bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNAs Are Independent Predictors of Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP
Authors: Alencar Alvaro J. , Malumbres Raquel , Kozloski Goldi A. , Advani Ranjana , Talreja Neha , Chinichian Shideh , Briones Javier , Natkunam Yasodha , Sehn Laurie H. , Gascoyne Randy D. , Tibshirani Rob , Lossos Izidore S.
Published: April 2011

Purpose: Diffuse large B-cell lymphoma (DLBCL) heterogeneity has prompted investigations for new biomarkers that can accurately predict survival. A previously reported 6-gene model combined with the International Prognostic Index (IPI) could predict patients' outcome. However, even these predictors are not capable of unambiguously identifying outcome, suggesting that additional biomarkers might improve their predictive power.

Experimental Design: We studied expression of 11 microRNAs (miRNA) that had previously been reported to have variable expression in DLBCL tumors. We measured the expression of each miRNA by quantitative real-time PCR analyses in 176 samples from uniformly treated DLBCL patients and correlated the results to survival.

Results: In a univariate analysis, the expression of miR-18a correlated with overall survival (OS), whereas the expression of miR-181a and miR-222 correlated with progression-free survival (PFS). A multivariate Cox regression analysis including the IPI, the 6-gene model–derived mortality predictor score and expression of the miR-18a, miR-181a, and miR-222, revealed that all variables were independent predictors of survival except the expression of miR-222 for OS and the expression of miR-18a for PFS.

Conclusion: The expression of specific miRNAs may be useful for DLBCL survival prediction and their role in the pathogenesis of this disease should be examined further. Clin Cancer Res; 17(12); 4125–35. ©2011 AACR.
Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 Trial
Authors: Davies D. Mark , de Vries Petrus J. , Johnson Simon R. , McCartney Deborah L. , Cox Jane A. , Serra Andreas L. , Watson Peter C. , Howe Christopher J. , Doyle Tim , Pointon Kate , Cross Justin J. , Tattersfield Anne E. , Kingswood J. Chris , Sampson Julian R.
Published: April 2011

Purpose: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders.

Experimental Design: In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function.

Results: The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus.

Conclusions: This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation. Clin Cancer Res; 17(12); 4071–81. ©2011 AACR.
Induction ofIn VitroandIn VivoNK Cell Cytotoxicity Using High-Avidity Immunoligands Targeting Prostate-Specific Membrane Antigen in Prostate Carcinoma
Authors: Jachimowicz Ron D. , Fracasso Giulio , Yazaki Paul J. , Power Barbara E. , Borchmann Peter , Engert Andreas , Hansen Hinrich P. , Reiners Katrin S. , Marie Madlener , von Strandmann Elke Pogge , Rothe Achim
Published: April 2011

Cancer that might develop as host natural killer (NK) cells fail to detect ligands for their activating NK receptors. Immunoligands represent promising immunotherapeutic tools to overcome this deficit. These are fusion proteins containing a single-chain antibody fragment (scFv) to target an available tumor antigen and ULBP2 to activate host NK cells by targeting the activatory receptor NKG2D. Prostate-specific membrane antigen (PSMA) is an integral non-shed type 2 membrane protein that is highly and specifically expressed on prostate epithelial cells and strongly upregulated in prostate cancer. Here, we compare the impact of various anti-PSMA immunoligand formats on the therapeutic efficacy against prostate carcinoma cells by activating NK cells via NKG2D. Shortening of the linker separating the heavy and light chain antibody domain leads to the formation of dimers, trimers, and higher molecular mass oligomers. NK cells are most efficiently activated by multimeric immunoligands, thus showing an altered cytokine release pattern. The high avidity format is also superior in in vitro NK-mediated tumor cell targeting as shown in cytotoxicity assays. Finally, the efficacy of a multimeric immunoligand is shown in a prostate carcinoma mouse xenograft model showing a strong activity against advanced established tumors. Mol Cancer Ther; 10(6); 1036–45. ©2011 AACR.
Beneficial Effects of Probiotic Bifidobacterium and Galacto-Oligosaccharide in Patients with Ulcerative Colitis: A Randomized Controlled Study
Authors: Ishikawa Hideki , Matsumoto Satoshi , Ohashi Yuji , Imaoka Akemi , Setoyama Hiromi , Umesaki Yoshinori , Tanaka Ryuichiro , Otani Toru
Published: April 2011

