bluuebunny/crossref_metadata_2025 huggingface dataset:
2′,4′,6′-Tris(methoxymethoxy) chalcone (TMMC) attenuates the severity of cerulein-induced acute pancreatitis and associated lung injury
Authors: Kim Tae-Hyeon , Bae Gi-Sang , Oh Hyo-Jeong , Kim Min-Sun , Park Kyoung-Chel , Koo Bon Soon , Kim Byung-Jin , Yang Yun-Sik , Park Dong-Eun , Lee Jae-Hoon , Seo Sang-Wan , Shin Yong Kook , Yun Ki-Jung , Sohn Dong Hwan , Kim Hyung-Jin , So Hong-Seob , Park Rae-Kil , Song Ho-Joon , Park Sung-Joo
Published: July 2011

Acute pancreatitis (AP) is an inflammatory disease involving acinar cell injury and rapid production and release of inflammatory cytokines, which play a dominant role in local pancreatic inflammation and systemic complications. 2′,4′,6′-Tris (methoxymethoxy) chalcone (TMMC), a synthetic chalcone derivative, displays potent anti-inflammatory effects. Therefore, we aimed to investigate whether TMMC might affect the severity of AP and pancreatitis-associated lung injury in mice. We used the cerulein hyperstimulation model of AP. Severity of pancreatitis was determined in cerulein-injected mice by histological analysis and neutrophil sequestration. The pretreatment of mice with TMMC reduced the severity of AP and pancreatitis-associated lung injury and inhibited several biochemical parameters (activity of amylase, lipase, trypsin, trypsinogen, and myeloperoxidase and production of proinflammatory cytokines). In addition, TMMC inhibited pancreatic acinar cell death and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 by inhibiting NF-κB and extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation. Neutralizing antibodies for TNF-α, IL-1β, and IL-6 inhibited cerulein-induced cell death in isolated pancreatic acinar cells. Moreover, pharmacological blockade of NF-κB/ERK1/2 reduced acinar cell death and production of TNF-α, IL-1β, and IL-6 in isolated pancreatic acinar cells. In addition, posttreatment of mice with TMMC showed reduced severity of AP and lung injury. Our results suggest that TMMC may reduce the complications associated with pancreatitis.
Reduced diffusion of charge-modified, conformationally intact anionic Ficoll relative to neutral Ficoll across the rat glomerular filtration barrier in vivo
Authors: Axelsson Josefin , Sverrisson Kristinn , Rippe Anna , Fissell William , Rippe Bengt
Published: July 2011

The glomerular filtration barrier (GFB) is commonly conceived as a negatively charged sieve to proteins. Recent studies, however, indicate that glomerular charge effects are small for anionic, carboxymethylated (CM) dextran vs. neutral dextran. Furthermore, two studies assessing the glomerular sieving coefficients (θ) for negative CM-Ficoll vs. native Ficoll have demonstrated an increased glomerular permeability for CM-Ficoll (Asgeirsson D, Venturoli D, Rippe B, Rippe C. Am J Physiol Renal Physiol 291: F1083–F1089, 2006; Guimarães M, Nikolovski J, Pratt L, Greive K, Comper W. Am Physiol Renal Physiol 285: F1118–F1124, 2003.). The CM-Ficoll used, however, showed a larger Stokes-Einstein radius ( ae) than neutral Ficoll, and it was proposed that the introduction of negative charges in the Ficoll molecule had made it more flexible and permeable. Recently, a negative FITC-labeled CM-Ficoll (CMI-Ficoll) was produced with a conformation identical to that of neutral FITC-Ficoll. Using these probes, we determined their θ:s in anesthetized Wistar rats (259 ± 2.5 g). After blood access had been achieved, the left ureter was cannulated for urine sampling. Either polysaccharide was infused (iv) together with a filtration marker, and urine and plasma were collected. Assessment of θ FITC-Ficoll was achieved by high-performance size-exclusion chromatography (HPSEC). CMI-Ficoll and native Ficoll had identical elugrams on the HPSEC. Diffusion of anionic Ficoll was significantly reduced compared with that of neutral Ficoll across the GFB for molecules of ae ∼20–35 Å, while there were no charge effects for Ficoll of ae = 35–80 Å. The data are consistent with a charge effect present in “small pores,” but not in “large pores,” of the GFB and mimicked those obtained for anionic membranes in vitro for the same probes.
Systemic administration of naked plasmid encoding HGF attenuates puromycin aminonucleoside-induced damage of murine glomerular podocytes
Authors: Bu Xuan , Zhou Yang , Zhang Hua , Qiu Wenjing , Chen Lu , Cao Hongdi , Fang Li , Wen Ping , Tan Ruoyun , Yang Junwei
Published: July 2011

