bluuebunny/crossref_metadata_2025 huggingface dataset:
A stochastic bitwidth estimation technique for compact and low-power custom processors
Authors: Özer Emre , Nisbet Andy P. , Gregg David
Published: May 2008

There is an increasing trend toward compiling from C to custom hardware for designing embedded systems in which the area and power consumption of application-specific functional units, registers, and memory blocks are heavily dependent on the bit-widths of integer operands used in computations. The actual bit-width required to store the values assigned to an integer variable during the execution of a program will not, in general, match the built-in C data types. Thus, precious area is wasted if the built-in data type sizes are used to declare the size of integer operands. In this paper, we introduce stochastic bit-width estimation that follows a simulation-based probabilistic approach to estimate the bit-widths of integer variables using extreme value theory. The estimation technique is also empirically compared to two compile-time integer bit-width analysis techniques. Our experimental results show that the stochastic bit-width estimation technique dramatically reduces integer bit-widths and, therefore, enables more compact and power-efficient custom hardware designs than the compile-time integer bit-width analysis techniques. Up to 37% reduction in custom hardware area and 30% reduction in logic power consumption using stochastic bit-width estimation can be attained over ten integer applications implemented on an FPGA chip.
Multimedia streaming via TCP
Authors: Wang Bing , Kurose Jim , Shenoy Prashant , Towsley Don
Published: May 2008

TCP is widely used in commercial multimedia streaming systems, with recent measurement studies indicating that a significant fraction of Internet streaming media is currently delivered over HTTP/TCP. These observations motivate us to develop analytic performance models to systematically investigate the performance of TCP for both live and stored-media streaming. We validate our models via
ns
simulations and experiments conducted over the Internet. Our models provide guidelines indicating the circumstances under which TCP streaming leads to satisfactory performance, showing, for example, that TCP generally provides good streaming performance when the achievable TCP throughput is roughly twice the media bitrate, with only a few seconds of startup delay.
Sonic hedgehog is associated with H+-K+-ATPase-containing membranes in gastric parietal cells and secreted with histamine stimulation
Authors: Zavros Yana , Orr Melissa A. , Xiao Chang , Malinowska Danuta H.
Published: May 2008

Sonic hedgehog (Shh) is found within gastric parietal cells and processed from a 45-kDa to a 19-kDa bioactive protein by an acid- and protease-dependent mechanism. To investigate whether Shh is associated with the parietal cell membrane compartment that becomes exposed to both acid and proteolytic enzymes during acid secretion, the cellular location of Shh within resting and stimulated gastric parietal cells was examined. Immunofluorescence microscopy of rabbit stomach sections showed that Shh colocalized predominantly with parietal and pit, not chief/zymogen or neck, cell markers. In resting and histamine-stimulated rabbit gastric glands Shh was expressed only in parietal cells close to H+-K+-ATPase-containing tubulovesicular and secretory membranes with some colocalizing with γ-actin at the basolateral membrane. Gastric gland microsomal membranes were prepared by differential and sucrose gradient centrifugation and immunoisolation with an anti-H+-K+-ATPase-α subunit antibody. The 45- and 19-kDa Shh proteins were detected by immunoblot in immunopurified H+-K+-ATPase-containing membranes from resting and stimulated gastric glands, respectively. Incubating glands with a high KCl concentration removed Shh from the membranes. Histamine stimulated 19-kDa Shh secretion from gastric glands into the medium. In human gastric cancer 23132/87 cells cultured on permeable membranes, histamine increased 19-kDa Shh secretion into both apical and basolateral media. These findings show that Shh is a peripheral protein associated with resting and stimulated H+-K+-ATPase-expressing membranes. In addition, Shh appears to be expressed at or close to the basolateral membrane of parietal cells.
A novel method of ligand peptidomics to identify peptide ligands binding to AQP2-expressing plasma membranes and intracellular vesicles of rat kidney
Authors: Lee Yu-Jung , Choi Hyo-Jung , Lim Jung-Suk , Earm Ji-Hyun , Lee Byung-Heon , Kim In-San , Frøkiær Jørgen , Nielsen Søren , Kwon Tae-Hwan
Published: May 2008

