bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of depolarizing GABAA-mediated membrane responses on excitability of Cajal-Retzius cells in the immature rat neocortex
Authors: Kolbaev S. N. , Achilles K. , Luhmann H. J. , Kilb W.
Published: July 2011

In immature neurons activation of ionotropic GABA receptors induces depolarizing membrane responses due to a high intracellular Cl− concentration ([Cl−]i). However, it is difficult to draw conclusions about the functional consequences of subthreshold GABAergic depolarizations, since GABAergic membrane shunting and additional effects on voltage-dependent ion channels or action potential threshold must be considered. To systematically investigate factors that determine the GABAergic effect on neuronal excitability we performed whole cell patch-clamp recordings from Cajal-Retzius cells in immature rat neocortex, using [Cl−]i between 10 and 50 mM. The effect of focal GABA application was quantified by measuring various parameters of GABAergic responses including the shift in minimal threshold current (rheobase). The rheobase shift was correlated with other parameters of the GABAergic responses by multiple linear regression analyses with a set of simple mathematical models. Our experiments demonstrate that focal GABA application induces heterogeneous rheobase shifts in Cajal-Retzius cells that could not be predicted reliably from [Cl−]i or the GABAergic membrane depolarization. Implementation of a linear mathematical model, which takes the GABAergic membrane conductance and the difference between action potential threshold and GABA reversal potential into account, resulted in a close correlation between calculated and experimentally obtained rheobase shifts. Addition of a linear term proportional to the GABAergic membrane depolarization improved the accuracy of correlation. The main advantage of using multiple linear regression with simple models is that direction and strength of GABAergic excitability shifts can be analyzed by using only measured parameters of GABAergic responses and with minimal a priori information about cellular parameters.
Revisiting the reticulum: feedforward and feedback contributions to motor program parameters in the crab cardiac ganglion microcircuit
Authors: García-Crescioni Keyla , Miller Mark W.
Published: July 2011

The neurogenic heartbeat of crustaceans is controlled by the cardiac ganglion (CG), a central pattern generator (CPG) microcircuit composed of nine neurons. In most decapods, five “large” motor neurons (MNs) project from the CG to the myocardium, where their excitatory synaptic signals generate the rhythmic heartbeat. The processes of four “small” premotor neurons (PMNs) are confined to the CG, where they provide excitatory drive to the MNs via impulse-mediated chemical signals and electrotonic coupling. This study explored feedforward and feedback interactions between the PMNs and the MNs in the CG of the blue crab ( Callinectes sapidus). Three methods were used to compare the activity of the MNs and the PMNs in the integrated CG to their autonomous firing patterns: 1) ligatures were tightened on the ganglion trunk that connects the PMNs and MNs; 2) TTX was applied focally to suppress selectively PMN or MN activity; and 3) sucrose pools were devised to block reversibly PMN or MN impulse conduction. With all treatments, the PMNs and MNs continued to produce autonomous rhythmic bursting following disengagement. Removal of PMN influence resulted in a significantly reduced MN duty cycle that was mainly attributable to a lower autonomous burst frequency. Conversely, after removal of MN feedback, the PMN duty cycle was increased, primarily due to a prolonged burst duration. Application of sucrose to block impulse conduction without eliminating PMN oscillations disclosed significant contributions of spike-mediated PMN-to-MN signals to the initiation and prolongation of the MN burst. Together, these observations support a view of the Callinectes CG composed of two classes of spontaneously bursting neurons with distinct endogenous rhythms. Compartmentalized feedforward and feedback signaling endow this microcircuit with syncytial properties such that the intrinsic attributes of the PMNs and MNs both contribute to shaping all parameters of the motor patterns transmitted to the myocardium.
Human Coronaviruses HCoV-NL63 and HCoV-HKU1 in Hospitalized Children with Acute Respiratory Infections in Beijing, China
Authors: Cui Li-Jin , Zhang Chen , Zhang Ting , Lu Rou-Jian , Xie Zheng-De , Zhang Ling-Lin , Liu Chuan-Yan , Zhou Wei-Min , Ruan Li , Ma Xue-Jun , Tan Wen-Jie
Published: July 2011

The human coronaviruses (HCoVs) HCoV-NL63 and HCoV-HKU1 are two recently discovered coronaviruses that circulate widely and are associated with acute respiratory infections (ARI). We detected HCoV-NL63 and HCoV-HKU1 in specimens collected from May 2008 to March 2010 from patients with ARI aged <7.75 years of age attending the Beijing Children's Hospital. Thirty-two (8.4%) and 57 (14.9%) of 382 specimens tested positive for HCoV-NL63 and HCoV-HKU1, respectively, by real-time RT-PCR. Use of a Luminex xTAG RVP Fast kit showed that coinfection with respiratory syncytial virus and parainfluenza 3 virus was common among patients infected with either virus type. In HCoV-HKU1-infected patients, the predominant clinical symptoms were cough, fever, and expectoration. In HCoV-NL63-infected patients they were cough, fever, and rhinorrhea. Phylogenetic studies showed that the HCoV-HKU1 nucleoprotein gene was relatively conserved compared to NCBI reference sequences, while the 1ab gene of HCoV-NL63 showed more variation.
Chern-Simons: Fano and Calabi-Yau
Authors: Hanany Amihay , He Yang-Hui
Published: July 2011

