bluuebunny/crossref_metadata_2025 huggingface dataset:
New Strategies in Hodgkin Lymphoma: Better Risk Profiling and Novel Treatments
Authors: Diefenbach Catherine , Steidl Christian
Published: February 2013

Recent advances in Hodgkin lymphoma research are expected to prelude a promising new treatment era for patients and their treating physicians. Scientific investigations over the last few years have provided new insights into risk stratification, and, simultaneously, a plethora of novel targeted therapies are emerging for patients with relapsed and refractory disease. These novel therapies will be tested primarily in high-risk patients because 75% of the patients are cured with conventional therapies. The challenges, as Hodgkin lymphoma therapy moves forward, will be using these biologic insights to identify the patients who may benefit earlier in treatment from these novel agents, and tailoring the therapy to the tumor biology of the patient. These dual aims are intertwined; as our therapeutic arsenal increases, these biologic determinants of risk may themselves inform the design of therapies and the choice of treatments for high-risk patients. Clin Cancer Res; 19(11); 2797–803. ©2013 AACR.
Extracellular Signal–Regulated Kinase 5: A Potential Therapeutic Target for Malignant Mesotheliomas
Authors: Shukla Arti , Miller Jill M. , Cason Christopher , Sayan Mutlay , MacPherson Maximilian B. , Beuschel Stacie L. , Hillegass Jedd , Vacek Pamela M. , Pass Harvey I. , Mossman Brooke T.
Published: February 2013

Purpose: Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal–regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment.

Experimental Design: ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models.

Results: We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth.

Conclusion: ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma. Clin Cancer Res; 19(8); 2071–83. ©2013 AACR.
Targeting miR-21 InhibitsIn VitroandIn VivoMultiple Myeloma Cell Growth
Authors: Leone Emanuela , Morelli Eugenio , Di Martino Maria T. , Amodio Nicola , Foresta Umberto , Gullà Annamaria , Rossi Marco , Neri Antonino , Giordano Antonio , Munshi Nikhil C. , Anderson Kenneth C. , Tagliaferri Pierosandro , Tassone Pierfrancesco
Published: February 2013

Purpose: Deregulated expression of miRNAs plays a role in the pathogenesis and progression of multiple myeloma. Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of multiple myeloma.

Experimental Design: Here, we investigated the in vitro and in vivo anti-multiple myeloma activity of miR-21 inhibitors.

Results: Either transient-enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of primary patient multiple myeloma cells or interleukin-6–dependent/independent multiple myeloma cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of multiple myeloma cells, showing its tumor-promoting potential in multiple myeloma. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B, and BTG2), together with functional impairment of both AKT and extracellular signal–regulated kinase signaling, were achieved by transfection of miR-21 inhibitors into multiple myeloma cells. In vivo delivery of miR-21 inhibitors in severe combined immunodeficient mice bearing human multiple myeloma xenografts expressing miR-21induced significant antitumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors.

Conclusion: Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-multiple myeloma activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease. Clin Cancer Res; 19(8); 2096–106. ©2013 AACR.
Phase Ib Dose-Escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Progressive Multiple Myeloma
Authors: Niesvizky Ruben , Martin Thomas G. , Bensinger William I. , Alsina Melissa , Siegel David S. , Kunkel Lori A. , Wong Alvin F. , Lee Susan , Orlowski Robert Z. , Wang Michael
Published: February 2013

Purpose: Carfilzomib, a selective proteasome inhibitor, has shown safety and efficacy in relapsed and/or refractory multiple myeloma. This phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a phase II expansion study.

Experimental Design: Patients with multiple myeloma who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15 to 27 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly.

Results: Forty patients enrolled in six cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median duration of response and progression-free survival were 11.8 and 10.2 months, respectively.

Conclusion: The maximum planned CRd dose, carfilzomib 27 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg, was recommended for further study, with promising safety and efficacy. Clin Cancer Res; 19(8); 2248–56. ©2013 AACR.
Dual PI3K/AKT/mTOR Inhibitor BEZ235 Synergistically Enhances the Activity of JAK2 Inhibitor against Cultured and Primary Human Myeloproliferative Neoplasm Cells
Authors: Fiskus Warren , Verstovsek Srdan , Manshouri Taghi , Smith Jacqueline E. , Peth Karissa , Abhyankar Sunil , McGuirk Joseph , Bhalla Kapil N.
Published: February 2013