Aquaporin-2 (AQP2), the vasopressin-regulated water channel in collecting duct principal cells, plays a key role in the regulation of body water balance. We aimed to isolate high-affinity peptide ligands that bind to immunoisolated AQP2-expressing plasma membrane (PM) or intracellular vesicle (ICV) preparations from rat kidney by the in vitro phage display technique. Immunoblotting revealed that AQP2 was exclusively expressed in the immunoisolated AQP2 membrane fractions (PM and ICV), compared with the nonimmunoisolated or preimmune IgG pulldown rat kidney samples. Moreover, AQP1 or H+-ATPase (B1 subunit) expression was minimal in the immunoisolated AQP2 membrane fractions, indicating the specificity of AQP2 membrane isolation. A phage peptide library based on T7 415-1b phage vector displaying CX7C was constructed. After three rounds of biopanning, seven phage clones of high frequency were selected, which showed high affinity to the AQP2-containing PM or ICV fractions compared with a nonrecombinant T7 insertless phage clone. In contrast, these phage clones showed lower affinity to H+-ATPase-containing fractions. Fluorescein-conjugated peptide labeling was associated with intracellular compartment and PM of primary cultured inner medullary collecting duct cells, relative to absent or very weak labeling with fluorescein-conjugated control peptide. Library analyses demonstrated proteins that had motifs homologous to the peptide ligands, albeit with a high probability of a random match due to short peptide sequences. In summary, we applied the in vitro phage display technique to identify high-affinity peptide ligands to AQP2-expressing membranes. Library analyses identified proteins having homologous motifs, which need to be examined for involvement in AQP2 trafficking and regulation.
Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis
Authors: Chen Jiarong , Terada Tomohiro , Ogasawara Ken , Katsura Toshiya , Inui Ken-ichi
Published: May 2008

During cholestasis, bile acids are mainly excreted into the urine, but adaptive renal responses to cholestasis, especially molecular mechanisms for renal secretion of bile acids, have not been well understood. Organic anion transporters (OAT1 and OAT3) are responsible for membrane transport of anionic compounds at the renal basolateral membranes. In the present study, we investigated the pathophysiological roles of OAT1 and OAT3 in terms of renal handling of bile acids. The Eisai hyperbilirubinemic rats (EHBR), mutant rats without multidrug resistance-associated protein 2, showed higher serum and urinary concentrations of bile acids, compared with Sprague-Dawley (SD) rats (wild type). The protein expression level of rat OAT3 was significantly increased in EHBR compared with SD rats, whereas the expression of rat OAT1 was unchanged. The transport activities of rat and human OAT3, but not OAT1, were markedly inhibited by various bile acids such as chenodeoxycholic acid and cholic acid. Cholic acid, glycocholic acid, and taurocholic acid, which mainly increased during cholestasis, are transported by OAT3. The plasma concentration of β-lactam antibiotic cefotiam, a specific substrate for OAT3, was more increased in EHBR than in SD rats despite upregulation of OAT3 protein. This may be due to the competitive inhibition of cefotiam transport by bile acids via OAT3. In conclusion, the present study clearly demonstrated that OAT3 is responsible for renal secretion of bile acids during cholestasis and that the pharmacokinetic profile of OAT3 substrates may be affected by cholestasis.
Indoleamine 2,3-dioxygenase expression promotes renal ischemia-reperfusion injury
Authors: Mohib Kanishka , Wang Shuang , Guan Qiunong , Mellor Andrew L. , Sun Hongtao , Du Caigan , Jevnikar Anthony M.
Published: May 2008

Indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan to N-formyl kynurenine and has a proapoptotic role in renal tubular epithelial cells (TEC) in response to IFN-γ and TNF-α in vitro. TEC produce abundant amounts of IDO in vitro in response to inflammation but a pathological role for IDO in renal injury remains unknown. We investigated the role of IDO in a mouse model of renal ischemia-reperfusion injury (IRI). IRI was induced by clamping the renal pedicle of C57BL/6 mice for 45 min at 32°C. Here, we demonstrate upregulation of IDO in renal tissue at 2 h after reperfusion which reached maximal levels at 24 h. Inhibition of IDO following IRI prevented the increase in serum creatinine observed in vehicle-treated mice (86.4 ± 25 μmol/l, n = 11) compared with mice treated with 1-methyl-d-tryptophan, a specific inhibitor of IDO (33.7 ± 8.7 μmol/l, n = 10, P = 0.031). The role of IDO in renal IRI was further supported by results in IDO-KO mice which maintained normal serum creatinine levels (32.5 ± 2.0 μmol/l, n = 6) following IRI compared with wild-type mice (123 ± 30 μmol/l, n = 9, P = 0.008). Our data suggest that attenuation of IDO expression within the kidney may represent a novel strategy to reduce renal injury as a result of ischemia reperfusion.
Mechanisms of orthostatic intolerance following very prolonged exercise
Authors: Lucas Samuel J. E. , Cotter James D. , Murrell Carissa , Wilson Luke , Anson J. Greg , Gaze David , George Keith P. , Ainslie Philip N.
Published: May 2008