Background/Aim: In previous studies, we described the beneficial effects of bifidobacteria-fermented milk in patients with ulcerative colitis (UC). Here, we examined the effects of a live Bifidobacterium breve strain Yakult, a probiotic contained in bifidobacteria-fermented milk, and galacto-oligosaccharide (GOS) as synbiotics in UC patients. Methods: Forty-one patients with mild to moderate UC were assigned to two groups; one group was treated with the synbiotics and the other was not (control). The treatment group ingested 1 g of the probiotic powder (109 CFU/g) three times a day, and 5.5 g of GOS once a day for one year. At the start and the end of this study, colonoscopic index and the amount of myeloperoxidase in a lavage solution were used as disease activity indices. Bacterial counts in the feces at the start and the end of this study were also examined. Results: After a one-year treatment with the synbiotics, the clinical status of the UC patients as assessed by colonoscopy, significantly improved. Furthermore, the amount of myeloperoxidase in the lavage also decreased in these patients after the synbiotic treatment. The synbiotics significantly reduced the fecal counts of Bacteroidaceae and fecal pH. Conclusion: Administration of live B. breve strain Yakult and GOS can improve the clinical condition of patients with UC. These results encouraged us to perform a large-scale randomized, placebo-controlled trial.
Primate Prefrontal Cortex Evolution: Human Brains Are the Extreme of a Lateralized Ape Trend
Authors: Smaers J.B. , Steele J. , Case C.R. , Cowper A. , Amunts K. , Zilles K.
Published: April 2011

The prefrontal cortex is commonly associated with cognitive capacities related to human uniqueness: purposeful actions towards higher-level goals, complex social information processing, introspection, and language. Comparative investigations of the prefrontal cortex may thus shed more light on the neural underpinnings of what makes us human. Using histological data from 19 anthropoid primate species (6 apes including humans and 13 monkeys), we investigate cross-species relative size changes along the anterior (prefrontal) and posterior (motor) axes of the cytoarchitectonically defined frontal lobe in both hemispheres. Results reveal different scaling coefficients in the left versus right prefrontal hemisphere, suggest that the primary factor underlying the evolution of primate brain architecture is left hemispheric prefrontal hyperscaling, and indicate that humans are the extreme of a left prefrontal ape specialization in relative white to grey matter volume. These results demonstrate a neural adaptive shift distinguishing the ape from the monkey radiation possibly related to a cognitive grade shift between (great) apes and other primates.
Stereology of the Neocortex in Odontocetes: Qualitative, Quantitative, and Functional Implications
Authors: Kern A. , Siebert U. , Cozzi B. , Hof P.R. , Oelschläger H.H.A.
Published: April 2011

We investigated the quantitative morphology of the neocortex (gray matter) in 2 toothed whale (odontocete) species (harbor porpoise, Phocoena phocoena; bottlenose dolphin, Tursiops truncatus) with stereological methods. The 4 primary projection areas (motor, somatosensory, auditory, and visual fields) are analyzed for their cell densities in layers III and V with standard design-based stereology methods. Along cortical areas M1, S1, A1, and V1 in Tursiops, neuron density is always higher in layer III than in layer V, whereas the data in Phocoena are variable. Moreover, neuron density in layer III is generally around 1.5 times higher in Tursiops than in Phocoena. Maximal density values are seen in layer III of A1 and V1 in Tursiops and the ratio of layer III/layer V density is maximal in A1 of this species. Thus, layer III could have a higher capacity in the bottlenose dolphin with regard to intrinsic connectivity. Extant knowledge on toothed whale neurobiology and behavior suggests that quantitative/stereological differences between the 2 odontocete species regarding the neuron density of standard cortical units may be correlated with specific adaptations to their respective habitats. In contrast to layers V and VI which mainly serve as an executive system, layer III could represent an intermediate level in sensory and premotor processing which works more tangentially in the cortices via horizontal connections with other cortical areas, respectively. The generally higher density of cortical layer III in Tursiops suggests a higher connectivity of this layer in view of the more agile and complicated behavior of these gregarious animals including versatile phonation by complex sound and ultrasound signals.
MMP20 Cleaves E-Cadherin and Influences Ameloblast Development
Authors: Bartlett John D. , Yamakoshi Yasuo , Simmer James P. , Nanci Antonio , Smith Charles E.
Published: April 2011

Dental enamel development occurs in stages as observed by the changing morphology of the ameloblasts that are responsible for enamel formation. During the secretory stage of development, proteins including MMP20 are secreted into the enamel matrix. MMP20 is required for proper enamel formation as mutation of the Mmp20 gene causes autosomal recessive amelogenesis imperfecta. Here, we examined in detail the morphology of the Mmp20-null ameloblast cell layer. Intriguingly, we found that the Mmp20-null mouse secretory stage ameloblasts retract their Tomes’ processes as if preparing to enter the maturation stage but later reextend their Tomes’ processes as if resuming the secretory stage. We also demonstrated that MMP20 cleaves epithelial cadherin, i.e. E-cadherin. Cadherins are transmembrane proteins with extracellular domains that provide adhesive contacts between neighboring cells. Their intracellular domains bind to the cell cytoskeleton through catenins, including β-catenin. When specific MMPs cleave the cadherin extracellular domain, β-catenin is released and may locate to the cell nucleus as a transcription factor. Therefore, MMP20 may influence ameloblast developmental progression through hydrolysis of cadherin extracellular domains with associated release of transcription factor(s).
Enamel-Calibrated Lamellar Bone Reveals Long Period Growth Rate Variability in Humans
Authors: Bromage Timothy G. , Juwayeyi Yusuf M. , Smolyar Igor , Hu Bin , Gomez Santiago , Chisi John
Published: April 2011