Podocyte injury is considered to play important roles in the pathogenesis of human glomerular disease. There is accumulating evidence suggesting that hepatocyte growth factor (HGF) elicits preventive activity for glomerular cells in animal models of chronic renal diseases. In this study, we demonstrated that delivery of a naked plasmid vector encoding the human HGF gene into mice by a hydrodynamic-based in vivo gene transfection approach markedly reduced proteinuria and attenuated podocyte injury in a mouse model induced by puromycin aminonucleoside (PAN) injection. Systemic administration by rapid injection via the tail vein of a naked plasmid containing HGF cDNA driven under a cytomegalovirus promoter (pCMV-HGF) produced a remarkable level of human HGF protein in the circulation. Tissue distribution studies suggested that the kidney expressed a high level of the HGF transgene. Meanwhile, compared with tubules and interstitium, a higher level of exogenous HGF protein was detected in the glomeruli. Administration of pCMV-HGF dramatically abated the urine albumin excretion and podocyte injury in PAN nephropathy in mice. Exogenous expression of HGF produced evidently beneficial effects, leading to restoration of Wilms' tumor-1 (WT1) and α-actinin-4 expression and attenuation of ultrastructural damage of the podocytes. In vitro, HGF not only restored WT1 and α-actinin-4 expression but also inhibited albumin leakage of podocytes incubated with PAN in a Transwell culture chamber. These results suggest that HGF might provide a novel strategy for amelioration of podocyte injury.
The tight junction protein claudin-3 shows conserved expression in the nephric duct and ureteric bud and promotes tubulogenesis in vitro
Authors: Haddad Nicholas , Andalousi Jasmine El , Khairallah Halim , Yu Melissa , Ryan Aimee K. , Gupta Indra R.
Published: July 2011

The claudin family of proteins is required for the formation of tight junctions that are contact points between epithelial cells. Although little is known of the cellular events by which epithelial cells of the ureteric bud form tubules and branch, tubule formation is critical for kidney development. We hypothesize that if claudin-3 (Cldn3) is expressed within tight junctions of the ureteric bud, this will affect ureteric bud cell shape and tubule formation. Using transmission electron microscopy, we identified tight junctions within epithelial cells of the ureteric bud. Whole mount in situ hybridization and immunoassays were performed in the mouse and chick and demonstrated that Cldn3 transcript and protein were expressed in the nephric duct, the ureteric bud, and its derivatives at critical time points during tubule formation and branching. Mouse inner medullary collecting duct cells (mIMCD-3) form tubules when seeded in a type I collagen matrix and were found to coexpress CLDN3 and the tight junction marker zonula occludens-1 in the cell membrane. When these cells were stably transfected with Cldn3 fused to the enhanced green fluorescent protein reporter, multiple clones showed a significant increase in tubule formation compared with controls ( P < 0.05) due in part to an increase in cell proliferation ( P < 0.01). Cldn3 may therefore promote tubule formation and expansion of the ureteric bud epithelium.
Calcineurin mediates bladder wall remodeling secondary to partial outlet obstruction
Authors: Chang Andy Y. , Sliwoski Joanna , Butler Stephan , Hearn George , Lassmann Jenny , Chacko Samuel , Canning Douglas A. , Zderic Stephen A.
Published: July 2011

We hypothesized that the calcineurin-nuclear factor of activated T-cells (NFAT) pathway is activated following partial bladder outlet obstruction (pBOO), which would allow for pharmacologic treatment to prevent the ensuing bladder wall hypertrophy. Using a model of pBOO in male mice, we were able to demonstrate increased nuclear importation of the transcription factors NFAT and myocyte enhanching factor 2 both of which are under control of calcineurin in both the whole bladder wall as well as the urothelium. We further confirmed that this pathway was activated using transgenic mice containing an NFAT-luciferase reporter construct. Mice were randomized following pBOO to treatment with or without cyclosporine A (CsA), a known inhibitor of calcineurin. The bladder-to-body mass ratio (mg bladder wt/g body wt) of 0.95 ± 0.03 in shams increased to 3.1 ± 0.35 following pBOO, and it dropped back to 1.7 ± 0.22 in the CsA+ group ( P < 0.001). Luciferase values (RLU) of 1,130 ± 133 in shams increased to 2,010 ± 474 following pBOO and were suppressed to 562 ± 177 in the CsA+ group ( P < 0.05). The myosin heavy chain mRNA (A/B) isoform ratio of 0.07 ± 0.03 in shams increased to 1.04 ± 0.19 following pBOO but it diminished to 0.24 ± 0.1 in the CsA+ group ( P < 0.001). In vitro whole organ physiology studies demonstrated improved responses in those bladders from mice treated with CsA. The mRNAs for all four known calcineurin-responsive NFAT isoforms are expressed in the bladder wall, although NFATc3and NFATc4predominate. Both NFATc3 and NFATc4 are expressed in urothelial as well as smooth muscle cells. We conclude that pBOO activates the calcineurin-NFAT pathway and that CsA treatment decreased bladder hypertrophy, shifted the pattern of myosin isoform mRNA expression back toward that seen in normal controls, and resulted in improved in vitro whole organ performance.
Frequency-dependent interaural delays in the medial superior olive: implications for interaural cochlear delays
Authors: Day Mitchell L. , Semple Malcolm N.
Published: July 2011