Nine men completed a 24-h exercise trial, with physiological testing sessions before (T1, ∼0630), during (T2, ∼1640; T3, ∼0045; T4, ∼0630), and 48-h afterwards (T5, ∼0650). Participants cycled and ran/trekked continuously between test sessions. A 24-h sedentary control trial was undertaken in crossover order. Within testing sessions, participants lay supine and then stood for 6 min, while heart rate variability (spectral analysis of ECG), middle cerebral artery perfusion velocity (MCAv), mean arterial pressure (MAP; Finometer), and end-tidal Pco2 (PetCO2) were measured, and venous blood was sampled for cardiac troponin I. During the exercise trial: 1) two, six, and four participants were orthostatically intolerant at T2, T3, and T4, respectively; 2) changes in heart rate variability were only observed at T2; 3) supine MAP (baseline = 81 ± 6 mmHg) was lower ( P < 0.05) by 14% at T3 and 8% at T4, whereas standing MAP (75 ± 7 mmHg) was lower by 16% at T2, 37% at T3, and 15% at T4; 4) PetCO2 was reduced ( P < 0.05) at all times while supine (−3–4 Torr) and standing (−4–5 Torr) during exercise trial; 5) standing MCAv was reduced ( P < 0.05) by 23% at T3 and 30% at T4 during the exercise trial; 6) changes in MCAv with standing always correlated ( P < 0.01) with changes in PetCO2 ( r = 0.78–0.93), but only with changes in MAP at T1, T2, and T3 ( P < 0.05; r = 0.62–0.84); and 7) only two individuals showed minor elevations in cardiac troponin I. Recovery was complete within 48 h. During prolonged exercise, postural-induced hypotension and hypocapnia exacerbate cerebral hypoperfusion and facilitate syncope.
Progressive recruitment of muscle fibers is not necessary for the slow component of V̇o2kinetics
Authors: Zoladz Jerzy A. , Gladden L. Bruce , Hogan Michael C. , Nieckarz Zenon , Grassi Bruno
Published: May 2008

The “slow component” of O2uptake (V̇o2) kinetics during constant-load heavy-intensity exercise is traditionally thought to derive from a progressive recruitment of muscle fibers. In this study, which represents a reanalysis of data taken from a previous study by our group (Grassi B, Hogan MC, Greenhaff PL, Hamann JJ, Kelley KM, Aschenbach WG, Constantin-Teodosiu D, Gladden LB. J Physiol 538: 195–207, 2002) we evaluated the presence of a slow component-like response in the isolated dog gastrocnemius in situ ( n = 6) during 4 min of contractions at ∼60–70% of peak V̇o2. In this preparation all muscle fibers are maximally activated by electrical stimulation from the beginning of the contraction period, and no progressive recruitment of fibers is possible. Muscle V̇o2was calculated as blood flow multiplied by arteriovenous O2content difference. The muscle fatigued (force decreased by ∼20–25%) during contractions. Kinetics of adjustment were evaluated for 1) V̇o2, uncorrected for force development; 2) V̇o2normalized for peak force; 3) V̇o2normalized for force-time integral. A slow component-like response, described in only one muscle out of six when uncorrected V̇o2was considered, was observed in all muscles when V̇o2/peak force and V̇o2/force-time were considered. The amplitude of the slow component-like response, expressed as a fraction of the total response, was higher for V̇o2/peak force (0.18 ± 0.06, means ± SE) and for V̇o2/force-time (0.22 ± 0.05) compared with uncorrected V̇o2(0.04 ± 0.04). A progressive recruitment of muscle fibers may not be necessary for the development of the slow component of V̇o2kinetics, which may be caused by the metabolic factors that induce muscle fatigue and, as a consequence, reduce the efficiency of muscle contractions.
A Computer‐Aided Diagnosis System for Breast Cancer Using Independent Component Analysis and Fuzzy Classifier
Authors: Abdel-Qader Ikhlas , Abu-Amara Fadi
Published: May 2008