Mammalian teeth exhibit incremental structures representing successive forming fronts of enamel at varying time scales, including a short daily increment called a cross striation and a long period called a stria of Retzius, the latter of which, in humans, occurs on average every 8–9 days. The number of daily increments between striae is called the repeat interval, which is the same period as that required to form one increment of bone, i.e. the lamella, the fundamental – if not archetypal – unit of bone. Lamellae of known formation time nevertheless vary in width, and thus their measures provide time-calibrated growth rate variability. We measured growth rate variability for as many as 6 years of continuously forming primary incremental lamellar bone from midshaft femur histological sections of sub-Saharan Africans of Bantu origin and known life history. We observed periodic growth rate variability in approximately 6- to 8-week intervals, and in some cases annual rhythms were visible. Endogenous biological periodicities, cycles manifest in the external environment, and/or perturbations of development are all potentially contained within growth rate variability studies of lamellar incremental patterns. Because lamellae are formed within defined periods of time, quantitative measures of widths of individual lamellae provide time-resolved growth rate variability that may reveal rhythms in human bone growth heretofore unknown.
In vitro Analyses of the Dysregulated R206H ALK2 Kinase-FKBP12 Interaction Associated with Heterotopic Ossification in FOP
Authors: Groppe Jay C. , Wu Jingfeng , Shore Eileen M. , Kaplan Frederick S.
Published: April 2011

A single recurrent mutation in the regulatory subdomain of a bone morphogenetic protein type I receptor kinase has been linked to heterotopic ossification in classic fibrodysplasia ossificans progressiva (FOP). As a result of a substitution at 1 residue by only 1 other side chain (Arg206His) in just 1 of the 4 type I BMP receptors (ALK2/ACVR1), soft connective tissues progressively metamorphose through an endochondral process into cartilage that is replaced by bone. The substitution of arginine for histidine, also a basic residue yet with the singular property of ionization/protonation over the physiological pH range, led to the hypothesis of an aberrant, pH-sensitive switch mechanism for the ligand-independent activation of BMP signaling through the mutant receptor kinase in patients presenting with classic FOP. To test a potential aspect of the putative pH-dependent mechanism, i.e. loss of autoinhibition of the kinase mediated by the inhibitory protein FKBP12, in vitrointeraction analyses with purified wild-type and R206H ALK2 kinase and FKBP12 proteins were performed. Interactions between the kinases and inhibitory proteins were analyzed qualitatively and quantitatively by native gel electrophoresis and HPLC size exclusion chromatography and with an optical biosensor (Octet; ForteBio). Binding of inhibitory protein by the R206H mutant was diminished 3-fold relative to the wild type kinase at a physiological pH, yet below this value (<∼7.5) pronounced nonspecific interactions, particularly with the mutant, prevented comparative evaluations. In conclusion, substitution with histidine leads to partial loss of inhibition of the mutant type I receptor through diminished binding of FKBP12, which may act as a gradient reader in morphogenetic contexts.
Genetics of Pancreatitis: A Guide for Clinicians
Authors: Witt Heiko
Published: April 2011

It is now generally believed that pancreatitis results from pancreatic autodigestion. An inappropriate conversion of pancreatic zymogens to active enzymes within the pancreatic parenchyma is thought to initiate the inflammatory process. A key role has been attributed to the activation of trypsinogen to trypsin, converting all proteolytic proenzymes to their active form. Several gain-of-function mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with chronic pancreatitis (CP). These mutations lead to enhanced intrapancreatic trypsinogen activation. In contrast, a variant in the anionic trypsinogen (PRSS2) gene, p.G191R, has been described that mitigates intrapancreatic trypsin activity and thereby plays a protective role. Beside trypsinogen mutations, loss-of-function variants in SPINK1, encoding a pancreatic trypsin inhibitor, are strongly associated with idiopathic CP. Approximately 15–40% of patients with so-called idiopathic CP carry p.N34S on one allele or on both alleles. Chymotrypsin C (CTRC) degrades all human trypsin isoforms with high specificity. Two CTRC alterations, p.R254W and p.K247_R254del, are significantly associated with idiopathic as well as alcohol-related CP. Functional analysis of the variants revealed impaired activity and/or reduced secretion. Thus, loss-of-function mutations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between CFTR, the gene mutated in cystic fibrosis, and idiopathic CP is now well established, the pathogenic mechanisms are poorly understood. Nearly 25–30% of patients carry at least one CFTR mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a CFTR alteration and a PRSS1, SPINK1, or CTRC variant, respectively.
Gut-Liver Axis and Sensing Microbes
Authors: Szabo Gyongyi , Bala Shashi , Petrasek Jan , Gattu Arijeet
Published: April 2011