Hemopoietic progenitor cells (HPC) from myeloproliferative neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 cells, and primary CD34+ myelofibrosis (MF)-MPN cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs. Mol Cancer Ther; 12(5); 577–88. ©2013 AACR.
Tumor-Initiating Cells and FZD8 Play a Major Role in Drug Resistance in Triple-Negative Breast Cancer
Authors: Yin Shuping , Xu Liping , Bonfil R. Daniel , Banerjee Sanjeev , Sarkar Fazlul H. , Sethi Seema , Reddy Kaladhar B.
Published: February 2013

Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially conducted gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant increase in the expression of FZD8, one of Wnt receptors, and its downstream targets LEF1 and TCF in residual CRL2335 tumor cells after treatment with cisplatin plus TRAIL. Increased FZD8 levels were further confirmed in other TNBC cell lines. Inhibition of FZD8 by siRNA in CRL2335 cells in the presence of cisplatin plus TRAIL reduced β-catenin and survivin levels and increased apoptosis compared with scrambled siRNA–treated cells. In vivo data show that cisplatin plus TRAIL treatment significantly reduces tumor volume in NOD/SCID mice. However, we found that cisplatin plus TRAIL treatment predominantly eliminated non–tumor-initiating cells, as shown by whole-body fluorescent imaging of mice injected with mammosphere-forming CRL2335 cells stably transfected with DsRed. This led to TIC enrichment in residual tumors, as confirmed by immunostaining for TIC markers. Moreover, an increase in FZD8 expression was observed in residual tumors treated with cisplatin and TRAIL. Taken together, our findings suggest that FZD8-mediated Wnt signaling may play a major role in mediating resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBCs. Mol Cancer Ther; 12(4); 491–8. ©2013 AACR.
Postmortem Brain Levels of Urate and Precursors in Parkinson's Disease and Related Disorders
Authors: McFarland Nikolaus R. , Burdett Thomas , Desjardins Cody A. , Frosch Matthew P. , Schwarzschild Michael A.
Published: February 2013

Background: Increasing evidence suggests that urate may play an important role in neurodegenerative disease. In Parkinson's disease (PD) higher, but still normal, levels of blood and cerebrospinal fluid urate have been associated with a lower rate of disease progression. Objective: We explored the hypothesis that lower levels of urate and its purine precursors in brain may be associated with PD and related neurodegenerative disorders, including Alzheimer's disease (AD) and Lewy body dementia (DLB). Methods: Human postmortem brain tissues were obtained from PD, AD, and DLB patients and non-neurodegenerative disease controls. We measured urate and other purine pathway analytes in the frontal and temporal cortex, striatum, and cerebellum, using high-performance liquid chromatography with electrochemical and ultraviolet detection. Results: Age was well-matched among groups. Mean postmortem interval for samples was 16.3 ± 9.9 h. Urate levels in cortical and striatal tissue trended lower in PD and AD compared to controls in males only. These findings correlated with increased urate in male versus female control tissues. By contrast, in DLB urate levels were significantly elevated relative to PD and AD. Measurement of urate precursors suggested a decrease in xanthine in PD compared to AD in females only, and relative increases in inosine and adenosine in DLB and AD samples among males. Xanthine and hypoxanthine were more concentrated in striatal tissue than in other brain regions. Conclusions: Though limited in sample size, these findings lend support to the inverse association between urate levels and PD, as well as possibly AD. The finding of increased urate in DLB brain tissue is novel and warrants further study.
Distinguishing Subtypes in Primary Progressive Aphasia: Application of the Sydney Language Battery
Authors: Savage Sharon , Hsieh Sharpley , Leslie Felicity , Foxe David , Piguet Olivier , Hodges John R.
Published: February 2013

Background/Aims: Primary progressive aphasia (PPA) comprises three main subtypes, varying in clinical features, patterns of brain atrophy, and underlying pathology. Differentiation of these variants is important for treatment and planning; however, simple, effective cognitive tests to aid diagnosis are lacking. This study introduces a new language battery - the SYDBAT (Sydney Language Battery) - to assist clinicians. Methods: Fifty-seven PPA patients and 54 age- and education-matched healthy controls were compared on naming, repetition, word comprehension, and semantic association subtests. Results: Significant group differences were found for all tasks, reflecting different language profiles for each group. Using discriminative function analysis, 80% of PPA cases were correctly classified from three SYDBAT scores, from which a simple diagnostic algorithm was defined. Conclusion: The SYDBAT is a fast and simple tool which provides a valuable adjunct to clinicians diagnosing PPA.
Cytokine Secretion and Markers of Inflammation in Relation to Acidosis among Chronic Hemodialysis Patients
Authors: Ori Yaacov , Bergman Michael , Bessler Hanna , Zingerman Boris , Levy-Drummer Rachel S. , Gafter Uzi , Salman Hertzel
Published: February 2013