Screening mammograms is a repetitive task that causes fatigue and eye strain since for every thousand cases analyzed by a radiologist, only 3–4 are cancerous and thus an abnormality may be overlooked. Computer‐aided detection (CAD) algorithms were developed to assist radiologists in detecting mammographic lesions. In this paper, a computer‐aided detection and diagnosis (CADD) system for breast cancer is developed. The framework is based on combining principal component analysis (PCA), independent component analysis (ICA), and a fuzzy classifier to identify and label suspicious regions. This is a novel approach since it uses a fuzzy classifier integrated into the ICA model. Implemented and tested using MIAS database. This algorithm results in the classification of a mammogram as either normal or abnormal. Furthermore, if abnormal, it differentiates it into a benign or a malignant tissue. Results show that this system has 84.03% accuracy in detecting all kinds of abnormalities and 78% diagnosis accuracy.
PPAR Ligands for Cancer Chemoprevention
Authors: Yasui Yumiko , Kim Mihye , Tanaka Takuji
Published: May 2008

Peroxisome proliferators‐activated receptors (PPARs) that are members of the nuclear receptor superfamily have three different isoforms: PPARα, PPARδ, and PPARγ. PPARs are ligand‐activated transcription factors, and they are implicated in tumor progression, differentiation, and apoptosis. Activation of PPAR isoforms lead to both anticarcinogenesis and anti‐inflammatory effect. It has so far identified many PPAR ligands including chemical composition and natural occurring. PPAR ligands are reported to activate PPAR signaling and exert cancer prevention and treatment in vitro and/or in vivo studies. Although the effects depend on the isoforms and the types of ligands, biological modulatory activities of PPARs in carcinogenesis and disease progression are attracted for control or combat cancer development. This short review summarizes currently available data on the role of PPAR ligands in carcinogenesis.
Design and Calibration Tests of an Active Sound Intensity Probe
Authors: Kletschkowski Thomas , Sachau Delf
Published: May 2008

The paper presents an active sound intensity probe that can be used for sound source localization in standing wave fields. The probe consists of a sound hard tube that is terminated by a loudspeaker and an integrated pair of microphones. The microphones are used to decompose the standing wave field inside the tube into its incident and reflected part. The latter is cancelled by an adaptive controller that calculates proper driving signals for the loudspeaker. If the open end of the actively controlled tube is placed close to a vibrating surface, the radiated sound intensity can be determined by measuring the cross spectral density between the two microphones. A one‐dimensional free field can be realized effectively, as first experiments performed on a simplified test bed have shown. Further tests proved that a prototype of the novel sound intensity probe can be calibrated.
Effect of Imperfections and Damping on the Type of Nonlinearity of Circular Plates and Shallow Spherical Shells
Authors: Touzé Cyril , Camier Cédric , Favraud Gaël , Thomas Olivier
Published: May 2008

The effect of geometric imperfections and viscous damping on the type of nonlinearity
(i.e., the hardening or softening behaviour) of circular plates and shallow spherical shells with free
edge is here investigated. The Von Kármán large‐deflection theory is used to derive the continuous
models. Then, nonlinear normal modes (NNMs) are used for predicting with accuracy the coefficient,
the sign of which determines the hardening or softening behaviour of the structure. The
effect of geometric imperfections, unavoidable in real systems, is studied by adding a static initial
component in the deflection of a circular plate. Axisymmetric as well as asymmetric imperfections
are investigated, and their effect on the type of nonlinearity of the modes of an imperfect plate is
documented. Transitions from hardening to softening behaviour are predicted quantitatively for imperfections
having the shapes of eigenmodes of a perfect plate. The role of 2:1 internal resonance in
this process is underlined. When damping is included in the calculation, it is found that the softening
behaviour is generally favoured, but its effect remains limited.
Targeting mTOR in HIV-Negative Classic Kaposi's Sarcoma
Authors: Merimsky Ofer , Jiveliouk Irina , Sagi-Eisenberg Ronit
Published: May 2008

A 66-year old female with HIV-negative classic Kaposi's sarcoma responded to mTOR targeting by rapamycin. The response was well documented by PET-CT. This case provides supporting evidence that the mTOR pathway may be important in the tumorigenesis of KS and that rapamycin may have activity in this disease.
q‐Analogue of Wright Function
Authors: El-Shahed Moustafa , Salem Ahmed
Published: May 2008