We present the complete classification of smooth toric Fano threefolds, known to the algebraic geometry literature, and perform some preliminary analyses in the context of brane tilings and Chern-Simons theory on M2-branes probing Calabi-Yau fourfold singularities. We emphasise that these 18 spaces should be as intensely studied as their well-known counterparts: the del Pezzo surfaces.
The Many Forms and Functions of Long Term Plasticity at GABAergic Synapses
Authors: Maffei Arianna
Published: July 2011

On February 12th 1973, Bliss and Lomo submitted their findings on activity-dependent plasticity of glutamatergic synapses. After this groundbreaking discovery, long-term potentiation (LTP) and depression (LTD) gained center stage in the study of learning, memory, and experience-dependent refinement of neural circuits. While LTP and LTD are extensively studied and their relevance to brain function is widely accepted, new experimental and theoretical work recently demonstrates that brain development and function relies on additional forms of plasticity, some of which occur at nonglutamatergic synapses. The strength of GABAergic synapses is modulated by activity, and new functions for inhibitory synaptic plasticity are emerging. Together with excitatory neurons, inhibitory neurons shape the excitability and dynamic range of neural circuits. Thus, the understanding of inhibitory synaptic plasticity is crucial to fully comprehend the physiology of brain circuits. Here, I will review recent findings about plasticity at GABAergic synapses and discuss how it may contribute to circuit function.
Why Treat Apogeotropic BPPVs of the Horizontal Canal? About 30 Observations
Authors: Lorin Philippe , Foubert Francois , Debaty Marie
Published: July 2011

Benign paroxysmal positional vertigo (BPPV), of the horizontal canal, in the apogeotropic form (AHBPPV) was described in 1995. Based on 30 observations of typical AHBPPVs of the horizontal canal, we endeavor to discuss the relevance of physiotherapy.Material and Method.Thirty observations of typical apogeotropic BPPVs of the horizontal canal treated with a 360°barbeque rotation on the BPPV side, reviewed in consultation at 1 and 3 weeks and reevaluated the following year.Results.Our cohort of 30 patients had an average age of 58.6 years. The apogeotropic BPPVs of the horizontal canal, which can be transformed into BPPVs of the posterior canal or into geotropic-type BPPVs of the horizontal canal do not recover more quickly. Patients who follow the positional advice do not recover more quickly than those who do not (P  =  0.152). The 15 patients treated on average 13.73 days after the onset of the disease did not recover more quickly after the start of therapeutic treatment than those treated later (P  =  0.032).Conclusion.Here, we demonstrate that the direction of rotation during the maneuvers is of no importance for the results. We show that transformability is not a guarantee of rapid recovery and that the therapist’s effectiveness is limited when it comes to the short-term results.
CI431, an Aqueous Compound from Ciona intestinalis L., Induces Apoptosis through a Mitochondria‐Mediated Pathway in Human Hepatocellular Carcinoma Cells
Authors: Cheng Linyou , Liu Ming , Wang Cuicui , Liu Haizhou , Zhang Yuyan , Lin Xiukun
Published: July 2011

In the present studies, a novel compound with potent anti‐tumor activity from Ciona intestinalis L. was purified by acetone fractionation, ultrafiltration, gel chromatography and High Performance Liquid Chromatography. The molecular weight of the highly purified compound, designated CI431, was 431Da as determined by HPLC‐MS analysis. CI431 exhibited significant cytotoxicity to several cancer cell types. However, only a slight inhibitory effect was found when treating the benign human liver cell line BEL‐7702 with the compound. To explore its mechanism against hepatocellular carcinoma, BEL‐7402 cells were treated with CI431 in vitro. We found that CI431 induced apoptotic death in BEL‐7402 cells in a dose‐ and time‐dependent manner. Cell cycle analysis demonstrated that CI431 caused cell cycle arrest at the G2/M phase, and a sub‐G1 peak appeared after 24 h. The mitochondrial‐mediated pathway was implicated in this CI431‐induced apoptosis as evidenced by the disruption of mitochondrial membrane potential. The results suggest that the CI431 induces apoptosis in BEL‐7402 human hepatoma cells by intrinsic mitochondrial pathway.
Internet-Based Support for Cardiovascular Disease Management
Authors: Jarvis-Selinger Sandra , Bates Joanna , Araki Yuriko , Lear Scott A.
Published: July 2011

With significant declines in cardiovascular disease (CVD) mortality, attention has shifted to patient management. Programs designed to manage CVD require the involvement of health professionals for comanagement and patients' self-management. However, these programs are commonly limited to large urban centers, resulting in limited access for rural patients. The use of telehealth potentially overcomes geographical barriers and can improve access to care for patients. The current research explores how an Internet-based platform might facilitate collaboration among healthcare providers comanaging patients and enhance behavioural change in patients. Forty-eight participants were interviewed including: (a) patients (n=12), (b) physicians (n=11), (c) nurses (n=13), and (d) allied health professionals (n=10). The results were organized and analyzed in three central themes: (1) role of technology for CVD management, (2) challenges to technology adoption, and (3) incentives for technology adoption. Health care providers and patients supported future implementation of Internet-based technology support for CVD management.
Key Working for Families with Young Disabled Children
Authors: Carter Bernie , Thomas Megan
Published: July 2011