Background: Various cytokines are increased in hemodialysis (HD) patients, and are considered prognostic markers. Metabolic acidosis is common among chronic HD patients and is associated with survival. The relationship between acidosis and cytokines in HD patients has not been fully explored. The study aim was to measure pro- and anti-inflammatory cytokines in HD patients, with relation to bicarbonate levels. Methods: Forty-seven stable HD patients were included (male/female 28/19, mean age 70.4 ± 14.5 years). Blood tests were taken before a midweek dialysis session. Cytokine secretion from peripheral blood mononuclear cells was measured. Results: Acidosis versus no acidosis (serum HCO3- 21.5 ± 0.2 vs. 24.9 ± 0.3 mEq/l, p < 0.001) was associated with decreased secretion of the anti-inflammatory interleukin-10 (IL-10, 1.16 ± 0.11 vs. 1.71 ± 0.20 ng/ml, p = 0.023). Patients with acidosis had higher parathyroid hormone (PTH), calcium-phosphate product, protein intake and transferrin. Higher IL-10 was associated with increased IL-6 secretion, higher bicarbonate, younger age and lower PTH. Conclusions: In stable chronic HD patients, a possible direct relation exists between metabolic acidosis and IL-10.
Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON)
Authors: de Zeeuw Dick , Akizawa Tadao , Agarwal Rajiv , Audhya Paul , Bakris George L. , Chin Melanie , Krauth Melissa , Lambers Heerspink Hiddo J. , Meyer Colin J. , McMurray John J. , Parving Hans-Henrik , Pergola Pablo E. , Remuzzi Giuseppe , Toto Robert D. , Vaziri Nosratola D. , Wanner Christoph , Warnock David G. , Wittes Janet , Chertow Glenn M.
Published: February 2013

Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.
Transglutaminase 2 Accelerates Vascular Calcification in Chronic Kidney Disease
Authors: Chen Neal X. , O'Neill Kalisha , Chen Xianming , Kiattisunthorn Kraiwiporn , Gattone Vincent H. , Moe Sharon M.
Published: February 2013

Background: Transglutaminase 2 (TGM2) is a calcium-dependent enzyme that can cross-link nearly all extracellular matrix (ECM) proteins and can facilitate cell-ECM interaction through integrins. Given the importance of the ECM in vascular calcification we tested the hypothesis that increased TGM2 activity may accelerate vascular calcification in chronic kidney disease (CKD). Methods: We utilized thoracic aortas and vascular smooth muscle cells (VSMC) from the Cy/+ rat, a model of progressive CKD that develops arterial calcification on a normal phosphorus diet, compared to normal rats. Results: VSMC isolated from CKD rats had increased expression and activity of TGM2 compared to cells from normal rats. The increased calcification and expression of alkaline phosphatase activity observed in VSMC from CKD rats compared to normal was inhibited in a dose-dependent manner with the TGM inhibitors cystamine and Z006. Matrix vesicles (MV) from CKD rat VSMC also had increased TGM2 expression and the calcification of MV on type I collagen could be inhibited with cystamine and accelerated by exogenous cross-linking of fibronectin or type I collagen with TGM2. Finally, the calcification of aorta rings from CKD rats in ex vivo cultures was inhibited with TGM2 inhibitor. Conclusion: These data demonstrate a role of TGM2 in the pathogenesis of vascular calcification in CKD through enhancement of MV-ECM calcification.
Association between Milder Brain Deformation before a Shunt Operation and Improvement in Cognition and Gait in Idiopathic Normal Pressure Hydrocephalus
Authors: Yamamoto Daisuke , Kazui Hiroaki , Wada Tamiki , Nomura Keiko , Sugiyama Hiromichi , Shimizu Yoshiro , Yoshiyama Kenji , Yoshida Tetsuhiko , Kishima Haruhiko , Yamashita Fumio , Yoshimine Toshiki , Takeda Masatoshi
Published: February 2013