We introduce a q‐analogues of Wright function
and its auxiliary functions as Barnes integral representations and series expansion. The relations
between q‐analogues of Wright function
and some other functions are investigated.
Cancers Exhibit a Mutator Phenotype: Clinical Implications
Authors: Loeb Lawrence A. , Bielas Jason H. , Beckman Robert A.
Published: May 2008

Malignancies are characterized by mutations. We have hypothesized that the thousands of mutations in most human cancers do not result from the low mutation rates exhibited by normal human cells. Instead, cancer cells express a mutator phenotype (i.e., the mutation rate in the cancer cells is much greater than that in normal cells). We consider the following points: (a) Mutations in genes that govern genetic stability could be the cause of a mutator phenotype exhibited by human cancers. (b) A mutator phenotype increases the efficiency of acquiring mutations including those associated with cancer. (c) Recent experimental evidence indicates that human tumors contain a vast array of both clonal mutations and nonexpanded (random) mutations. (d) The presence of nonexpanded mutations in tumors has fundamental clinical implications for cancer risk assessment, grading, and prognosis including the rapid emergence of resistance to chemotherapeutic agents. Lastly, (e) if a mutator phenotype drives carcinogenesis, drugs that target mutator pathways might prevent cancer by delay. [Cancer Res 2008;68(10):3551–7]
Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Low Circulating Insulin-Like Growth Factor I Levels
Authors: Moore Tricia , Carbajal Steve , Beltran Linda , Perkins Susan N. , Yakar Shoshana , LeRoith Derek , Hursting Stephen D. , DiGiovanni John
Published: May 2008

Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I–deficient (LID) mice, which have a 75% reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism. [Cancer Res 2008;68(10):3680–8]
The Spy1/RINGO Family Represents a Novel Mechanism Regulating Mammary Growth and Tumorigenesis
Authors: Golipour Azadeh , Myers Dorothy , Seagroves Tiffany , Murphy Daniel , Evan Gerard I. , Donoghue Daniel J. , Moorehead Roger A. , Porter Lisa A.
Published: May 2008

Spy1A is a unique cell cycle activator known to mediate cell cycle progression and override the DNA damage response. This study focused on determining the role of this protein on postnatal mammary gland morphogenesis and neoplasia. Herein, we show that Spy1A levels are tightly regulated during mammary gland development and that ectopic expression stimulates precocious development and results in disrupted morphology of the gland. This follows the same trend as the oncogene c-Myc, and we show that Spy1A expression is regulated downstream of c-Myc signaling. Importantly, we show that overexpression of Spy1A accelerates tumorigenesis in vivo. Collectively, this work is the first report that the Spy1/RINGO family of proteins may play an essential role in regulating both normal and abnormal growth processes in the breast. [Cancer Res 2008;68(10):3591–600]
Imaging Pharmacodynamics of the α-Folate Receptor–Targeted Thymidylate Synthase Inhibitor BGC 945
Authors: Pillai Radhakrishna G. , Forster Martin , Perumal Meg , Mitchell Fraser , Leyton Julius , Aibgirhio Franklin I. , Golovko Oksana , Jackman Ann L. , Aboagye Eric O.
Published: May 2008

The assessment of tissue-specific pharmacodynamics is desirable in the development of tumor-targeted therapies. Plasma deoxyuridine (dUrd) levels, a measure of systemic thymidylate synthase (TS) inhibition, has limited application for studying the pharmacodynamics of novel TS inhibitors targeted to the high affinity α-folate receptor (FR). Here, we have evaluated the utility of [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) for imaging the tissue pharmacodynamics of BGC 945, an FR-targeted antifolate TS inhibitor; the nontargeted antifolate BGC 9331 was used for comparison. TS inhibition by both drugs induced a concentration-dependent increase in [3H]thymidine uptake in FR-positive human epidermoid KB cells. Membrane-associated equilibrative nucleoside transporter type 1 levels increased from 55,720 ± 6,101 to 118,700 ± 5,193 and 130,800 ± 10,800 per cell at 100 μg/mL of BGC 9331 and BGC 945, respectively, suggesting this as a potential mechanism of increased nucleoside uptake. In keeping with these in vitro findings, tumor [18F]FLT accumulation in KB xenografts increased by ≥2-fold after drug treatment with maximal levels at 1 to 4 hours and 4 to 24 hours after BGC 9331 and BGC 945 treatment, respectively. Of interest to FR targeting, BGC 9331, but not BGC 945, induced accumulation of [18F]FLT uptake in intestine, a proliferative and TS-responsive tissue. For both drugs, quantitative changes in tumor [18F]FLT uptake were associated with increased tumor dUrd levels. In conclusion, we have validated the utility of [18F]FLT-PET to image TS inhibition induced by antifolates and shown the tumor-specific activity of BGC 945. This imaging biomarker readout will be useful in the early clinical development of BGC 945. [Cancer Res 2008;68(10):3827–34]
Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice
Authors: Glen Colin D. , Smith Andrew G. , Dubrova Yuri E.
Published: May 2008