For families with a disabled child, the usual challenges of family life can be further complicated by the need to access a wide range of services provided by a plethora of professionals and agencies. Key working aims to support children and their families in navigating these complexities ensuring easy access to relevant, high quality, and coordinated care. The aim of this paper is to explore the key worker role in relation to “being a key worker” and “having a key worker”. The data within this paper draw on a larger evaluation study of the Blackpool Early Support Pilot Programme. The qualitative study used an appreciative and narrative approach and utilised mixed methods (interviews, surveys and a nominal group workshop). Data were collected from 43 participants (parents, key workers, and other stakeholders). All stakeholders who had been involved with the service were invited to participate. In the paper we present and discuss the ways in which key working made a difference to the lives of children and their families. We also consider how key working transformed the perspectives of the key workers creating a deeper and richer understanding of family lives and the ways in which other disciplines and agencies worked. Key working contributed to the shift to a much more family-centred approach, and enhanced communication and information sharing between professionals and agencies improved. This resulted in families feeling more informed. Key workers acted in an entrepreneurial fashion, forging new relationships with families and between families and other stakeholders. Parents of young disabled children and their service providers benefited from key working. Much of the benefit accrued came from strong, relational, and social-professional networking which facilitated the embedding of new ways of working into everyday practice. Using an appreciative inquiry approach provided an effective and relevant way of engaging with parents, professionals, and other stakeholders to explore what was working well with key working within an Early Support Pilot Programme.
Influence of Parameters of Cold Isostatic Pressing on TiO2Films for Flexible Dye-Sensitized Solar Cells
Authors: Peng Yong , Liu Jefferson Zhe , Wang Kun , Cheng Yi-Bing
Published: July 2011

Cold Isostatic Pressing (CIP) is used to make TiO2working electrodes for flexible dye-sensitized solar cells (DSCs). Different CIP processes, varying pressures from 50 MPa to 200 MPa and holding time 1 s up to 600 s, are performed to study the effect of CIP on the resistivity of TiO2electrode thin films and the power conversion efficiency (PCE) of DSCs. The results show that the CIP process has significantly improved the PCE of DSC devices. Electrochemical impedance spectroscopy (EIS) analysis indicates a clear correlation between the PCE enhancement and the resistivity reduction in TiO2thin films after various CIP processes. Porosity reduction and localized joints formed between some TiO2nanoparticles due to the friction heat in the CIP process are believed to be responsible for the resistivity reduction of the TiO2working electrode thin films.
Pilot Study on Clinical Effectiveness of Autofluorescence Imaging for Early Gastric Cancer Diagnosis by Less Experienced Endoscopists
Authors: Tada Kazuhiro , Oda Ichiro , Yokoi Chizu , Taniguchi Tomoyasu , Sakamoto Taku , Suzuki Haruhisa , Nonaka Satoru , Yoshinaga Shigetaka , Saito Yutaka , Gotoda Takuji
Published: July 2011

This study aimed to assess and compare effectiveness of Autofluorescence imaging (AFI) in diagnosis of early gastric cancer (EGC) between experienced and less experienced endoscopists. Fifty selected images (20 neoplastic lesions and 30 benign lesions/areas) of both white light endoscopy (WLE) and AFI were blindly reviewed by two groups; first consisted of five experienced endoscopists and second included five less experienced endoscopists. Sensitivity, specificity, and accuracy were 70%, 78%, and 75%, respectively, for AFI and 81%, 76%, and 78%, respectively, for WLE in the experienced group. In the less experienced group, sensitivity, specificity and accuracy were 80%, 81% and 80%, respectively, for AFI and 65%, 77%, and 72%, respectively, for WLE. Interobserver variability for the less experienced group was better with AFI than WLE. AFI improved sensitivity of endoscopic diagnosis of neoplastic lesions by less experienced endoscopists, and its use could beneficially enhance the clinical effectiveness of EGC screening.
Identification of a Novel Mutation in a Pseudohypoparathyroidism Family
Authors: Miao Zhi-Min , Wang Can , Wang Bin-Bin , Meng Dong-Mei , Su Dong-Mei , Cheng Zhi , Wen Qiao-Lian , Han Lin , Yu Qing , Ma Xu , Li Chang-Gui
Published: July 2011

Pseudohypoparathyroidism type Ia (PHP Ia) is defined as a series of disorders characterized by multihormone resistance in end-organs and Albright hereditary osteodystrophy (AHO) phenotype. PHP Ia is caused by heterozygous inactivating mutations in GNAS, which encodes the stimulatory G-protein alpha subunit (Gsa). A patient with typical clinical manifestations of pseudohypoparathyroidism (PHP) (round face, short stature, centripetal obesity, brachydactyly, and multi-hormone resistance: parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and gonadotropins) presented at our center. The sequence of the GNAS gene from the patient and her families revealed a novel missense mutation (Y318H) in the proband and her mother. An in vitro Gsa functional study showed that Gsa function was significantly impaired. These results stress the importance of GNAS gene investigation.
No Null‐Helix Mannheim Curves in the Minkowski Space	𝔼13
Authors: Lee Jae Won
Published: July 2011