Neurons in the medial superior olive (MSO) are tuned to the interaural time difference (ITD) of sound arriving at the two ears. MSO neurons evoke a strongest response at their best delay (BD), at which the internal delay between bilateral inputs to MSO matches the external ITD. We performed extracellular recordings in the superior olivary complex of the anesthetized gerbil and found a majority of single units localized to the MSO to exhibit BDs that shifted with tone frequency. The relation of best interaural phase difference to tone frequency revealed nonlinearities in some MSO units and others with linear relations with characteristic phase between 0.4 and 0.6 cycles. The latter is usually associated with the interaction of ipsilateral excitation and contralateral inhibition, as in the lateral superior olive, yet all MSO units exhibited evidence of bilateral excitation. Interaural cochlear delays and phase-locked contralateral inhibition are two mechanisms of internal delay that have been suggested to create frequency-dependent delays. Best interaural phase-frequency relations were compared with a cross-correlation model of MSO that incorporated interaural cochlear delays and an additional frequency-independent delay component. The model with interaural cochlear delay fit phase-frequency relations exhibiting frequency-dependent delays with precision. Another model of MSO incorporating inhibition based on realistic biophysical parameters could not reproduce observed frequency-dependent delays.
Recovery of hindlimb locomotion after incomplete spinal cord injury in the cat involves spontaneous compensatory changes within the spinal locomotor circuitry
Authors: Martinez Marina , Delivet-Mongrain Hugo , Leblond Hugues , Rossignol Serge
Published: July 2011

After incomplete spinal cord injury (SCI), compensatory changes occur throughout the whole neuraxis, including the spinal cord below the lesion, as suggested by previous experiments using a dual SCI paradigm. Indeed, cats submitted to a lateral spinal hemisection at T10-T11 and trained on a treadmill for 3–14 wk re-expressed bilateral hindlimb locomotion as soon as 24 h after spinalization, a process that normally takes 2–3 wk when a complete spinalization is performed without a prior hemisection. In this study, we wanted to ascertain whether similar effects could occur spontaneously without training between the two SCIs and within a short period of 3 wk in 11 cats. One day after the complete spinalization, 9 of the 11 cats were able to re-express hindlimb locomotion either bilaterally ( n = 6) or unilaterally on the side of the previous hemisection ( n = 3). In these 9 cats, the hindlimb on the side of the previous hemisection (left hindlimb) performed better than the right side in contrast to that observed during the hemispinal period itself. Cats re-expressing the best bilateral hindlimb locomotion after spinalization had the largest initial hemilesion and the most prominent locomotor deficits after this first SCI. These results provide evidence that 1) marked reorganization of the spinal locomotor circuitry can occur without specific locomotor training and within a short period of 3 wk; 2) the spinal cord can reorganize in a more or less symmetrical way; and 3) the ability to walk after spinalization depends on the degree of deficits and adaptation observed in the hemispinal period.
Robotic-assisted stepping modulates monosynaptic reflexes in forearm muscles in the human
Authors: Nakajima Tsuyoshi , Kitamura Taku , Kamibayashi Kiyotaka , Komiyama Tomoyoshi , Zehr E. Paul , Hundza Sandra R. , Nakazawa Kimitaka
Published: July 2011

Although the amplitude of the Hoffmann (H)-reflex in the forelimb muscles is known to be suppressed during rhythmic leg movement, it is unknown which factor plays a more important role in generating this suppression—movement-related afferent feedback or feedback related to body loading. To specifically explore the movement- and load-related afferent feedback, we investigated the modulation of the H-reflex in the flexor carpi radialis (FCR) muscle during robotic-assisted passive leg stepping. Passive stepping and standing were performed using a robotic gait-trainer system (Lokomat). The H-reflex in the FCR, elicited by electrical stimulation to the median nerve, was recorded at 10 different phases of the stepping cycle, as well as during quiet standing. We confirmed that the magnitude of the FCR H-reflex was suppressed significantly during passive stepping compared with during standing. The suppressive effect on the FCR H-reflex amplitude was seen at all phases of stepping, irrespective of whether the stepping was conducted with body weight loaded or unloaded. These results suggest that movement-related afferent feedback, rather than load-related afferent feedback, plays an important role in suppressing the FCR H-reflex amplitude.
A Framework for Photovoltaic and Thermosiphon Systems
Authors: Guidoni Gustavo , Papatella Frederico , Pereira Elizabeth , Song Mark
Published: July 2011

Pessimistic forecasts are growing in the Brazilian energy scenario demanding the use of renewable sources of energy such as the solar one. As metropolitan regions have become more populous, private and public companies have developed new technologies based on renewable energy sources. In order to supply such demand, new computer techniques have to be developed. This paper presents a framework to assist the developer to model new components and simulate solar energy applications. By applying the framework concepts, such as source code reuse, one can create a complete environment to evaluate solar energy data. The framework supports software development and tool implementation to be used in photovoltaic and thermosiphon processes.
Strategies for Diagnosis and Prevention of Venous Thromboembolism during Pregnancy
Authors: Bagaria Shalini Jain , Bagaria V. B.
Published: July 2011