Understanding and estimating the genetic hazards of exposure to chemical mutagens and anticancer drugs in humans requires the development of efficient systems for monitoring germ line mutation. The suitability of a single-molecule PCR–based approach for monitoring mutation induction at the mouse expanded simple tandem repeat (ESTR) locus Ms6-hm by chemical mutagens and anticancer drugs has been validated. The frequency of ESTR mutation was evaluated in the germ line of male mice exposed to the well-characterized alkylating agent and mutagen, ethylnitrosourea, and four widely used anticancer drugs, bleomycin, cyclophosphamide, mitomycin C, and procarbazine. The dose-response of ethylnitrosourea-induced mutation was found to be very close to that previously established using a pedigree-based approach for ESTR mutation detection. Paternal exposure to the clinically relevant doses of bleomycin (15–30 mg/kg), cyclophosphamide (40–80 mg/kg), and mitomycin C (2.5–5 mg/kg) led to statistically significant, dose-dependent increases in ESTR mutation frequencies in the germ line of treated male mice. Exposure to procarbazine led to a maximal increase in mutation frequency at 50 mg/kg, with a plateau at the higher concentrations. The results of this study show that the single-molecule PCR technique provides a new and efficient experimental system for monitoring the genetic effects of anticancer drugs, capable of detecting increases in mutation rates at clinically relevant doses of exposure. In addition, this approach dramatically reduces the number of mice needed for the measurement of germ line mutation induction. [Cancer Res 2008;68(10):3630–6]
Development of an Empirically Calibrated Model of Gastric Cancer in Two High-Risk Countries
Authors: Yeh Jennifer M. , Kuntz Karen M. , Ezzati Majid , Hur Chin , Kong Chung Yin , Goldie Sue J.
Published: May 2008

Although epidemiologic studies have established the relationship between Helicobacter pylori and gastric cancer and promising results that H. pylori treatment can reduce cancer incidence among individuals without preexisting precancerous lesions, there is no consensus on whether screening for H. pylori should be conducted. Our objective was to synthesize the available data to develop and empirically calibrate a mathematical model of gastric cancer and H. pylori in China and Colombia that could be used to provide qualitative insight into the benefits and cost-effectiveness of primary and secondary gastric cancer prevention strategies. The model represents the natural history of noncardia intestinal type gastric adenocarcinomas as a sequence of transitions among health states (e.g., normal gastric mucosa, chronic nonatrophic gastritis, gastric atrophy, intestinal metaplasia, dysplasia, and gastric cancer) stratified by H. pylori status. Initial plausible ranges for each parameter were established using data from published literature. A likelihood-based empirical calibration approach was used to identify multiple good-fitting parameter sets that were consistent with epidemiologic data. We then used these parameter sets to estimate a range of likely outcomes associated with H. pylori screening. This modeling approach allows for parameter uncertainty surrounding the natural history of H. pylori and gastric cancer to be reflected in the results of comparative analyses of different gastric cancer prevention strategies. As better data become available, the model can be refined and recalibrated, and, as such, be used as an iterative tool to assess the likely health and economic outcomes associated with gastric cancer prevention strategies. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1179–87)
FGFR2 Is a Breast Cancer Susceptibility Gene in Jewish and Arab Israeli Populations
Authors: Raskin Leon , Pinchev Mila , Arad Chana , Lejbkowicz Flavio , Tamir Ada , Rennert Hedy S. , Rennert Gad , Gruber Stephen B.
Published: May 2008