We investigated the association between the degree of deformation of the brain before shunt operation and improvement of gait and cognitive impairment after shunt operation in 16 patients with idiopathic normal pressure hydrocephalus (iNPH). We evaluated gait and cognitive impairment and measured the cerebrospinal fluid volume in the ventricles/sylvian fissure (vVS) and the subarachnoid space at high convexity/midline areas (vHCM) using MR images with voxel-based morphometry before and 3 months after shunt operation. We used the ratio of vVS to vHCM (vVS/vHCM) as an index of the severity of brain deformation. After shunt operation, improvements were observed in gait, as shown by the Timed Up and Go (TUG) test and 10-meter reciprocating walking test (WT), and in cognitive function, as shown by the Mini-Mental State Examination, Alzheimer Disease Assessment Scale, Frontal Assessment battery (FAB), and Trail Making test A (TMT-A). The vVS/vHCM ratio was negatively correlated with improvement of the FAB, TMT-A and TUG. Preoperative vVS/vHCM was not significantly correlated with preoperative clinical assessments. The rate of change of vVS/vHCM was positively correlated with improvement in the WT. The improvements of gait and cognitive function were larger in iNPH patients with milder deformation of the brain before shunt operation.
Evidence on the pathogenic role of auto-antibodies in acute cardiovascular diseases
Authors: Carbone Federico , Nencioni Alessio , Mach François , Vuilleumier Nicolas , Montecucco Fabrizio
Published: February 2013

Atherothrombosis is the major determinant of acute ischaemic cardiovascular events, such as myocardial infarction and stroke. Inflammatory processes have been linked to all phases of atherogenesis In particular, the identification of autoimmunity mediators in the complex microenvironment of chronic inflammation has become the focus of attention in both early and advanced atherogenic processes. Autoantibodies against self-molecules or new epitopes generated by oxidative processes infiltrate atherosclerotic plaques and were shown to modulate the activity of immune cells by binding various types of receptors. However, despite mounting evidence for a pathophysiological role of autoantibodies in atherothrombosis, the clinical relevance for circulating autoantibodies in cardiovascular outcomes is still debated. This review aims at illustrating the mechanisms by which different types of autoantibodies might either promote or repress atherothrombosis and to discuss the clinical studies assessing the role of auto-antibodies as prognostic biomarkers of plaque vulnerability.
Kallikrein-related peptidases (KLKs) in gastrointestinal cancer: Mechanistic and clinical aspects
Authors: Kontos Christos K. , Mavridis Konstantinos , Talieri Maroulio , Scorilas Andreas
Published: February 2013

The human tissue kallikrein (KLK1) and kallikrein-related peptidases (KLKs) are secreted serine proteases with diverse expression patterns and physiological roles in different systems, including the digestive system. The aberrant expression of KLKs in gastrointestinal malignancies as well as their implication in carcinogenesis including cell growth regulation, angiogenesis, invasion, and metastasis, has prompted scientists to investigate their potential as cancer biomarkers. Expression of distinct KLKs is associated with various clinic-pathological parameters of patients with gastric, colorectal, pancreatic, hepatic, and esophageal cancer. Moreover, several KLKs possess significant favourable or unfavourable prognostic value in these human malignancies. Identification of novel diagnostic, prognostic and predictive biomarkers will contribute utmost to clinical decision-making, since early diagnosis of gastrointestinal cancer and early detection of recurrence following surgery are critical for the effective treatment of patients and for a positive clinical outcome. The current review provides a brief overview of the functional role of KLKs in gastric, colorectal, pancreatic, hepatic, and esophageal cancer, and describes the current status of KLKs as potential tumour biomarkers in these human malignancies.
Genetic Determinant for Amino Acid Metabolites and Changes in Body Weight and Insulin Resistance in Response to Weight-Loss Diets
Authors: Xu Min , Qi Qibin , Liang Jun , Bray George A. , Hu Frank B. , Sacks Frank M. , Qi Lu
Published: February 2013

Background—

Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial.

Methods and Results—

We genotyped the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 near the
PPM1K
gene in 734 overweight or obese adults who were assigned to 1 of 4 diets varying in macronutrient content. At 6 months, dietary fat significantly modified genetic effects on changes in weight, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) after adjustment for the confounders (all
P
for interaction ≤0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all
P
≤ 0.02 in an additive pattern), whereas an opposite genotype effect on changes in insulin and HOMA-IR was observed in the low-fat diet group (
P
=0.02 and
P
=0.04, respectively). At 2 years, the gene-diet interactions remained significant for weight loss (
P
=0.008) but became null for changes in serum insulin and HOMA-IR resulting from weight regain.