We study a null Mannheim curve with time‐like or space‐like Mannheim partner
curve in the Minkowski 3‐space .
We get the characterization of a null Mannheim curve. Then, we investigate there
is no null‐helix Mannheim curve in .
On the Sodium Concentration Diffusion with Three‐Dimensional Extracellular Stimulation
Authors: Consiglieri Luisa , Domingos Ana Rute
Published: July 2011

We deal with the transmembrane sodium diffusion in a nerve. We study a mathematical model of a nerve fibre in response to an imposed extracellular stimulus. The presented model is constituted by a diffusion‐drift vectorial equation in a bidomain, that is, two parabolic equations defined in each of the intra‐ and extra‐regions. This system of partial differential equations can be understood as a reduced three‐dimensional Poisson‐Nernst‐Planck model of the sodium concentration. The representation of the membrane includes a jump boundary condition describing the mechanisms involved in the excitation‐contraction couple. Our first novelty comes from this general dynamical boundary condition. The second one is the three‐dimensional behaviour of the extracellular stimulus. An analytical solution to the mathematical model is proposed depending on the morphology of the excitation.
The Histological and Immunohistochemical Aspects of Bile Reflux in Patients with Gastroesophageal Reflux Disease
Authors: Nakos Andreas , Kouklakis Georgios , Pitiakoudis Michail , Zezos Petros , Efraimidou Eleni , Giatromanolaki Alexandra , Polychronidis Alexandros , Liratzopoulos Nikolaos , Sivridis Efthimios , Simopoulos Konstantinos
Published: July 2011

Introduction. The pathogenesis of GERD is strongly related with mixed acid and bile reflux. Benign and malignant esophageal and gastric lesions have been associated with synergetic activity between those parameters. Bile reflux causes reactive gastropathy evaluated with Bile Reflux Index (BRI). The aim was to investigate if the sequence:bile reflux-intestinal metaplasia-GERD-esophagitis,is associated with apoptotic/oncogenetic disturbances.Materials/Methods. Fifteen asymptomatic subjects and 53 GERD patients underwent gastroscopy with biopsies. The specimens examined histologically and immunohistochemically for p53, Ki-67, Bax, and Bcl-2.Results. Elevated BRI score detected in 47% (25/53) of patients with GERD and in 13% (2/15) of controls (P=0.02). Severe esophageal lesions were significantly more common in BRI (+) patients (14/25) compared to BRI (−) ones (P=0.0049). Immunohistochemical analysis did not show associations between BRI score and biomarker expression.Conclusions. Bile reflux gastropathy is associated with GERD severity, but not with oncogene expression or apoptotic discrepancies of the upper GI mucosa.
Enhanced Antitumoral Activity of Extracts Derived from Cultured Udotea flabellum (Chlorophyta)
Authors: Moo-Puc Rosa , Robledo Daniel , Freile-Pelegrin Yolanda
Published: July 2011

Very few studies have been performed to evaluate the effect of culture conditions on the production or activity of active metabolites in algae. Previous studies suggest that the synthesis of bioactive compounds is strongly influenced by irradiance level. To investigate whether the antiproliferative activity of Udotea flabellum extracts is modified after cultivation, this green alga was cultured under four photon flux densities (PFD) for 30 days. After 10, 20, and 30 days, algae were extracted with dichloromethane: methanol and screened for antiproliferative activity against four human cancer cell lines (laryngeal—Hep‐2, cervix—HeLa, cervix squamous—SiHa and nasopharynx—KB) by SRB assay. Lipid and phenol content were evaluated by standardized methods on algae organic extracts. After 10 days of cultivation, organic U. flabellum extracts showed a significant increase in antiproliferative activity on Hela and SiHa cells when compared to noncultured algae extracts. Extracts obtained after 10 and 20 days of culture were active on KB and Hep‐2 cells. Total phenol and polyunsaturated fatty acid content in organic extracts changed with cultivation time but not by irradiance treatment. Extracts from U. flabellum obtained after 10 and 20 days of culture have been selected for fractionation and isolation of active compounds.
Modulating Microtubule Stability Enhances the Cytotoxic Response of Cancer Cells to Paclitaxel
Authors: Ahmed Ahmed Ashour , Wang Xiaoyan , Lu Zhen , Goldsmith Juliet , Le Xiao-Feng , Grandjean Geoffrey , Bartholomeusz Geoffrey , Broom Bradley , Bast Robert C.
Published: July 2011

The extracellular matrix protein TGFBI enhances the cytotoxic response of cancer cells to paclitaxel by affecting integrin signals that stabilize microtubules. Extending the implications of this knowledge, we tested the more general hypothesis that cancer cell signals which increase microtubule stability before exposure to paclitaxel may increase its ability to stabilize microtubules and thereby enhance its cytotoxicity. Toward this end, we carried out an siRNA screen to evaluate how genetic depletion affected microtubule stabilization, cell viability, and apoptosis. High content microscopic analysis was carried out in the absence or presence of paclitaxel. Kinase knockdowns that stabilized microtubules strongly enhanced the effects of paclitaxel treatment. Conversely, kinase knockdowns that enhanced paclitaxel-mediated cytotoxicity sensitized cells to microtubule stabilization by paclitaxel. The siRNA screen identified several genes that have not been linked previously to microtubule regulation or paclitaxel response. Gene shaving and Bayesian resampling used to classify these genes suggested three pathways of paclitaxel-induced cell death related to apoptosis and microtubule stability, apoptosis alone, or neither process. Our results offer a functional classification of the genetic basis for paclitaxel sensitivity and they support the hypothesis that stabilizing microtubules prior to therapy could enhance antitumor responses to paclitaxel treatment. Cancer Res; 71(17); 5806–17. ©2011 AACR.
Hedgehog Signaling: Networking to Nurture a Promalignant Tumor Microenvironment
Authors: Harris Lillianne G. , Samant Rajeev S. , Shevde Lalita A.
Published: July 2011