Genetic variation in FGFR2 is a newly described risk factor for breast cancer. We estimated the relative risk and contribution of FGFR2 polymorphisms to breast cancer risk in diverse ethnic groups within Jewish and other Middle Eastern populations. We genotyped four FGFR2 single nucleotide polymorphisms (SNP) and tested for association of these SNPs and haplotypes with breast cancer risk in a population-based case-control study of 1,529 women with breast cancer and 1,528 controls. We found significant associations between breast cancer risk and all four studied SNPs in FGFR2 (Ptrend for all SNPs < 0.0001). In ethnicity-specific analysis, all four SNPs were significantly associated with breast cancer risk in Ashkenazi and Sephardi Jews, with a similar but not significant trend in Arabs. Haplotype analysis identified five common haplotypes (>1%). The previously described AAGT risk haplotype was significantly associated with breast cancer risk in Ashkenazi [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.07-1.45; P = 0.0059] and Sephardi Jews (OR, 1.46; 95% CI, 1.17-1.80; P = 0.0006) compared with the reference GGAC haplotype. The AAAC haplotype was significantly associated with breast cancer risk in Sephardi Jews (OR, 1.97; 95% CI, 1.16-3.35; P = 0.0125) but not in Ashkenazi Jews (OR, 0.83; 95% CI, 0.41-1.62; P = 0.5613) or in Arabs (OR, 1.31; 95% CI, 0.80-2.14; P = 0.2881). Genetic variation in FGFR2, identified by rs1219648, may account for a substantial fraction of breast cancer in Arab (12%), Ashkenazi (15%), and Sephardi Jewish (22%) populations. The identification of population-specific risk haplotypes in FGFR2 is likely to help identify causal variants for breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1060–5)
Efficacy of Gemcitabine in Patients with Non–Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene
Authors: Kim Soo-Ok , Jeong Ju-Yeon , Kim Mi-Ran , Cho Hyun-Ju , Ju Jin-Yung , Kwon Yong-Soo , Oh In-Jae , Kim Kyu-Sik , Kim Yu-Il , Lim Sung-Chul , Kim Young-Chul
Published: May 2008

Purpose: High ribonucleotide reductase M1 (RRM1) expression in resected lung cancers has been associated with better clinical outcomes. However, gemcitabine-treated patients with high tumoral RRM1 expression generally evidence poor prognoses due to the decreased efficacy of gemcitabine therapy. This study was designed in accordance with the hypothesis that polymorphisms (−37 and −524) of the RRM1 promoter gene sequence, which regulate RRM1 expression, could influence the efficacy and prognosis of lung cancer patients treated with gemcitabine-based chemotherapy.

Experimental Design: A retrospective dataset of 97 patients with advanced non–small cell lung cancer treated with gemcitabine regimens as a first-line treatment was studied in this work. The allelotyping of RRM1 promoter polymorphisms was conducted via real-time PCR using genomic DNA obtained from peripheral WBC.

Results: The RRM1 promoter allelotype was RR37CC-R524TT in 58 patients, RR37AC-RR524CT in 29 patients, and other allelotypes in 10 patients. The response rate for gemcitabine-containing chemotherapy was 49.5%. The response rate was significantly higher in the RR37AC-RR524CT group (65.5%) compared with the group containing other allelotypes (42.6%; P = 0.039). Overall survival and progression-free survival did not differ significantly by allelotype.

Conclusions: We detected significant differences in response rates to gemcitabine-based chemotherapy according to the allelotypes of the RRM1 promoter sequence, which could be determined using the germline DNA. Further functional and clinical studies will be required before this can be used as a predictive marker.
Association between Metabolic Syndrome and Risk of Stroke: A Meta-Analysis of Cohort Studies
Authors: Li Wei , Ma Dongrui , Liu Ming , Liu Hua , Feng Shejun , Hao Zilong , Wu Bo , Zhang Shihong
Published: May 2008

Background: Our purpose was to investigate the association between metabolic syndrome and risk of stroke by meta-analysis. Methods: Electronic databases through July 2007 were searched to identify prospective cohort studies that examined the association between metabolic syndrome and risk of stroke. Two reviewers independently assessed eligibility and used a standardized form to collect data from published studies. The study quality was assessed by the Newcastle-Ottawa Scale. Results: We found 13 eligible studies that included 92,732 participants.Compared to individuals without metabolic syndrome, subjects with metabolic syndrome had a 1.6-fold increased risk of stroke (95% CI, 1.48–1.75). The relative risk of stroke associated with metabolic syndrome was 2.2 in the studies using the World Health Organization definition and 1.6 in those using the Adult Treatment Panel III definition, but the difference was not statistically significant. Conclusions: This analysis shows that metabolic syndrome is an important risk factor for incident stroke. A diagnosis of metabolic syndrome may prove useful in clinical management, and its elements should ultimately become important therapeutic targets for the reduction of the stroke burden in the general population.
Şerefeddin Sabuncuoğlu (1385–1468) on Pediatric Skull Fractures
Authors: Turgut Mehmet
Published: May 2008