Conclusions—

Individuals carrying the C allele of the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertaking an energy-restricted high-fat diet.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00072995.
The Neurobiology of Rhyme Judgment by Deaf and Hearing Adults: An ERP Study
Authors: MacSweeney Mairéad , Goswami Usha , Neville Helen
Published: February 2013

We used electrophysiology to determine the time course and distribution of neural activation during an English word rhyme task in hearing and congenitally deaf adults. Behavioral performance by hearing participants was at ceiling and their ERP data replicated two robust effects repeatedly observed in the literature. First, a sustained negativity, termed the contingent negative variation, was elicited following the first stimulus word. This negativity was asymmetric, being more negative over the left than right sites. The second effect we replicated in hearing participants was an enhanced negativity (N450) to nonrhyming second stimulus words. This was largest over medial, parietal regions of the right hemisphere. Accuracy on the rhyme task by the deaf group as a whole was above chance level, yet significantly poorer than hearing participants. We examined only ERP data from deaf participants who performed the task above chance level (n = 9). We observed indications of subtle differences in ERP responses between deaf and hearing groups. However, overall the patterns in the deaf group were very similar to that in the hearing group. Deaf participants, just as hearing participants, showed greater negativity to nonrhyming than rhyming words. Furthermore the onset latency of this effect was the same as that observed in hearing participants. Overall, the neural processes supporting explicit phonological judgments are very similar in deaf and hearing people, despite differences in the modality of spoken language experience. This supports the suggestion that phonological processing is to a large degree amodal or supramodal.
Individual Sequence Representations in the Medial Temporal Lobe
Authors: Kalm Kristjan , Davis Matthew H. , Norris Dennis
Published: February 2013

Much of what we need to remember consists of sequences of stimuli, experiences, or events. Repeated presentation of a specific sequence establishes a more stable long-term memory, as shown by increased recall accuracy over successive trials of an STM task. Here we used fMRI to study the neural mechanisms that underlie sequence learning in the auditory–verbal domain. Specifically, we track the emergence of neural representations of sequences over the course of learning using multivariate pattern analysis. For this purpose, we use a serial recall task, in which participants have to recall overlapping sequences of letter names, with some of those sequences being repeated and hence learned over the course of the experiment. We show that voxels in the hippocampus come to encode the identity of specific repeated sequences although the letter names were common to all sequences in the experiment. These changes could have not been caused by changes in overall level of activity or to fMRI signal-to-noise ratios. Hence, the present results go beyond conventional univariate fMRI methods in showing a critical contribution of medial-temporal lobe memory systems to establishing long-term representations of verbal sequences.
Development sites and early stages of eleven species of Clusiidae (Diptera) occurring in Europe
Authors: ROTHERAY GRAHAM E , HORSFIELD DAVID
Published: February 2013

Two hundred and ninety-six rearing records of 11 clusiid species (Diptera, Clusiidae) were obtained from 8 tree species in England, Finland, France, Norway, Russiaand Scotland, mainly during the period 1994 to 2004. Larvae and puparia were found between annual layers of whitewood (sapwood and heartwood) of wet, decay-softened, dead wood. Levels of host tree specificity were low, most species were reared from 2–4 host trees, maximum 6. The clusiid larva is distinguished by: a small, translucent head skeleton with an obliquely-shaped apex to the artium; a pseudocephalon fixed in an inverted position except for an external, flattened section bearing the antennomaxillary organs; a spherical prothorax with a truncate rim embedded with sensilla and, a wedge-shaped anal segment bearing a pair of conspicuous, sclerotised, red-brown hooks on the inner margins of which are the posterior spiracular plates. Many of these features support a distinctive feeding mechanism, spot-sucking of biofilm coating wet, decaying whitewood. Early stage characters support the results of recent supraspecific taxonomic and systematic investigations, such as the synonymy of Paraclusia Czerny under Clusia Haliday and the recognition of species groups in Clusiodes Coquillett. Based on early stages, supraspecific clusiid taxa are easily recognised but at species level, differences are relatively fine-grained and minor. A key is provided to identify puparia of species reared in this study.
A contribution to the systematics of Neotropical Tanytarsus van der Wulp: first descriptions from Ecuador (Diptera: Chironomidae: Tanytarsini)
Authors: GIŁKA WOJCIECH , ZAKRZEWSKA MARTA
Published: February 2013