‘Detoxification’ of gut-derived toxins and microbial products from gut-derived microbes is a major role of the liver. While the full repertoire of gut-derived microbial products that reach the liver in health and disease is yet to be explored, the levels of bacterial lipopolysaccharide (LPS), a component of Gram-negative bacteria, is increased in the portal and/or systemic circulation in several types of chronic liver diseases. Increased gut permeability and LPS play a role in alcoholic liver disease where alcohol impairs the gut epithelial integrity through alterations in tight junction proteins. In addition, non-alcoholic fatty liver disease is also associated with increased serum LPS levels and activation of the pro-inflammatory cascade plays a central role in disease progression. Microbial danger signals are recognized by pattern recognition receptors such as the Toll-like receptor 4 (TLR4). Increasing evidence suggests that TLR4-mediated signaling via the MyD88-dependent or MyD88-independent pathways may play different roles in liver diseases associated with increased LPS exposure of the liver as a result of gut permeability. For example, we showed that in alcoholic liver disease, the MyD88-independent, IRF3-dependent TLR4 cascade plays a role in steatosis and inflammation. Our recent data demonstrate that chronic alcohol exposure in the liver leads to sensitization of Kupffer cells to LPS via a mechanism involving upregulation of microRNA-155 in Kupffer cells. Thus, understanding the cell-specific recognition and intracellular signaling events in sensing gut-derived microbes will help to achieve an optimal balance in the gut-liver axis and ameliorate liver diseases.
Pathophysiological Similarities and Synergisms in Alcoholic and Non-Alcoholic Steatohepatitis
Authors: Hellerbrand Claus
Published: April 2011

Chronic alcohol consumption is one of the main etiological factors for liver disease worldwide, however only a fraction of drinkers develop significant hepatic inflammation (alcoholic steatohepatitis), and even less progress to significant hepatic fibrosis and cirrhosis. The pathophysiological significance of hepatic lipid accumulation in the absence of significant alcohol consumption is also increasingly recognized. Non-alcoholic fatty liver disease (NAFLD) is regarded as the hepatic manifestation of the metabolic syndrome, and it is the most common cause of liver enzyme elevations in Western countries. Similarly to alcoholic liver disease, NAFLD encompasses mild hepatic steatosis to non-alcoholic steatohepatitis with significant necroinflammation and progressive fibrosis. Several clinical studies suggest a strong causative link between the consumption of alcohol and progressive liver disease in individuals with high fat intake and/or diabetes. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects on the progression of liver injury are additive or synergistic. This review describes single as well as combined effects of alcohol and (components of) the metabolic syndrome on hepatic steatosis, inflammation and fibrosis. In addition to direct effects on the liver, the view is expanded to other organs affected by chronic alcohol consumption or the metabolic syndrome, to understand also extrahepatic pathophysiological mechanisms involved in hepatocellular injury. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important synergistic effects of either condition with regard to crucial triggers of liver injury.
Comparison of Area 17 Cellular Composition in Laboratory and Wild-Caught Rats Including Diurnal and Nocturnal Species
Authors: Campi Katharine L. , Collins Christine E. , Todd William D. , Kaas Jon , Krubitzer Leah
Published: April 2011

In this study we examine the size of primary sensory areas in the neocortex and the cellular composition of area 17/V1 in three rodent groups: laboratory nocturnal Norway rats (Long-Evans; Rattus norvegicus), wild-caught nocturnal Norway rats (R. norvegicus), and laboratory diurnal Nile grass rats (Arvicanthis niloticus). Specifically, we used areal measures of myeloarchitecture of the primary sensory areas to compare area size and the isotropic fractionator method to estimate the number of neurons and nonneurons in area 17 in each species. Our results demonstrate that the percentage of cortex devoted to area 17 is significantly greater and the percentage of cortex devoted to S1 is significantly smaller in the diurnal Nile grass rat compared with the nocturnal Norway rat groups. Further, the laboratory rodent groups have a greater percentage of cortex devoted to auditory cortex compared with the wild-caught group. We also demonstrate that wild-caught rats have a greater density of neurons in area 17 compared to laboratory-reared animals. However, there were no other clear cellular composition differences in area 17 or differences in the percentage of brain weight devoted to area 17 between nocturnal and diurnal rats. Thus, there are differences in primary sensory area size between diurnal versus nocturnal and laboratory versus wild-caught rat groups and cellular density between wild-caught and laboratory rat groups. Our results demonstrate that the differences in the size and cellular composition of cortical areas do not fit with what would be expected based on brain scaling differences alone, and have a consistent relationship with lifestyle and sensory morphology.
Neophobia and Learning Mechanisms: How Captive Orangutans Discover Medicinal Plants
Authors: Gustafsson Erik , Krief Sabrina , Jalme Michel Saint
Published: April 2011