Pregnancy and the postpartum period have an increased incidence of venous thromboembolism (VTE). The condition is unique during this period for several reasons. Primarily, because there is complexity in diagnosing this condition in view of altered physiology and preexisting edema in pregnancy and also because there are restrictions on the use of certain drugs and a need for vigilant monitoring of anticoagulant activities of drugs during the period. The problem is compounded and assumes the highest order of significance since two lives are involved and all the investigations and management done should also take into account the potential adverse effects on the foetus. In order to prevent the development of VTE during pregnancy, sound clinical evaluation for risk factors, risk stratification, and optimal use of resource both mechanical and pharmacological is necessary. This paper details strategies in preventing development of deep vein thrombosis and treatment of VTEs.
A Diode-Laser-System for Laser-Assisted Bending of Brittle Materials
Authors: Bammer F. , Schuöcker D. , Schumi T. , Holzinger B. , Humenberger G.
Published: July 2011

We developed a small and compact system of diode lasers, which can be inserted into the lower tools of a bending press. The parts of the system allow easy plug and play operation and can be installed for any bending length. The diode laser, which is based on 200 W laser bars on microchannel cooler, allows the heating of sheet metals in the forming zone shortly before and during the bending process. There is no unnecessary heating of other parts of the bending equipment, no wear of the tool, and, if properly done, no damage of the surface of the metal. The power per bending length is 16 kW/m.
A Double-Blind, Randomized Clinical Trial of Niacinamide 4% versus Hydroquinone 4% in the Treatment of Melasma
Authors: Navarrete-Solís Josefina , Castanedo-Cázares Juan Pablo , Torres-Álvarez Bertha , Oros-Ovalle Cuauhtemoc , Fuentes-Ahumada Cornelia , González Francisco Javier , Martínez-Ramírez Juan David , Moncada Benjamin
Published: July 2011

Background. Multiple modalities have been used in the treatment of melasma with variable success. Niacinamide has anti-inflammatory properties and is able to decrease the transfer of melanosomes.Objective. To evaluate the therapeutic effect of topical niacinamide versus hydroquinone (HQ) in melasma patients.Patients and Methods. Twenty-seven melasma patients were randomized to receive for eight weeks 4% niacinamide cream on one side of the face, and 4% HQ cream on the other. Sunscreen was applied along the observation period. They were assessed by noninvasive techniques for the evaluation of skin color, as well as subjective scales and histological sections initially and after the treatment with niacinamide.Results. All patients showed pigment improvement with both treatments. Colorimetric measures did not show statistical differences between both sides. However, good to excellent improvement was observed with niacinamide in 44% of patients, compared to 55% with HQ. Niacinamide reduced importantly the mast cell infiltrate and showed improvement of solar elastosis in melasma skin. Side effects were present in 18% with niacinamide versus 29% with HQ.Conclusion. Niacinamide induces a decrease in pigmentation, inflammatory infiltrate, and solar elastosis. Niacinamide is a safe and effective therapeutic agent for this condition.
A Note on the Strong Law of Large Numbers for Arrays of Rowwise ρ˜‐Mixing Random Variables
Authors: Shen Aiting , Hu Shuhe
Published: July 2011

Let {Xni, i ≥ 1, n ≥ 1} be an array of rowwise ‐mixing random
variables. Some strong law of large numbers for arrays of rowwise ‐mixing
random variables is studied under some simple and weak conditions.
Coaxially Aligned Polyaniline Nanofibers Doped with 3-Thiopheneacetic Acid through Interfacial Polymerization
Authors: Zhang Lixia , Waterhouse Geoffrey I. N. , Zhang Lijuan
Published: July 2011

Coaxially aligned polyaniline (PANI) nanofibers doped with 3-thiopheneacetic acid (TAA) were chemically synthesized by the interfacial polymerization of aniline in the presence of TAA, using iron (III) chloride hexahydrate (FeCl3·6H2O) as the oxidant. The morphology, crystallinity, room temperature conductivity, and coaxial alignment of the PANI-TAA nanofibers were highly dependent on the organic solvent used for the interfacial polymerization, the oxidant, and also the molar ratio of the aniline to TAA. Hexane, diethyl ether, dichloromethane, chloroform, and acetone were used as the organic solvents, and chloroform proved to be the best solvent for the formation of PANI-TAA nanofibers. The redox potential of the oxidant is the key to controlling the morphology and diameter of the PANI-TAA nanofibers. The use of FeCl3as the oxidant leads to the formation of thin (∼50 nm) PANI-TAA nanofibers, which increased in length, crystallinity, conductivity, and coaxial alignment as the molar ratio of TAA to aniline was increased from 0.1 : 1 to 1 : 1. By comparison, only granular PANI was obtained when ammonium persulfate (APS), which has a higher redox potential, was used as the oxidant. The doping function of TAA in the PANI-TAA nanofibers was confirmed by means of FTIR and UV-Visible spectroscopy.
Fixed Point Theorems by Ways of Ultra‐Asymptotic Centers
Authors: Dhompongsa S. , Nanan N.
Published: July 2011

We use an approach on ultra‐asymptotic centers to obtain fixed point theorems
for two classes of nonself multivalued mappings. The results extend and improve several known ones.
On Simultaneous Farthest Points in L∞(I, X)
Authors: Al-Sharif Sh. , Rawashdeh M.
Published: July 2011

