile range, 0.049–0.246 μg/L] versus 0.012 μg/L [interquartile range, 0.006–0.034 μg/L];
P
<0.001) and higher absolute changes in hs-cTnT in the first hour (0.019 μg/L [interquartile range, 0.007–0.067 μg/L] versus 0.001 μg/L [interquartile range, 0–0.003 μg/L];
P
<0.001) than patients with cardiac noncoronary artery disease. Similar findings were obtained with the hs-cTnI assays. Adding changes of hs-cTn in the first hour to its presentation value yielded a diagnostic accuracy for AMI as quantified by the area under the receiver-operating characteristics curve of 0.94 for hs-cTnT (0.92 for both hs-cTnI assays). Algorithms using ST-elevation, presentation values, and changes in hs-cTn in the first hour accurately separated patients with AMI and those with cardiac noncoronary artery disease. These findings were confirmed when the final diagnosis was readjudicated with the use of hs-cTnT values and validated in an independent validation cohort.

Conclusion—

The combined use of hs-cTn at presentation and its early absolute change excellently discriminates between patients with AMI and those with cardiac noncoronary artery disease.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00470587.
Cotton Mather and Boston's “Seafaring Tribe”
Authors: Pitt Steven J. J.
Published: May 2012

This essay tells the compelling story of Cotton Mather's struggle to ride the stormy waves of colonial Boston's rise as an Atlantic port by focusing his ministerial and intellectual energies on a growing and volatile seafaring population. Seafarers' reactions to his efforts produced a complex, at times paradoxical, relationship.
Beyond the “Halfway Covenant”: Church Membership, Extended Baptism, and Outreach in Cambridge, Massachusetts, 1656–1667
Authors: Gerbner Katharine
Published: May 2012

Jonathan Mitchel, minister of the Cambridge Church (1656–67), used the extension and liberalization of baptism in the 1650s and 60s–later denigrated as the halfway covenant–to bring the unchurched and their children into fellowship, thus indicating a strategy of reaching out to the community, not of appeasing a lapsing or fastidious second generation.
“Don't Speak to me, but Write on this”: The Childhood Almanacs of Mary and Katherine Byles
Authors: Eamon Michael J.
Published: May 2012

In mid-eighteenth-century Boston, Mather Byles Sr. gave almanacs to his daughters to use as diaries and commonplace books. This collection, now residing in Ottawa, offers a rare glimpse into the everyday musings of two colonial American girls and highlights the importance of annotated print, a frequently neglected historical source.
Cloud Simulations in Response to Turbulence Parameterizations in the GISS Model E GCM
Authors: Yao Mao-Sung , Cheng Ye
Published: May 2012

The response of cloud simulations to turbulence parameterizations is studied systematically using the GISS general circulation model (GCM) E2 employed in the Intergovernmental Panel on Climate Change’s (IPCC) Fifth Assessment Report (AR5). Without the turbulence parameterization, the relative humidity (RH) and the low cloud cover peak unrealistically close to the surface; with the dry convection or with only the local turbulence parameterization, these two quantities improve their vertical structures, but the vertical transport of water vapor is still weak in the planetary boundary layers (PBLs); with both local and nonlocal turbulence parameterizations, the RH and low cloud cover have better vertical structures in all latitudes due to more significant vertical transport of water vapor in the PBL. The study also compares the cloud and radiation climatologies obtained from an experiment using a newer version of turbulence parameterization being developed at GISS with those obtained from the AR5 version. This newer scheme differs from the AR5 version in computing nonlocal transports, turbulent length scale, and PBL height and shows significant improvements in cloud and radiation simulations, especially over the subtropical eastern oceans and the southern oceans. The diagnosed PBL heights appear to correlate well with the low cloud distribution over oceans. This suggests that a cloud-producing scheme needs to be constructed in a framework that also takes the turbulence into consideration.
Characteristics of Mesoscale Organization in WRF Simulations of Convection during TWP-ICE
Authors: Del Genio Anthony D. , Wu Jingbo , Chen Yonghua
Published: May 2012

Compared to satellite-derived heating profiles, the Goddard Institute for Space Studies general circulation model (GCM) convective heating is too deep and its stratiform upper-level heating is too weak. This deficiency highlights the need for GCMs to parameterize the mesoscale organization of convection. Cloud-resolving model simulations of convection near Darwin, Australia, in weak wind shear environments of different humidities are used to characterize mesoscale organization processes and to provide parameterization guidance. Downdraft cold pools appear to stimulate further deep convection both through their effect on eddy size and vertical velocity. Anomalously humid air surrounds updrafts, reducing the efficacy of entrainment. Recovery of cold pool properties to ambient conditions over 5–6 h proceeds differently over land and ocean. Over ocean increased surface fluxes restore the cold pool to prestorm conditions. Over land surface fluxes are suppressed in the cold pool region; temperature decreases and humidity increases, and both then remain nearly constant, while the undisturbed environment cools diurnally. The upper-troposphere stratiform rain region area lags convection by 5–6 h under humid active monsoon conditions but by only 1–2 h during drier break periods, suggesting that mesoscale organization is more readily sustained in a humid environment. Stratiform region hydrometeor mixing ratio lags convection by 0–2 h, suggesting that it is strongly influenced by detrainment from convective updrafts. Small stratiform region temperature anomalies suggest that a mesoscale updraft parameterization initialized with properties of buoyant detrained air and evolving to a balance between diabatic heating and adiabatic cooling might be a plausible approach for GCMs.