First specific records of Tanytarsus van der Wulp from the Ecuadorian mainland based on detailed descriptions are presented. Tanytarsus cayambe sp. nov. shows an interesting set of characters known from several Neotropical Tanytarsus as well as from species of the recurvatus group of the northern distribution. Tanytarsus cotopaxi sp. nov. is placed in the riopreto species group; as a result an emended diagnosis for adult males of the group is proposed. The diagnostic description of Tanytarsus curvicristatus Contreras-Lichtenberg is also complemented.
Scale surface microstructure and scale size in the tooth-carp genus Aphanius (Teleostei, Cyprinodontidae) from endorheic basins in Southwest Iran
Authors: GHOLAMI ZEINAB , TEIMORI AZAD , ESMAEILI HAMID REZA , SCHULZ-MIRBACH TANJA , REICHENBACHER BETTINA
Published: February 2013

A substantial number of species within the tooth-carp Aphanius Nardo, 1827 (Cyprinodontidae, Teleostei) has been re-corded from the endorheic drainage systems of Iran, and several isolated populations in these systems may deserve species status. Descriptions of these species and populations have been based mainly on morphological and molecular data; how-ever, the characters related to the fish scales have not up to now been intensively studied and employed for the identifica-tion of the species belonging to this genus. The objective of this study is to test as to whether (i) scale surface morphology, (ii) scale surface microstructure, and (iii) scale size can be used to discriminate species and/or populations and, (iv) to discuss the possible causes of the observed differences. To achieve these objectives, scales of three species of the genus Aphanius from endorheic basins in SW Iran, viz. A. sophiae (nine populations from the Kor River Basin), A. farsicus (four populations from the Maharlu Lake Basin) and A. pluristriatus (a single population from the Mond River Basin) have been studied using SEM images, scale measurements, and uni- and multivariate statistics. It is opined that scale surface mor-phology and microstructure cannot help in distinguishing the species, but can be employed to discriminate certain popu-lations of A. sophiae (those from Safashahr, Kharameh, Tashk, Gol). In addition, scale size and J-indices, respectively, represent a valuable tool for species separation, which corroborates earlier studies for the use of these indices in taxonomy. Major driving forces of the differentiation within A. sophiae probably include habitat fragmentation resulting from the geological history and local adaptations. Thus the differentiation results from a balance between both genetic and envi-ronmental effects.
Doubling–Adding Method for Delta-Four-Stream Spherical Harmonic Expansion Approximation in Radiative Transfer Parameterization
Authors: Zhang Feng , Li Jiangnan
Published: February 2013

Though the single-layer solutions have been found for the δ-four-stream spherical harmonic expansion method (SHM) in radiative transfer, there is lack of a corresponding doubling–adding method (4SDA), which enables the calculation of radiative transfer through a vertically inhomogeneous atmosphere with multilayers. The doubling–adding method is based on Chandrasekhar's invariance principle, which was originally developed for discrete ordinates approximation. It is shown that the invariance principle can also be applied to SHM and δ-four-stream spherical harmonic expansion doubling–adding method (δ-4SDA) is proposed in this paper. The δ-4SDA method has been systematically compared to the δ-Eddington doubling–adding method (δ-2SDA), the δ-two-stream discrete ordinates doubling–adding method (δ-2DDA), and δ-four-stream discrete ordinates doubling–adding method (δ-4DDA). By applying δ-4SDA to a realistic atmospheric profile with gaseous transmission considered, it is found that the accuracy of δ-4SDA is superior to δ-2SDA or δ-2DDA, especially for the cloudy/aerosol conditions. It is shown that the relative errors of δ-4SDA are generally less than 1% in both heating rate and flux, while the relative errors of both δ-2SDA and δ-2DDA can be over 6%. Though δ-4DDA is slightly more accurate than δ-4SDA in heating rates, both of them are accurate enough to obtain the cloud-top solar heating. Here δ-4SDA is superior to δ-4DDA in computational efficiency. It is found that the error of aerosol radiative forcing can be up to 3 W m−2 by using δ-2SDA at the top of the atmosphere (TOA); such error is substantially reduced by applying δ-4SDA. In view of the overall accuracy and computational efficiency, δ-4SDA is suitable for application in climate models.
Using Virtual Human Technology to Capture Dentists’ Decision Policies about Pain
Authors: Wandner L.D. , Hirsh A.T. , Torres C.A. , Lok B.C. , Scipio C.D. , Heft M.W. , Robinson M.E.
Published: February 2013