In addition to its role in embryonic development, the Hedgehog pathway has been shown to be an active participant in cancer development, progression, and metastasis. Although this pathway is activated by autocrine signaling by Hedgehog ligands, it can also initiate paracrine signaling with cells in the microenvironment. This creates a network of Hedgehog signaling that determines the malignant behavior of the tumor cells. As a result of paracrine signal transmission, the effects of Hedgehog signaling most profoundly influence the stromal cells that constitute the tumor microenvironment. The stromal cells in turn produce factors that nurture the tumor. Thus, such a resonating cross-talk can amplify Hedgehog signaling, resulting in molecular chatter that overall promotes tumor progression. Inhibitors of Hedgehog signaling have been the subject of intense research. Several of these inhibitors are currently being evaluated in clinical trials. Here, we review the role of the Hedgehog pathway in the signature characteristics of cancer cells that determine tumor development, progression, and metastasis. This review condenses the latest findings on the signaling pathways that are activated and/or regulated by molecules generated from Hedgehog signaling in cancer and cites promising clinical interventions. Finally, we discuss future directions for identifying the appropriate patients for therapy, developing reliable markers of efficacy of treatment, and combating resistance to Hedgehog pathway inhibitors. Mol Cancer Res; 9(9); 1165–74. ©2011 AACR.
PPM1H Is a p27 Phosphatase Implicated in Trastuzumab Resistance
Authors: Lee-Hoeflich Si Tuen , Pham Thinh Q. , Dowbenko Don , Munroe Xander , Lee James , Li Li , Zhou Wei , Haverty Peter M. , Pujara Kanan , Stinson Jeremy , Chan Sara M. , Eastham-Anderson Jeffrey , Pandita Ajay , Seshagiri Somasekar , Hoeflich Klaus P. , Turashvili Gulisa , Gelmon Karen A. , Aparicio Samuel A. , Davis David P. , Sliwkowski Mark X. , Stern Howard M.
Published: July 2011

The HER2 oncogene is overexpressed or amplified in 20% of breast cancers. HER2-positive cancer historically portends a poor prognosis, but the HER2-targeted therapy trastuzumab mitigates this otherwise ominous distinction. Nevertheless, some patients suffer disease recurrence despite trastuzumab, and metastatic disease remains largely incurable due to innate and acquired resistance. Thus, understanding trastuzumab resistance remains an unmet medical need. Through RNA interference screening, we discovered that knockdown of the serine/threonine phosphatase PPM1H confers trastuzumab resistance via reduction in protein levels of the tumor suppressor p27. PPM1H dephosphorylates p27 at threonine 187, thus removing a signal for proteasomal degradation. We further determined that patients whose tumors express low levels of PPM1H trend towards worse clinical outcome on trastuzumab. Identifying PPM1H as a novel p27 phosphatase reveals new insight into how cancer cells destabilize a well-recognized tumor suppressor. Furthermore, low PPM1H expression may identify a subset of HER2-positive tumors that are harder to treat.

Significance: PPM1H is identified as a phosphatase impacting p27 stability. Low expression of PPM1H may be associated with poor outcome in breast cancer. Cancer Discovery; 1(4); 326–337. ©2011 AACR.

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ERα-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer
Authors: Miller Todd W. , Balko Justin M. , Fox Emily M. , Ghazoui Zara , Dunbier Anita , Anderson Helen , Dowsett Mitch , Jiang Aixiang , Smith R. Adam , Maira Sauveur-Michel , Manning H. Charles , González-Angulo Ana M. , Mills Gordon B. , Higham Catherine , Chanthaphaychith Siprachanh , Kuba Maria G. , Miller William R. , Shyr Yu , Arteaga Carlos L.
Published: July 2011

Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER+ xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers.

Significance: ERα retains genomic activity and drives a CDK4/E2F-dependent transcriptional program despite estrogen deprivation therapy. Combined inhibition of ER and PI3K induced regression of ER+ xenografts, supporting further development of strong ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for the treatment of antiestrogen-resistant breast cancers. Cancer Discovery; 1(4); 338–51. ©2011 AACR.