Great apes sometimes feed on items of low nutritional value with bioactive secondary compounds. These molecules may be toxic and neophobia is presumed to be an essential factor in avoiding the ingestion of noxious items. The aim of this study is to investigate, in captive orangutans, individual and social learning involved in the discovery and ingestion of new items. We presented novel aromatic plants – 11 fresh plants and 4 infused plants – to 4 captive weaned Bornean orangutans, both under isolated and group conditions, and recorded their behaviour and interactions between group members. All animals tasted by nibbling or ingested most of the plants presented. Regardless of the experimental condition, individual responses did not vary visibly across the sessions, despite numerous close observations, and food transfers between individuals were observed. Our results suggest that a low level of neophobia and a strong propensity to look to conspecifics for information allow Bornean orangutans to expand their diet after weaning. Our results also provide some evidence that olfaction is a key sense in determining food edibility based on previous experience.
Skeletal Muscle Gene Expression Profile Is Modified by Dietary Protein Source and Calcium during Energy Restriction
Authors: Tauriainen Eveliina , Storvik Markus , Finckenberg Piet , Merasto Saara , Martonen Essi , Pilvi Taru K. , Korpela Riitta , Mervaala Eero M.
Published: April 2011

Background/Aims: The potential of whey protein and calcium to modify skeletal muscle gene expression during energy restriction (ER) was investigated in a model of diet-induced obesity. Methods: Obese C57BL/6J mice received casein (calcium 0.4%) and two different high-calcium (1.8%) whey protein-based [whey protein isolate (WPI) + Ca and α-lactalbumin + Ca] diets for ER. Results: Compared to casein, WPI and α-lactalbumin-based diets altered 208 and 287 genes, respectively, of which 186 genes were common to WPI and α-lactalbumin diets. These genes represented 31 KEGG pathways. The Wnt signaling was the most enriched pathway among the 101 genes regulated by α-lactalbumin only, whereas the 22 genes regulated by WPI only were not associated with KEGG pathways. Unlike casein, WPI and α-lactalbumin diets decreased Aldh1a7, Fasn, leptin, Nr4a3 and Scd1 mRNA expression, indicating dietary protein source-dependent alterations in muscle lipid and fatty acid metabolism. Muscle weight or lean body mass maintenance did not differ between groups although modest changes in hypertrophy/atrophy signaling were found. Conclusion: The skeletal muscle gene expression profile is modified by the dietary protein source and calcium during ER which may explain, at least in part, the greater anti-obesity effect of whey proteins and calcium compared to casein.
Effect of SOM230 (Pasireotide) on Corticotropic Cells: Action in Dogs with Cushing’s Disease
Authors: Castillo Victor , Theodoropoulou Marily , Stalla Johanna , Gallelli Maria Florencia , Cabrera-Blatter Maria Fernanda , Haedo Mariana R. , Labeur Marta , Schmid Herbert A. , Stalla Günter K. , Arzt Eduardo
Published: April 2011

SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing’s disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. The objective of this study was to evaluate whether SOM230 controls both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing’s disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2-month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the Gi α-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing’s disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing’s disease.
The Emerging Role of Innate Immunity in the Heart and Vascular System
Authors: Mann Douglas L.
Published: April 2011

Recent studies suggest that the heart possesses an innate immune system that is intended to delimit tissue injury, as well as orchestrate homoeostatic responses, within the heart. The extant literature suggests that this intrinsic stress response system is mediated, at least in part, by a family of pattern recognition receptors, most notably the Toll-like receptors. Although the innate immune system provides a short-term adaptive response to tissue injury, the beneficial effects of this phylogenetically ancient system may be lost if innate immune signaling becomes sustained and/or excessive; in which case, the salutary effects of activation of these pathways are contravened by the known deleterious effects of inflammatory signaling. Herein, the biology of innate immune signaling in the heart is reviewed, as well as the literature suggesting that the innate immune system is involved in the pathogenesis of atherosclerosis, acute coronary syndromes, stroke, viral myocarditis, sepsis, ischemia/reperfusion injury, and heart failure. The review concludes by discussing new therapies that are being developed to modulate the innate immune system.
Derivation of Human Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling
Authors: Narsinh Kamileh , Narsinh Kazim H. , Wu Joseph C.
Published: April 2011

The successful derivation of human induced pluripotent stem cells (hiPSCs) by dedifferentiation of somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC derivatives offer incredible potential for new disease models and regenerative medicine therapies. However, many questions remain regarding the optimal starting materials and methods to enable safe, efficient derivation of hiPSCs suitable for clinical applications. Initial reprogramming experiments were carried out using lentiviral or retroviral gene delivery methods. More recently, various nonviral methods that avoid permanent and random transgene insertion have emerged as alternatives. These include transient DNA transfection using plasmids or minicircles, protein transduction, or RNA transfection. In addition, several small molecules have been found to significantly augment hiPSC derivation efficiency, allowing the use of a fewer number of genes during pluripotency induction. We review these various methods for the derivation of hiPSCs, focusing on their ultimate clinical applicability, with an emphasis on their potential for use as cardiovascular therapies and disease-modeling platforms.
A Stochastic Model for the Transition to Strong Convection
Authors: Stechmann Samuel N. , Neelin J. David
Published: April 2011