Healthcare professionals use race, gender, and age cues when making pain management decisions. Use of these demographic cues, therefore, is an important topic in the study of healthcare disparities. This study used virtual human (VH) technology to investigate the effects of VH patients’ demographic cues on dentists’ pain management decisions. Eighty-nine dentists viewed patients with different demographic cues. Analyses revealed that dentists rated pain intensity higher and were more willing to prescribe opioids to female, African-American, and younger patients than to their demographic counterparts. Results also found significant 2-way interactions between race and age for both pain assessment and treatment decisions. The interaction results suggest that the race difference (Caucasian < African American) was more pronounced for younger than for older patients. This is the first study to examine demographic cue use in dentists’ decision-making for pain. The study found that dentists used demographic cues when making pain management decisions. Currently, there are no guidelines for decision- making practices for gender-, race-, or age-related pain. Since dentists see thousands of patients during their careers, the use of demographic cues could affect a substantial portion of the population. The findings could improve future training programs for dentists and dental students.
Modeling Pacing Behavior and Test Speededness Using Latent Growth Curve Models
Authors: Kahraman Nilufer , Cuddy Monica M. , Clauser Brian E.
Published: February 2013

This research explores the usefulness of latent growth curve modeling in the study of pacing behavior and test speededness. Examinee response times from a high-stakes, computerized examination, collected before and after the examination was subjected to a timing change, were analyzed using a series of latent growth curve models to detect identifiable patterns of examinee pacing behavior. To help explain how examinees progress through the examination, the influences of two important predictor variables were tested: examinees’ native language and overall proficiency. Results illustrate how group-specific changes in the relationship between proficiency and response times and a phase-specific interaction effect would have gone unnoticed if a longitudinal perspective had not been used. The findings suggest that growth curve modeling is a useful tool for modeling change in test speed as a continuous process.
Tissue Mineral Concentrations Are Profoundly Altered in Neonatal Piglets Fed Identical Diets via Gastric, Central Venous, or Portal Venous Routes
Authors: Bertolo Robert F. , Pencharz Paul B. , Ball Ronald O.
Published: February 2013

Background: Because gut absorption and liver sequestration are major mechanisms of mineral homeostasis, intestinal and hepatic bypass with parenteral feeding can lead to mineral toxicities. We employed a piglet model with multiple feeding routes to identify target organs susceptible to abnormal accumulation of minerals and to determine the importance of intestinal or hepatic metabolism. Methods: Fifteen 2‐ to 4‐day‐old piglets were fed identical complete elemental diets continuously for 8 days via central venous (intravenous [IV]), gastric (intragastric [IG]), or portal (intraportal [IP]) catheters. Concentrations of calcium, phosphorus, magnesium, zinc, copper, iron, manganese, sodium, potassium, and chloride were measured in small intestinal mucosa, liver, kidney, and femur. Results: Compared with IG‐fed piglets, mineral sequestration patterns in IV‐ and IP‐fed piglets can be attributed to bypass of intestinal absorption inefficiencies, with moderate accumulations of minerals in tissues involved in mineral homeostasis. However, differences between IP and IV feeding were notable for iron, manganese, and copper, suggesting first‐pass hepatic metabolism is key to homeostasis of these minerals. Moreover, manganese and copper sequestration patterns reflected that for zinc, suggesting induction of metallothionein by parenteral zinc could interfere with metabolism of other minerals. Conclusions: We conclude that parenteral delivery of minerals to neonates needs to consider not only absorption efficiency but also mineral interactions and potentially toxic accumulation in target tissues, with particular concern for iron, copper, and zinc.
The urban university as good citizen: The American University of Beirut’s Neighborhood Initiative
Authors: Myntti Cynthia
Published: February 2013

The American University of Beirut’s Neighborhood Initiative was launched in 2007 to encourage faculty and students to contribute to solving the problems affecting the district of Beirut located just outside the university walls. Among the issues addressed are congestion, poor walkability, near absence of greenery, an aging population, and growing disparities between rich and poor residents. Four challenges confront the Initiative: attracting over-committed faculty to work on local problems; raising funds for programmatic activities; creating meaningful relationships with neighbors and other stakeholders; and addressing the economic trends now transforming the neighborhood.
Rules or Consequences? The Role of Ethical Mind-Sets in Moral Dynamics
Authors: Cornelissen Gert , Bashshur Michael R. , Rode Julian , Le Menestrel Marc
Published: February 2013