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Testing Gene-Gene Interactions in the Case-Parents Design
Authors: Yu Zhaoxia
Published: July 2011

The case-parents design has been widely used to detect genetic associations as it can prevent spurious association that could occur in population-based designs. When examining the effect of an individual genetic locus on a disease, logistic regressions developed by conditioning on parental genotypes provide complete protection from spurious association caused by population stratification. However, when testing gene-gene interactions, it is unknown whether conditional logistic regressions are still robust. Here we evaluate the robustness and efficiency of several gene-gene interaction tests that are derived from conditional logistic regressions. We found that in the presence of SNP genotype correlation due to population stratification or linkage disequilibrium, tests with incorrectly specified main-genetic-effect models can lead to inflated type I error rates. We also found that a test with fully flexible main genetic effects always maintains correct test size and its robustness can be achieved with negligible sacrifice of its power. When testing gene-gene interactions is the focus, the test allowing fully flexible main effects is recommended to be used.
Intracranial Air Correlates with Preoperative Cerebral Atrophy and Stereotactic Error during Bilateral STN DBS Surgery for Parkinson’s Disease
Authors: Azmi Hooman , Machado Andre , Deogaonkar Milind , Rezai Ali
Published: July 2011

Objective: We examine the effect of intracranial air on stereotactic accuracy during bilateral deep brain stimulation (DBS) surgery for Parkinson’s disease (PD). We also assess factors that may predict an increased risk of intracranial air during these surgeries. Methods: 32 patients with PD underwent bilateral DBS surgery. The technique used for implantation of the leads has been standardized in over 800 subthalamic nucleus (STN) implantations. For lead implantation, the goal of the neurophysiological technique is identification of the STN and its borders with 3 microelectrode recording (MER) tracks. We examined the number of tracks and the degree of deviation from the planned target on each side. Total intracranial air (TIA) was then compared in these groups. We also examined the relationship between the TIA and length of surgery, ventricular volume and the degree of atrophy. Results: Side 2 in this series required more MER tracks. The TIA was larger in patients with more than 3 MER tracks on side 2 of surgery. There was more deviation from the target on side 2. In addition, the TIA in patients with >1 mm of vector deviation on side 2 was more than in those without. The TIA correlated with the number of tracks on side 2 as well as with the degree of the second euclidean deviation on side 2. There was a correlation of degree of atrophy with TIA. Conclusion: In bilateral STN DBS for PD, intracranial air may contribute to error in stereotactic accuracy especially on the second side. In addition, there is a correlation between the accumulated volume of intracranial air and the degree of cerebral atrophy.
Human Retinal Development in an in situ Whole Eye Culture System
Authors: Engelsberg Karl , Ghosh Fredrik
Published: July 2011

Phenotypic characterization of human retinogenesis may be facilitated by use of the tissue culture system paradigm. Traditionally, most culture protocols involve isolation of retinal tissue and/or cells, imposing various degrees of trauma, which in many cases leads to abnormal development. In this paper, we present a novel culture technique using whole embryonic eyes to investigate whether the retina in situ can develop normally in vitro. All procedures were carried out in accordance with the Declaration of Helsinki. Human embryos were obtained from elective abortions with the informed consent of the women seeking abortion. A total of 19 eyes were enucleated. The ages of the embryonic retinas were 6–7.5 weeks. Eyecups from 2 eyes were fixed immediately, to be used as controls. The remaining 17 eyes were placed on culture plates and divided into 3 groups kept for 7 (n = 4), 14 (n = 7) and 28 (n = 6) days in vitro (DIV). After fixation, the specimens were processed for hematoxylin and eosin staining, immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Antibodies against recoverin (rods and cones), protein kinase C (PKC; rod bipolar cells) and vimentin (Müller cells) were used. TUNEL was used to detect apoptotic cells. In hematoxylin- and eosin-stained sections, the control retinas displayed a neuroblast cell layer (NBL) and an inner marginal zone. Specimens kept 7–14 DIV had a similar appearance, while 28-day specimens consisted of an NBL with almost no marginal zone. Thirteen of the 17 cultured retinas displayed completely normal lamination without rosettes or double folds. Pyknotic cells were found at the inner margin of the retinas, and the proportion of these cells increased with time in vitro. TUNEL staining revealed a few scattered cells in 7-DIV specimens, and the amount of stained cells in the inner part of the retinas progressively increased in 14- and 28-DIV specimens. Vimentin labeling showed cells arranged in a vertical pattern in all retinas. Labeling with recoverin revealed photoreceptors in 4 of the retinas kept for 14 DIV, and in all retinas kept for 28 DIV. After 28 DIV, 2 of the eyes labeled with PKC contained rod bipolar cells with minimal axons. Here we showed that human embryonic retinas can be kept in culture in situ within the eye for at least 4 weeks. Abnormal lamination is not as frequent as in isolated full-thickness retinas, indicating that physical and biochemical contact with surrounding tissues is vital for proper development. Several types of the retina-specific neuronal and glial cells were seen to differentiate according to the in vivo schedule. The results are important for future studies of retinal development, and the technique can also be used for testing the effects of various drugs on the immature retina.
Deep Brain Stimulation and Behavioural Changes: Is Comedication the Most Important Factor?
Authors: Lulé Dorothée , Heimrath Johanna , Pinkhardt Elmar H. , Ludolph Albert C. , Uttner Ingo , Kassubek Jan
Published: July 2011