Let X be a Banach space and let G be a closed bounded subset of X. For (x1, x2, …, xm) ∈ Xm, we set  ρ(x1, x2, …, xm, G) = sup {max 1≤i≤m  ∥xi − y∥ : y ∈ G}. The set G is called simultaneously remotal if, for any (x1, x2, …, xm) ∈ Xm, there exists g ∈ G such that  ρ(x1, x2, …, xm, G) = max 1≤i≤m  ∥xi − g∥. In this paper, we show that if G is separable simultaneously remotal in X, then the set of ∞‐Bochner integrable functions, L∞(I, G), is simultaneously remotal in L∞(I, X). Some other results are presented.
Logarithmically Complete Monotonicity Properties Relating to the Gamma Function
Authors: Zhao Tie-Hong , Chu Yu-Ming , Wang Hua
Published: July 2011

We prove that the function fα,β(x) = Γβ(x + α)/xαΓ(βx) is strictly logarithmically completely monotonic on (0, ∞) if and [fα,β(x)] −1 is strictly logarithmically completely monotonic on (0, ∞) if , where φ1(α, β) = (α2 + α − 1)β2 + (2α2 − 3α + 1)β − α and φ2(α, β) = (α − 1)β2 + (2α2 − 5α + 2)β − 1.
Quality of Life in Prodromal HD: Qualitative Analyses of Discourse from Participants and Companions
Authors: Ready Rebecca E. , O'Rourke Justin J. F. , Paulsen Jane S.
Published: July 2011

Persons who are at risk for Huntington's Disease (HD) can be tested for the HD gene expansion before symptom onset. People with the gene expansion, but no clinical diagnosis, are in the prodromal phase of HD. This study explored quality of life (QOL) in prodromal HD. Interviews about QOL, conducted with 9 prodromal HD participants and 6 companions, were transcribed. Discourse was coded for emotional valence, content (e.g., coping, spirituality, interpersonal relationships, HD in others, and employment), and time frame (e.g., current, past, and future). Respondents were more positive than negative about the present, which was their major focus. The most common statements were about positive attitudes. Positive statements were made about spirituality, and negative statements were made about HD in other people. Relationships, employment, and coping with HD reflected both positivity and negativity. Participants and companions spoke of the future with different concerns. Applicability of findings to the clinical management of HD are discussed.
High-Yield Synthesis of Uniform Ag Nanowires with High Aspect Ratios by Introducing the Long-Chain PVP in an Improved Polyol Process
Authors: Zhu Jie-Jun , Kan Cai-Xia , Wan Jian-Guo , Han Min , Wang Guang-Hou
Published: July 2011

Polyvinyl pyrrolidone (PVP) with different molecular weights was used as capping agent to synthesize silver nanowires through a polyol process. The results indicated that the yields and aspect ratios of silver nanowires were controlled by the chain length of PVP and increased with increasing the molecular weight (MW) of PVP. When the long-chain PVP-K90 (MW = 800,000) was used, the product was uniform in size and was dominated by nanowires with high aspect ratios. The growth mechanism of the nanowires was studied. It is proposed that the chemical adsorption of Ag+on the PVP chains at the initial stage promotes the growth of Ag nanowires.
A Study on the Reliability of Sasang Constitutional Body Trunk Measurement
Authors: Jang Eunsu , Kim Jong Yeol , Lee Haejung , Kim Honggie , Baek Younghwa , Lee Siwoo
Published: July 2011

Objective. Body trunk measurement for human plays an important diagnostic role not only in conventional medicine but also in Sasang constitutional medicine (SCM). The Sasang constitutional body trunk measurement (SCBTM) consists of the 5-widths and the 8-circumferences which are standard locations currently employed in the SCM society. This study suggests to what extent a comprehensive training can improve the reliability of the SCBTM.Methods. We recruited 10 male subjects and 5 male observers with no experience of anthropometric measurement. We conducted measurements twice before and after a comprehensive training. Relative technical error of measurement (%TEMs) was produced to assess intra and inter observer reliabilities.Results. Post-training intra-observer %TEMs of the SCBTM were 0.27% to 1.85% reduced from 0.27% to 6.26% in pre-training, respectively. Post-training inter-observer %TEMs of those were 0.56% to 1.66% reduced from 1.00% to 9.60% in pre-training, respectively. Post-training % total TEMs which represent the whole reliability were 0.68% to 2.18% reduced from maximum value of 10.18%.Conclusion. A comprehensive training makes the SCBTM more reliable, hence giving a sufficiently confident diagnostic tool. It is strongly recommended to give a comprehensive training in advance to take the SCBTM.
The Tibetan Uterotonic Zhi Byed 11: Mechanisms of Action, Efficacy, and Historical Use for Postpartum Hemorrhage
Authors: Coelius Rebecca Lynn , Stenson Amy , Morris Jessica L. , Cuomu Mingji , Tudor Carrie , Miller Suellen
Published: July 2011