Recent research on the dynamics of moral behavior has documented two contrasting phenomena—moral consistency and moral balancing. Moral balancing refers to the phenomenon whereby behaving ethically or unethically decreases the likelihood of engaging in the same type of behavior again later. Moral consistency describes the opposite pattern—engaging in ethical or unethical behavior increases the likelihood of engaging in the same type of behavior later on. The three studies reported here supported the hypothesis that individuals’ ethical mind-set (i.e., outcome-based vs. rule-based) moderates the impact of an initial ethical or unethical act on the likelihood of behaving ethically on a subsequent occasion. More specifically, an outcome-based mind-set facilitated moral balancing, and a rule-based mind-set facilitated moral consistency.
Hurting You Hurts Me Too
Authors: Legate Nicole , DeHaan Cody R. , Weinstein Netta , Ryan Richard M.
Published: February 2013

Much research has documented the harmful psychological effects of being ostracized, but research has yet to determine whether compliance with ostracizing other people is psychologically costly. We conducted two studies guided by self-determination theory to explore this question, using a paradigm that borrows from both ostracism research and Milgram’s classic study of obedience. Supporting our guiding hypothesis that compliance with ostracizing others carries psychological costs, the results of Experiment 1 showed that such compliance worsened mood compared with complying with instructions to include others and with receiving no instructions involving inclusion or exclusion, an effect explained by thwarted psychological needs resulting from ostracizing others. Experiment 2 revealed increases in negative affect both when individuals ostracized others and when individuals were ostracized themselves. Our findings point to the robust psychological costs associated with ostracizing other people, with implications for group behaviors.
Learning to See, but Not Discriminate, Visual Forms Is Impaired in Aging
Authors: Kuai Shu-Guang , Kourtzi Zoe
Published: February 2013

Despite the central role of learning in visual recognition, it is largely unknown whether visual form learning is maintained in older age. We examined whether training improved performance in both young and older adults at two key stages of visual recognition: integration of local elements and global form discrimination. We used a shape-discrimination task (concentric vs. radial patterns) in which young and older adults showed similar performance before training. Using a parametric stimulus space that allowed us to manipulate global features and background noise, we were able to distinguish integration and discrimination processes. We found that training improves global form discrimination in both young and older adults. However, learning to integrate local elements is impaired in older age, possibly because of reduced tolerance to external noise. These findings suggest that visual selection processes, rather than global feature representations, provide a fundamental limit for learning-dependent plasticity in the aging brain.
Complications Following Treatment of Supination External Rotation Ankle Fractures Through the Posterolateral Approach
Authors: Little Milton T. M. , Berkes Marschall B. , Lazaro Lionel E. , Sculco Peter K. , Helfet David L. , Lorich Dean G.
Published: February 2013

Background:

The posterolateral approach to the ankle is a valuable approach for the treatment of ankle fractures (SER) ankle fractures. The purpose of this study was to determine the complication rate for ankle fractures treated through the posterolateral approach. We hypothesized that this approach would be associated with a low incidence of complications and good clinical outcomes.

Methods:

A total of 112 patients with SER ankle fractures treated through a posterolateral approach met inclusion criteria. Prospectively collected data were examined retrospectively from chart review, preoperative plain radiographs, and MRI as well as postoperative radiographs. The mean age was 51.5 (range, 18 to 86) years. The primary outcome of the study was major (surgical debridement, flap, or split thickness skin graft) and minor (epidermolysis requiring local wound care) wound complications. The secondary outcomes included infection, symptomatic hardware, reoperation, loss of reduction, malreduction, nonunion, Foot and Ankle Outcome Scores, range of motion, and other perioperative complications.

Results:

There were 11 minor wound related complications (9.8%) and 3 major wound complications (2.7%), 1 of which required a split thickness skin graft. The overall postoperative wound infection rate was 4.4% (5 of 112); 2 patients required hardware removal due to deep infection. Of patients, 7% (8 of 112) reported symptomatic lateral sided hardware and thus underwent removal of implants. The overall reoperation rate was 12.5%. The complication rate was 23%. No patients experienced loss of reduction.

Conclusions:

The posterolateral approach to the ankle was a valuable approach for SER ankle fractures. This series demonstrated many key aspects of this approach including access to the apex of the fibula fracture for posterior antiglide plating, access to the posterior malleolus for fixation, access to the posterior inferior tibiofibular ligament for repair, minimal major wound complications, good functional outcomes, and minimal need for reoperation.

Level of Evidence:

Level IV, retrospective evaluation of prospectively collected data.