Background: Adverse effects of dopaminergic medication (DA; levodopa and dopamine agonists) on impulsive behaviour and decision-making in patients with Parkinson’s disease (PD) have been repeatedly reported. Deep brain stimulation (DBS) is increasingly used for the treatment of parkinsonian motor symptoms, but the excellent efficacy of DBS contrasts with a growing number of reports that the treatment may result in behavioural complications. Aims: We investigated impulsive behaviour under different therapeutic treatments. Methods: Fifteen patients with PD with DBS (PD-DBS) were assessed with electrical stimulation switched on and off, respectively. Data were compared with those of 15 patients with PD without DBS implantation under DA medication (PD-DA), matched for age and disease duration. Impulsive behaviour (gambling performance) was measured together with neuropsychological assessments regarding depression, current mood and cognitive performance. Results: PD-DA patients performed worse in the gambling task than DBS patients with electrical stimulation turned off. A significant interaction of performance and medication was observed. When DBS was turned on, the differences in performance were less pronounced. Conclusion: For gambling performance, the medication dose mainly explains differences in impulsive behaviour. Although DBS had a minor negative effect on impulsive behaviour, the positive effect of a reduced DA dosis after DBS might reduce impulse control abnormalities.
Development of Mu Rhythm in Infants and Preschool Children
Authors: Berchicci M. , Zhang T. , Romero L. , Peters A. , Annett R. , Teuscher U. , Bertollo M. , Okada Y. , Stephen J. , Comani S.
Published: July 2011

Mu rhythm is an idling rhythm that originates in the sensorimotor cortex during rest. The frequency of mu rhythm, which is well established in adults, is 8–12 Hz, whereas the limited results available from children suggest a frequency as low as 5.4 Hz at 6 months of age, which gradually increases to the adult value. Understanding the normal development of mu rhythm has important theoretical and clinical implications since we still know very little about this signal in infants and how it develops with age. We measured mu rhythm over the left hemisphere using a pediatric magnetoencephalography (MEG) system in 25 infants (11–47 weeks), 18 preschool children (2–5 years) and 6 adults (20–39 years) for two 5-min sessions during two intermixed conditions: a rest condition in which the hands were at rest, and a prehension condition in which the subject squeezed a pipette with his/her right hand. In all participants, mu rhythm was present over the frontoparietal area during the rest condition, but was clearly suppressed during the prehension condition. Mu rhythm peak frequency, determined from the amplitude spectra, increased rapidly as a function of age from 2.75 Hz at 11 weeks to 8.25 Hz at 47 weeks (r2 = 0.83). It increased very slowly during the preschool period (3.1 ± 0.9 years; 8.5 ± 0.54 Hz). The frequency in these children was, however, lower than in adults (10.3 ± 1.2 Hz). Our results show a rapid maturation in spontaneous mu rhythm during the first year of life.
Reciprocal Regulation of Bone and Energy Metabolism
Authors: Baldock Paul
Published: July 2011

Background: The primary relationship affecting skeletal tissue involves the association between fat mass and bone mass. However, there is some complexity in this relationship that may be explained by endocrine and neural pathways representing direct, reciprocal signalling between fat and bone tissue. For example, leptin signalling can directly stimulate osteoblastic differentiation and osteoblast proliferation and mineralization, but it also has central signalling actions in that it decreases cancellous bone volume. A novel regulatory loop between bone and adipose tissue suggests that uncarboxylated osteocalcin may affect energy homeostasis and afford a pathway by which fat mass can be regulated by bone mass. Conclusions: The multilayered and complex signals between fat and bone tissue involve both direct and indirect pathways. The endocrinologic nature of these signals highlights an emerging trend in medicine: identification of organ-based endocrine signals.
Novel Strategies for Improving Physical Function
Authors: Bhasin Shalender , Jasuja Ravi , Tu Powen , Storer Thomas W. , Guo Wen
Published: July 2011

Background: The number of elderly people is growing worldwide, and a substantial proportion of them report difficulty with mobility and in performing activities of daily living. The demographic trends have created enormous interest in development of function-promoting anabolic therapies. At present, androgens and myostatin inhibitors are the two leading classes of function-promoting anabolic therapies that are the most advanced in the drug development process. However, clinical development has been slowed by vexing trial design issues. Conclusions: Clinical investigators, regulatory agencies and the National Institutes of Health must continue working toward a consensus about the indications for study, efficacy outcomes and what differences in functional outcomes are needed to determine sample size estimates.
Bisphosphonate Therapy in Children with Secondary Osteoporosis
Authors: Papapoulos Socrates E.
Published: July 2011

Background: Increased bone fragility requiring effective treatments is a complication of various chronic conditions in children. Bisphosphonates, highly effective in the treatment of adults with osteoporosis, have also been used in children with secondary osteoporosis. However, results obtained in adults cannot be readily extrapolated to children due to differences in the pathophysiology and progression of the disease as well as in the pharmacokinetics of bisphosphonates. Conclusions: Available results of studies of bisphosphonates in children with secondary osteoporosis do not yet support their recommendation as standard therapy. Their use should be restricted to patients with fragility fractures and low bone mass.
Short Children Born Prematurely: Data from KIGS
Authors: Boguszewski Margaret C.S. , Karlsson Hanna , Wilton Patrick
Published: July 2011