Objective. To explore evidence for the traditional Tibetan medicine, Zhi Byed 11 (ZB11), for use as a uterotonic.Methods. The eleven ingredients in ZB11 were chemically analyzed by mass spectroscopy. A review was conducted of Western allopathic literature for scientific studies on ZB11’s individual components. Literature from Tibetan and other traditional paradigms were reviewed.Results. Potential mechanisms of action for ZB11 as a uterotonic include laxative effects, a dose-dependant increase in smooth muscle tissue peristalsis that may also affect the uterus smooth muscle, and chemical components that are prostaglandin precursors and/or increase prostaglandin synthesis. A recent RCT demonstrated comparable efficacy to misoprostol in reducing severe postpartum hemorrhage (PPH) (>1000 mL) and greater effect than placebo. Historical and anecdotal evidence for ZB11 and its ingredients for childbirth provide further support.Discussion. ZB11 and its ingredients are candidates for potentially effective uterotonics, especially in low-resource settings. Further research is warranted to understand the mechanisms of action and synergy between ingredients.
New Strategies in Overcoming Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancer
Authors: Oxnard Geoffrey R. , Arcila Maria E. , Chmielecki Juliann , Ladanyi Marc , Miller Vincent A. , Pao William
Published: July 2011

The management of non–small cell lung carcinoma (NSCLC) has been transformed by the observation that lung adenocarcinomas harboring mutations in epidermal growth factor receptor (EGFR) are uniquely sensitive to EGFR tyrosine kinase inhibitors (TKI). In these patients, acquired resistance to EGFR-TKI develops after a median of 10 to 14 months, at which time the current standard practice is to switch to conventional cytotoxic chemotherapy. Several possible mechanisms for acquired resistance have been identified, the most common being the development of an EGFR T790M gatekeeper mutation in more than 50% of cases. In this review, we discuss recent advances in the understanding of acquired TKI resistance in EGFR-mutant lung cancer and review therapeutic progress with second generation TKIs and combinations of targeted therapies. Clin Cancer Res; 17(17); 5530–7. ©2011 AACR.
Genetic Variation Predicting Cisplatin Cytotoxicity Associated with Overall Survival in Lung Cancer Patients Receiving Platinum-Based Chemotherapy
Authors: Tan Xiang-Lin , Moyer Ann M. , Fridley Brooke L. , Schaid Daniel J. , Niu Nifang , Batzler Anthony J. , Jenkins Gregory D. , Abo Ryan P. , Li Liang , Cunningham Julie M. , Sun Zhifu , Yang Ping , Wang Liewei
Published: July 2011

Purpose: Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.

Experimental Design: A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells.

Results: Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells.

Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. Clin Cancer Res; 17(17); 5801–11. ©2011 AACR.
Forced Dimerization Increases the Activity of ΔEGFR/EGFRvIII and Enhances Its Oncogenicity
Authors: Hwang Yeohyeon , Chumbalkar Vaibhav , Latha Khatri , Bogler Oliver
Published: July 2011

Delta epidermal growth factor receptor (ΔEGFR), an in-frame deletion mutant of the extracellular ligand-binding domain, which occurs in about 30% of glioblastoma, is a potent oncogene that promotes tumor growth and progression. The signaling of ΔEGFR is ligand-independent and low intensity, allowing it to evade the normal mechanisms of internalization and degradation by the endocytic machinery and hence is persistent. The basis of the oncogenic potential of ΔEGFR remains incompletely understood, including whether dimerization plays an important role in its signal and whether its oncogenic potential is dependent on its relatively low intensity, when compared with the acutely activated wild-type receptor. To examine these two important questions, we have generated a chimeric ΔEGFR that allows forced dimerization via domains derived from variants of the FKBP12 protein that are brought together by FK506 derivatives. Forced dimerization of chimeric ΔEGFR significantly increased the intensity of its signal, as measured by receptor phosphorylation levels, suggesting that the naturally occurring ΔEGFR does not form strong or stable dimers as part of its low level signal. Interestingly, the increased activity of dimerized, chimeric ΔEGFR did not promote receptor internalization, implying that reduced rate of endocytic downregulation of ΔEGFR is an inherent characteristic. Significantly, forced dimerization enhanced the oncogenic signal of the receptor, implying that the ΔEGFR is a potent oncogene despite, not because of its low intensity. Mol Cancer Res; 9(9); 1199–208. ©2011 AACR.
Coxibs and Other Nonsteroidal Anti-Inflammatory Drugs in Animal Models of Cancer Chemoprevention
Authors: Fischer Susan M. , Hawk Ernest T. , Lubet Ronald A.
Published: July 2011

Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most promising cancer chemopreventive agents in development today. This article examines the data on the efficacy of these agents in animal model studies of cancer prevention carried out by the authors. The studies evaluated here are restricted to our rodent models of colon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs were administered as either cancer preventive or therapeutic agents. These studies may shed light on several questions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this have for human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib in animal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-target effects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Some questions raised by human trials and epidemiology are discussed and related to our observations in animal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibs and certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. On the basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID for preventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are less clear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies may help inform and shape human trials of these commonly employed, relatively inexpensive, and highly effective compounds. Cancer Prev Res; 4(11); 1728–35. ©2011 AACR.
Characterization of New Founder Alu-Mediated Rearrangements in MSH2 Gene Associated with a Lynch Syndrome Phenotype
Authors: Pérez-Cabornero Lucia , Borrás Flores Ester , Sanz Mar Infante , Sampedro Eladio Velasco , Becares Alberto Acedo , Aras Enrique Lastra , González Jorge Cuevas , Riu Marta Pineda , Asensio Teresa Ramón y Cajal , Munar Gabriel Capellá , Pino Cristina Miner , Domínguez Mercedes Durán
Published: July 2011