A simple stochastic model is designed and analyzed in order to further understand the transition to strong convection. The transition has been characterized recently in observational data by an array of statistical measures, including (i) a sharp transition in mean precipitation, and a peak in precipitation variance, at a critical value of column water vapor (CWV), (ii) an approximate power law in the probability density of precipitation event size, (iii) exponential tails in the probability density of CWV values, when conditioned on either precipitating or nonprecipitating locations, and (iv) long and short autocorrelation times of CWV and precipitation, respectively, with approximately exponential and power-law decays in their autocorrelation functions, respectively. The stochastic model presented here captures these four statistical features in time series of CWV and precipitation at a single location. In addition, analytic solutions are given for the exponential tails, which directly relates the tails to model parameters. The model parameterization includes three stochastic components: a stochastic trigger turns the convection on and off (a two-state Markov jump process), and stochastic closures represent variability in precipitation and in “external” forcing (Gaussian white noise). This stochastic external forcing is seen to be crucial for obtaining extreme precipitation events with high CWV and long lifetimes, because it can occasionally compensate for the heavy precipitation and encourage more of it. This stochastic model can also be seen as a simplified stochastic convective parameterization, and it demonstrates simple ways to turn a deterministic parameterization—the trigger and/or closure—into a stochastic one.
Presentations and Treatment of Childhood Scleroderma: Localized Scleroderma, Eosinophilic Fasciitis, Systemic Sclerosis, and Graft-Versus-Host Disease
Authors: Hedrich Christian Michael , Fiebig Barbara , Hahn Gabriele , Suttorp Meinolf , Gahr Manfred
Published: April 2011

Juvenile scleroderma is a rare connective tissue disease that involves the skin and subcutaneous tissue. Among all presentations of juvenile scleroderma, localized scleroderma (JLSc) is the most frequent, followed by systemic disease (JSSc) and eosinophilic fasciitis (EF). In posttransplantation chronic graft-versus-host disease (GvHD), scleroderma-like skin involvement can occur. Systemic forms of juvenile scleroderma and GvHD can affect the internal organs, such as the lungs, the gastrointestinal tract, the heart, and kidneys and cause disability and severe, sometimes lethal, complications. Here, the authors give an overview of different presentations of juvenile scleroderma. They report their experience with the different forms and presentations of scleroderma, diagnostic workups, treatment, and outcome of all forms of childhood scleroderma in the context of the existing literature.
Epidemiology of Bowling-Related Injuries Presenting to US Emergency Departments, 1990-2008
Authors: Kerr Zachary Y. , Collins Christy L. , Dawn Comstock R.
Published: April 2011

Objective. To examine bowling-related injuries presenting to US emergency departments (EDs) from 1990 to 2008. Methods. Bowling-related injury data were analyzed from the US Consumer Product Safety Commission’s National Electronic Injury Surveillance System. Results. From 1990 to 2008, 8754 bowling injuries presented to US EDs, correlating to an estimated 375 468 injuries nationwide. Common body parts injured were the finger (19.0%), trunk (15.8%), and ankle/foot/toe (14.9%). Common diagnoses were sprain/strain (42.7%) and soft-tissue injury (20.3%). Children <7 years old had a higher proportion of finger injuries (49.2%) and injuries from dropping the ball (42.8%) than individuals ≥7 years old (15.9%, injury proportion ratio [IPR] = 3.09, 95% confidence interval [CI] = 2.76-3.45, P < .001; and 15.9%, IPR = 2.69, 95% CI = 2.32-3.12, P < .001, respectively). Seniors ≥65 years old sustained a greater proportion of injuries related to falling/slipping/tripping (72.4%) than individuals <65 years old (38.3%; IPR = 1.89, 95% CI = 1.74-2.05, P < .001). Conclusions. Bowling injuries vary by age and gender. Further research on such differences is needed to drive the development of targeted, evidence-based injury prevention strategies.
Prevention and Treatment of Childhood Obesity: Care Received by a State Medicaid Population
Authors: Lazorick Suzanne , Peaker Brandy , Perrin Eliana M. , Schmid Dorothee , Pennington Tamerra , Yow Angie , DuBard C. Annette
Published: April 2011