Background: Advances in neonatal care have enabled the survival of extremely preterm infants. Some of them have growth failure and remain short at later ages. As a consequence, children born prematurely may be candidates for growth hormone (GH) treatment. Aims: The goal of this study was to obtain information about children on GH therapy enrolled in the Pfizer International Growth Database (KIGS) who were born prematurely. Patients: The KIGS database was queried for data on prepubertal short children (height <–2 standard deviation score; SDS) born with gestational age below 37 weeks. Birth weight had to be available. Results: In total, 3,215 patients were selected and classified according to gestational age and birth weight as preterm (<37 weeks’ gestation), very preterm (VP; <33 weeks’ gestation), appropriate for gestational age (AGA; birth weight between –2 and +2 SDS) or small for gestational age (SGA; birth weight <–2 SDS). Of these, 1,928 children were preterm AGA, 629 very preterm AGA, 519 preterm SGA, and 139 very preterm SGA. Conclusions: KIGS is a cumulative database and provides a unique opportunity to evaluate the growth response to GH therapy of premature children born with differences in gestational ages, size at birth, rate of postnatal growth, and GH secretion status.
Response to Growth Hormone Treatment in Isolated Growth Hormone Deficiency versus Multiple Pituitary Hormone Deficiency
Authors: Darendeliler F. , Lindberg A. , Wilton P.
Published: July 2011

Background: Growth hormone (GH) therapy successfully increases height prognosis in children with GH deficiency (GHD); however, adult height data are still limited. Aim: This study investigated near-adult height (NAH) in patients with idiopathic GHD (i.e. those with a GH peak <10 µg/l with no organic pathology) divided into two groups: isolated GHD and multiple pituitary hormone deficiency (MPHD). Methods: All patients were registered in the Pfizer International Growth Study Database (KIGS). Median (10th to 90th percentile) values are given and measurements were expressed as standard deviation scores (SDS). Parental-adjusted height was determined. Results: GH therapy was started at a median age of 9.2 (range 4.9–12) years in patients with isolated GHD (n = 1,619, 60% males) and at 7.7 (range 2.8–12.2) years in those with MPHD (n = 554, 65% males; p < 0.001) at a median dose of 0.20 mg/kg/week. Height SDS at onset of therapy was –3.1 (range –4.5 to –2.1) and –3.8 (range –5.7 to –2.3), respectively (p < 0.001). The maximum GH peak and insulin-like growth factor I SDS were significantly (p < 0.05) lower in patients with MPHD than in those with isolated GHD. Both groups showed a significant (p < 0.05) increase in height SDS at 1 year that continued until the onset of puberty. Parental-adjusted height at the start of puberty was –0.1 (range –1.6 to 1.1) in patients with isolated GHD and –0.4 (range –1.9 to 1.2) in those with MPHD. Parental-adjusted NAH SDS in patients with isolated GHD was 0.0 (range –1.5 to 1.2) and slightly, but significantly, higher than NAH (–0.3, range –2.1 to 1.2; p < 0.001) in patients with MPHD. In patients with isolated GHD, total change in height SDS while receiving GH therapy was 1.6 (range 0.5–3.2), and the change in height SDS at puberty was 0.1 (range –0.7 to 1). The respective values were 2.6 (range 0.9–4.6) and 0.2 (range –1 to 1.3) in patients with MPHD. Parental-adjusted NAH was slightly lower in girls than in boys with isolated GHD, but no gender difference was observed in patients with MPHD. Multivariate analysis in patients with GHD and MPHD showed that higher birth weight, taller parents, greater height at onset, first-year responsiveness, and predicted height velocity were the most important predictors of NAH. Conclusions: 89% of patients with isolated GHD and 81% of those with MPHD reached an NAH within their genetic potential while receiving GH therapy. Most of the height gain occurred during prepubertal years.
Screening and Treatment of Dyslipidemias in Children and Adolescents
Authors: Daniels S.R.
Published: July 2011

Background/Aims: Cardiovascular disease is the most prominent cause of mortality worldwide. A key risk factor for atherosclerotic cardiovascular disease is the presence of dyslipidemia. Clinical approaches to evaluation and treatment of dyslipidemia in children and adolescents are presented. Methods: A review of published guidelines and presentation of illustrative cases. Results: Dyslipidemia is an important risk factor in early-stage atherosclerosis. Children and adolescents at high risk for dyslipidemia can be identified using a positive family history or the presence of other risk factors as a trigger. Once high-risk individuals are identified, primary treatment is lifestyle modification. In cases where low-density lipoprotein-cholesterol is high, pharmacologic intervention may be needed. Conclusions: Screening of appropriate children and adolescents for dyslipidemia and treating those at high risk are important for the long-term prevention of cardiovascular disease.
Childhood Cushing Disease: A Challenge in Diagnosis and Management
Authors: Shah Nalini S. , Lila Anurag
Published: July 2011

Background: Cushing syndrome (CS) in childhood is an extremely rare disorder that poses unique diagnostic difficulties. Different etiopathological states account for endogenous hypercortisolism in various age groups. Diagnosis is especially challenging in individuals with adrenocorticotropic hormone-dependent CS. The two most common etiologies are adrenal tumors and pituitary corticotrophin- secreting adenomas (Cushing disease). Case Report: We present the case of a 9-year-old boy that illustrates some of the challenges of diagnosing and managing patients with CS. Conclusions: Diagnosis is usually made by an experienced clinician using a combination of tests to establish a state of endogenous hypercortisolism followed by localization of its source.Management requires an individualized approach and multidisciplinary care. Even after curative therapy, these children require long-term follow-up into adulthood to assess growth and body composition and routine monitoring for metabolic anomalies and/or recurrence of the disease.