It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype–phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancer–related phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns. Cancer Prev Res; 4(10); 1546–55. ©2011 AACR.
Copy Number Variation Accuracy in Genome-Wide Association Studies
Authors: Lin Peng , Hartz Sarah M. , Wang Jen-Chyong , Krueger Robert F. , Foroud Tatiana M. , Edenberg Howard J. , Nurnberger, Jr John I. , Brooks Andrew I. , Tischfield Jay A. , Almasy Laura , Webb Bradley T. , Hesselbrock Victor M. , Porjesz Bernice , Goate Alison M. , Bierut Laura J. , Rice John P. ,   COGA Collaborators, COGEND Collaborators, GENEVA Investigators
Published: July 2011

Background/Aim: Copy number variations (CNVs) are a major source of alterations among individuals and are a potential risk factor in many diseases. Numerous diseases have been linked to deletions and duplications of these chromosomal segments. Data from genome-wide association studies and other microarrays may be used to identify CNVs by several different computer programs, but the reliability of the results has been questioned. Methods: To help researchers reduce the number of false-positive CNVs that need to be followed up with laboratory testing, we evaluated the relative performance of CNVPartition, PennCNV and QuantiSNP, and developed a statistical method for estimating sensitivity and positive predictive values of CNV calls and tested it on 96 duplicate samples in our dataset. Results: We found that the positive predictive rate increases with the number of probes in the CNV and the size of the CNV, with the highest positive predicted rates in CNVs of at least 500 kb and at least 100 probes. Our analysis also indicates that identifying CNVs reported by multiple programs can greatly improve the reproducibility rate and the positive predicted rate. Conclusion: Our methods can be used by investigators to identify CNVs in genome-wide data with greater reliability.
A Bayesian Hierarchical Model for Detecting Haplotype-Haplotype and Haplotype-Environment Interactions in Genetic Association Studies
Authors: Li Jun , Zhang Kui , Yi Nengjun
Published: July 2011

Objective: Genetic association studies based on haplotypes are powerful in the discovery and characterization of the genetic basis of complex human diseases. However, statistical methods for detecting haplotype-haplotype and haplotype-environment interactions have not yet been fully developed owing to the difficulties encountered: large numbers of potential haplotypes and unknown haplotype pairs. Furthermore, methods for detecting the association between rare haplotypes and disease have not kept pace with their counterpart of common haplotypes. Methods/Results: We herein propose an efficient and robust method to tackle these problems based on a Bayesian hierarchical generalized linear model. Our model simultaneously fits environmental effects, main effects of numerous common and rare haplotypes, and haplotype-haplotype and haplotype-environment interactions. The key to the approach is the use of a continuous prior distribution on coefficients that favors sparseness in the fitted model and facilitates computation. We develop a fast expectation-maximization algorithm to fit models by estimating posterior modes of coefficients. We incorporate our algorithm into the iteratively weighted least squares for classical generalized linear models as implemented in the R package glm. We evaluate the proposed method and compare its performance to existing methods on extensive simulated data. Conclusion: The results show that the proposed method performs well under all situations and is more powerful than existing approaches.
Negative Image of Blastomyces on Diff-Quik Stain
Authors: Youssef Dima , Shams Wael , Ganote Charles E. , Al-Abbadi Mousa A.
Published: July 2011

Background: Blastomycosis is caused by a dimorphic fungus that can be difficult to diagnose in certain situations. The disease is sometimes serious and can be deadly. Diagnosis by fungal serology and urinary antigens is not easy to establish and unreliable. Culture is also time-consuming and is not easy to perform. Thus, documentation of such an organism on cytology offers a quick and cost-effective alternative. This report describes for the first time identification of the ‘negative image’ of Blastomyces budding yeast. Case: A 79-year-old man presented with a left lung nodule associated with mediastinal and hilar lymphadenopathy. Fine needle aspiration was performed, and a ‘negative image’ of a yeast with wide base budding was noted on Diff-Quik (DQ)-stained smears. Blastomyces species were confirmed with periodic acid-Schiff fungal stain. Additionally, the fungal capsule contained focally polarizable material on Congo red stain and lacked mucin with mucicarmine stain. Conclusion:Blastomyces yeast forms can be easily identified with DQ staining by their ‘negative image’. This feature can be utilized as a quick and cost-effective cytological characteristic to further triage these specimens for confirmation. The information can be of great value to clinicians in making appropriate clinical decisions.
An Improved Delta-Centralization Method for Population Stratification
Authors: Gorroochurn Prakash , Hodge Susan E. , Heiman Gary A. , Greenberg David A.
Published: July 2011