Based on chart review for a representative cluster sample of North Carolina Medicaid enrollees aged 3 to 5 years (n = 1951) and 13 to 16 years (n = 1922) years, this study describes prevalence, practice patterns, and comorbidities related to overweight/obese immediately prior to 2007 Expert Recommendations. In total, 16% of children in both age groups were overweight, and 20% (ages 3-5 years) and 25% (ages 13-16 years) were obese. For 3- to 5-year-olds, body mass index percentile was infrequently recorded (22%) or plotted on growth charts (24%), and weight status category was rarely documented (10%). Results were similar for adolescents (21%, 20%, and 12%, respectively). In both groups, documentation of counseling in nutrition or physical activity was rare (16% for ages 3-5 years; 7% for ages 13-16 years). In adolescents, approximately 20% received recommended laboratory screening and overweight/ obesity was significantly associated with chart-documented asthma, back pain, prediabetes, gastroesophageal reflux disease, hypertension, and sleep apnea. Whether improvements in documentation of care followed these new guidelines deserves further research.
Diagnostic Yield of Genetic Testing in Children Diagnosed With Autism Spectrum Disorders at a Regional Referral Center
Authors: Roesser Jessica
Published: April 2011

The aim was to systematically review genetic testing guidelines in the evaluation of children with autism spectrum disorders (ASDs). The Clinical Report published by the American Academy of Pediatrics (AAP)1 recommended individualizing the workup, including karyotype and specific DNA testing for fragile X syndrome. A recent publication reported higher rates of abnormalities on CGH microarray (CMA) testing on children with ASD.2 The medical records of 507 children seen through the Kirch Developmental Services Center were abstracted for genetic testing and factors associated with this testing. Abnormalities were found on karyotype in 2.3% and in DNA for fragile X in 0.04%. The author concludes that the diagnostic yield of the genetic testing was low in this population. Furthermore, their findings support the theory that CMA can be considered as part of the initial genetic screening in children with ASD in most situations. Future studies will need to be done prospectively to evaluate children in a standard fashion.
University systems in the Arab East: Publish globally and perish locally vs publish locally and perish globally
Authors: Hanafi Sari
Published: April 2011

This article attempts to demonstrate how the university system and the system of social knowledge production greatly influence elite formation in the Arab East (in Egypt, Syria, the Palestinian territory, Jordan and Lebanon) by focusing on three intertwined factors: compartmentalization of scholarly activities, the demise of the university as a public sphere and the criteria for publication that count towards promotion. Universities have often produced compartmentalized elites inside each nation-state and they don’t communicate with one another: they are either elite that publish globally and perish locally or elite that publish locally and perish globally. The article pays special attention to elite universities.
Beyond Popular Cultural and Structural Arguments
Authors: Hughes Sherick A. , North Connie E.
Published: April 2011

This manuscript begins by distinguishing the common structural and cultural arguments that tend to guide popular urban achievement gap research. It highlights Jencks and Phillips, and Payne, as two cases of popular texts followed by critical responses to them. It concludes by imagining a compass to guide burgeoning scholars toward reading into research “more complexly” so as to enhance and proliferate critiques 1 of popular cultural and structural arguments and to dissuade abrupt, myopic, and polemic responses.
Examining the Relationship Between TELPAS Reading and TAKS Reading for Students With Limited English Proficiency
Authors: Badgett Kevin , Harrell Scott , Carman Carol A. , Lyles Lance
Published: April 2011

In the performance-driven culture of education today, though arguments regarding the definition of student success abound, few argue its importance. This issue is complicated with an additional dimension for those who are learning English as a second language. For those students who lack proficiency in the English language, academic content must be learned concurrently with the acquisition of the English language. The issue of language acquisition became part of the national education dialogue with the Supreme Court Decision Lau v. Nichols in 1974. It has continued to be a serious issue throughout the country and particularly in the southeast region of Texas. This article will examine how English-language learners (ELLs) are assessed. Specifically, it will focus on the relationship between the standardized academic exam administered to almost all students in Texas and the language acquisition exam for reading administered to almost all ELL students in the state. Furthermore, this article will examine the results of a regression analysis performed to determine the predictive value of using raw scores on the reading test for ELLs to predict raw scores on the standardized academic exam taken by those students at Grades 3, 5 and 8 in the same academic year.
Equality on Different Terms
Authors: Merry Michael S. , Driessen Geert
Published: April 2011

In this article the authors examine the reasons for the establishment of Hindu schools in the Netherlands and how the Dutch system of education facilitates these and other voluntarily separate schools. In particular, the authors explore the manner in which Hindu schools aim to cultivate and sustain attachments to their own group through a culturally specific approach to learning and belonging that promises greater educational equality. The authors argue that the special features of Dutch Hindu schools, as a form of voluntary separation, may better facilitate and promote equality of educational opportunity than other options available to the Dutch Hindu community.
Characteristics of Head-Mounted Displays and Their Effects on Simulator Sickness
Authors: Moss Jason D. , Muth Eric R.
Published: April 2011

Objective: We examined the effects of several display characteristics of head-mounted displays (HMDs) on simulator sickness (SS).

Background: Technological limitations, such as display delay and reduced field of view (FOV), affect perception when using an HMD and are often thought to be related to SS. Few studies have examined the relationship between FOV and geometric FOV (image scale factor) or how HMD characteristics may interact.

Method: Participants made active head movements to locate objects when viewing a live video via an HMD.

Results: Compared with no added delay, an additional 200 ms of display delay did not result in increased SS, as measured by the Simulator Sickness Questionnaire. Furthermore, an effect of image scale factor on SS was not revealed. However, SS was greater when peripheral vision was occluded than when it was not. Peripheral vision moderated the effects of image scale factor and delay on head movement velocity.

Conclusion: Occluding peripheral vision may subject HMD users to the potential detrimental consequences of HMD characteristics more than when peripheral vision of the external environment is available, resulting in more SS. Future research should investigate to what extent peripheral vision can be occluded without increasing SS and without sacrificing realism and presence.

Application: To reduce the occurrence of SS, a degree of peripheral vision of the external world should be provided. Furthermore, users and designers should be aware that head movement behavior may be affected by HMD characteristics.
The Perception of Pathologically-disordered Phonation by Gujarati, English, and Spanish Listeners
Authors: Esposito Christina M.
Published: April 2011

This study investigates the influence of linguistic experience on the perception of pathologically-disordered voices using 18 listeners of American English, which has allophonic breathiness, 12 listeners of Gujarati, which contrasts breathy and modal vowels, and 18 listeners of Spanish, which has neither allophonic nor phonemic breathiness. Listeners rated the similarity of pairs of pathologically-disordered voices. Multidimensional scaling was used to determine the properties that were most correlated with perception for each listener group. Results showed that Gujaratis’ perception was correlated with the difference between the amplitude of the first (H1*) and second (H2*) harmonic (H1*-H2*), which is associated with the production of phonation in Gujarati. English listeners’ judgments were correlated with the measure H1*-H2* and cepstral peak prominence, and Spanish listeners’ judgments were correlated with H1*-H2 and H1*-A1* (the amplitude of the principal harmonic near the first formant). When compared to Esposito (2006), which asked the same listeners to rate the similarity of breathy and modal vowels from Mazatec, results showed that Gujarati listeners classified the pathologically-disordered stimuli in the same way that they classified the Mazatec stimuli, while English and Spanish listeners perceived the pathologically-disordered stimuli and the Mazatec stimuli in slightly different ways.
Clarifying Relationships Between Ideology and Ideologically Oriented Cable TV News Use
Authors: Holbert R. Lance , Hmielowski Jay D. , Weeks Brian E.
Published: April 2011

Much recent debate in political communication has centered on the influence of ideologically oriented media outlets. Some argue that the current media environment is creating partisan echo chambers, while others contend that today’s political media afford citizens increased contact with a diverse range of opinion. The current study seeks to clarify relationships between political ideology, conservative cable TV news viewing (i.e., FOX News), and liberal cable TV news viewing (i.e., MSNBC), arguing that ideology serves as a suppressor of the relationship between the two seemingly disparate forms of cable TV news consumption. Analyses of primary 2009-2010 statewide survey data ( N = 305) reveal the relationship between FOX News and MSNBC consumption to be positive and this association increases substantially once the role of ideology as suppressor is addressed. A secondary analysis of 2010 PEW data ( N = 3,006) reveals a strong replication of the primary analysis results.
The Conflicting Influences of Religiosity on Attitude Toward Torture
Authors: Malka Ariel , Soto Christopher J.
Published: April 2011

This research examines the thesis that religiosity has conflicting influences on Americans’ attitudes about the use of torture on terrorism suspects: an organic influence favoring opposition to torture and a discursively driven influence favoring support of torture. In each of two national samples, religiosity had both a direct effect toward opposition to torture and an indirect effect—via conservative political alignment—toward support of torture. Multiple-group analyses revealed that the direct effect toward opposition to torture did not vary across Americans with differing levels of exposure to political discourse, whereas the indirect effect toward support of torture via conservative political alignment was much stronger among Americans highly exposed to political discourse. Among such individuals, the indirect effect was so strong that it completely counteracted the competing direct effect. Discussion focuses on the competing influences that a single nonpolitical psychological characteristic may have on a political preference.
The Induction of Shared Identity: The Positive Role of Individual Distinctiveness for Groups
Authors: Jans Lise , Postmes Tom , Van der Zee Karen I.
Published: April 2011

This article examines inductive processes of social identity formation, the bottom-up processes by which individual group members influence a social identity, integrating it with work on entitativity. Three studies tested the prediction that feelings of individual distinctiveness mediate the relation between inductive social identity formation and entitativity and that entitativity in turn predicts identification. The studies provided consistent support for this theoretical model over alternative models, using a range of different social groups and methods. Study 1 found support for the model in self-selected small groups. Study 2 supported it with a much broader set of groups that were not self-selected. Finally, Study 3 varied levels of inductive social identity formation systematically by varying group size and provided direct support for the hypothesized causal relations.