Dadd et al. [Hum Hered 2010;69:285–294] recently criticized our delta-centralization (DC) method of controlling for population stratification (PS) and concluded that DC does not work. To explore our method, the authors simulated data under the Balding-Nichols (BN) model, which is more general than the model we had used in our simulations. They determined that the DC method underestimated the PS parameter (δ) and inflated the type I error rates when applied to BN-simulated data, and from this they concluded that the DC method is invalid. However, we argue that this conclusion is premature. In this paper, we (1) show why δ is underestimated and type I error rates are inflated when BN-simulated data are used, and (2) present a simple adjustment to DC that works reasonably well for data from both kinds of simulations. We also show that the adjusted DC method has appropriate power under a range of scenarios.
On the Uses and Applications of the Most Commonly Used Measures of Linkage Disequilibrium from the Comparative Analysis of Their Statistical Properties
Authors: Zapata Carlos
Published: July 2011

Background/Objective: The analysis of linkage disequilibrium is relevant for the exploration of the structure and evolution of genomes and for the gene mapping of quantitative characters and human diseases. The strength of linkage disequilibrium between diallelic loci is commonly measured by the coefficients D′ and r. Recent studies suggest that r is more useful than D′ as a general measure of the strength of disequilibrium because it provides much more precise (lower sampling variance) and accurate (lower bias) estimates of disequilibrium. We compared for the first time the statistical properties of D′ and r taking into account their differences in range. Methods: The sampling properties of D′ and r were evaluated by simulation under a variety of realistic population conditions and varying sample sizes using standardised statistics that allow for comparisons of the precision, accuracy and efficiency of estimates with different ranges. Results: Simulations revealed that estimates of r do not tend to be significantly more precise, accurate or efficient than those of D′ when compared by means of standardised statistics. Conclusion: The supposed advantage of r over D′ based on direct comparisons of their sampling distributions is more apparent than real. The obtained results are useful to assess the uses and applications of these widely used disequilibrium measures.
Methods for Detecting Interactions between Imprinted Genes and Environmental Exposures Using Birth Cohort Designs with Mother-Offspring Pairs
Authors: Wang Shuang , Yu Zhaoxia , Miller Rachel L. , Tang Deliang , Perera Frederica P.
Published: July 2011

Genomic imprinting is a form of epigenetic regulation in mammals in which the same allele of a gene is expressed differently depending on the parental origin of the allele. Traditionally, the detection of imprinted genes that affect complex diseases has been focused on linkage designs with pedigrees or case-parent designs with case-parent trios. In the past two decades, the birth cohort design with mother-offspring pairs has been applied to understand better the effect of environmental influences during pregnancy and beginning of life on the growth and development of children. No work has been done on the detection of imprinted genes using birth cohort designs. Moreover, although the importance of imprinting has been well recognized, no study has looked at how environmental exposures modify the effects of imprinted genes. In this study, we show that the proposed imprinting test using the birth cohort design with mother-offspring pairs is an efficient test for testing the interactions between imprinted genes and environmental exposures. Through extensive simulation studies and a real data application, the proposed imprinting test has demonstrated much improved power in detecting gene-environment interactions than that of a test assuming the Mendelian dominant model when the true underlying genetic model is imprinting.
Revalidation and Retinal Detachment
Authors: Aylward Bill
Published: July 2011

Proposed changes in the medical regulatory environment in the UK will shortly introduce a system of revalidation of individual doctors, and this will include the regular and mandatory collection of treatment outcomes. Comparison of such outcomes requires an agreed set of items (a dataset) as well as an efficient method of collecting it, preferably electronically. Such a dataset must be large enough to encompass details on case mix to make comparisons valid, but small enough to be practical. There are considerable benefits of pooling outcome data for improved clinical care, research and education.
Molecular and Trophic Mechanisms of Pituitary Tumourigenesis
Authors: Levy Andy
Published: July 2011

Background: The paradox of pituitary tumours is that persistent growth is so atypical. By definition, all pituitary microadenomas regain complete trophic stability after an initial period of deregulated growth. Unlike tumours in many other organ systems, concern about significant growth of macroadenoma remnants after debulking is minimal. Despite reports of a relatively high prevalence of aneuploidy and clonal skewing in these tumours, prolonged efforts to implicate classical proto-oncogene activation and tumour suppressor mutations have been of limited success. No histological or molecular markers reliably predict behaviour. To date, the number of molecular genetic factors unequivocally linked to pituitary tumours can be counted on the fingers of one hand: (1) GNAS1 activation in acromegaly; (2) the MENIN and p27Kip1 (CDKN1B) mutations associated with multiple endocrine neoplasia type 1; (3) mutations of PRKA1RA with loss of 17q22–24 in Carney complex, and (4) aryl hydrocarbon receptor interacting protein gene mutations in 15% of familial isolated pituitary adenomas and 50% of familial isolated acromegaly. Together, these account for only a small proportion (<5%) of sporadic pituitary macroadenomas. Conclusion: In most instances, we still do not know what causes quantitative aberrations in trophic behaviour.