Şerefeddin Sabuncuoğlu (1385–1468) presents medieval management of pediatric skull fractures in his textbook Cerrahiyyetü’l Haniyye (Imperial Surgery). He was a Turkish surgeon who lived in the Ottoman Empire during the 15th century. Cerrahiyyetü’l Haniyye, the first example of surgical textbook in the Turkish medical literature, was beautifully illustrated with his own drawings. In this historical article, the sections of Cerrahiyyetü’l Haniyye pertinent to surgical techniques and instruments for pediatric head injury are critically reviewed.
Ventricular Catheter Tack-Down Screw
Authors: Crevier Louis , Fallah Aria , Jha Neilank , Hollenberg Robert D.
Published: May 2008

The frequent need for revision of ventriculoperitoneal shunts particularly in the pediatric population is a well-known complication of the procedure. A not infrequent etiology demanding revision is the dislodgement of the catheter, particularly, in our experience, with posterior fossa shunts. Suturing the shunt to the periosteum is a common practice amongst pediatric neurosurgeons. We describe a novel technique of fastening the reservoir directly to the skull with the aid of titanium screws providing a more secure attachment and potentially reducing the number of subsequent revisions related to proximal end displacement.
Tranilast Ameliorates Experimental Mesangial Proliferative Glomerulonephritis
Authors: Tokuyama Hirobumi , Kelly Darren J. , Cox Alison , Zhang Yuan , Thai Kerri , Nikolic-Paterson David J. , Gilbert Richard E.
Published: May 2008

Background: Immunoglobulin A nephropathy and its related animal model Thy1.1 nephritis are characterized by mesangial hypercellularity, extracellular matrix expansion and overexpression of the proproliferative and profibrotic growth factors, platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β). Tranilast [n-(3,4-dimethoxycinnamoyl) anthranilic acid] has been shown to block the actions of PDGF and TGF-β. Methods: Experimental mesangial proliferative glomerulonephritis was induced in male Wistar rats with a monoclonal anti-rat Thy-1.1 antibody (OX-7) with rats randomized to receive either tranilast 400 mg/kg/day or vehicle control. Collagen synthesis and proliferation of cultured mesangial cells following incubation with PDGF (50 ng/ml) and tranilast (10–100 µM) was determined by 3H-proline and 3H-thymidine incorporation, respectively. Results: Tranilast treatment resulted in a significant reduction in mesangial cell proliferation, macrophage infiltration, activated (α-smooth muscle actin positive) mesangial cells, glomerular type IV collagen deposition and proteinuria compared to control rats. Also, PDGF stimulation of mesangial cell 3H-thymidine and 3H-proline incorporation was reduced by tranilast in a dose-dependent manner. Conclusion: These in vitro data and the amelioration of the pathological findings of experimental mesangial proliferative glomerulonephritis by tranilast suggest the potential clinical utility of this approach as a therapeutic strategy in mesangial proliferative conditions such as immunoglobulin A nephropathy.
High Satisfaction with an Individualised Stroke Care Programme after Hospitalisation of Patients with a TIA or Minor Stroke: A Pilot Study
Authors: Arts Mark L.J. , Kwa Vincent I.H. , Dahmen Rutger
Published: May 2008

Background: Many hospitalised patients with a transient ischaemic attack (TIA) or minor stroke develop subtle cognitive disorders and emotional problems a few weeks after discharge, and are dissatisfied with the care they have received, even with specialised stroke care programmes. Therefore, an individualised stroke care programme was developed to match the therapy with the personal care needs. In this pilot study we evaluated the feasibility of the rehabilitation programme, the satisfaction of stroke patients with this programme, and the factors associated with satisfaction. Methods: Consecutive patients who were hospitalised with a TIA or minor stroke, with no apparent residual deficits, were eligible. Occupational and neuropsychological screening was applied 4–6 weeks after discharge, and therapy was provided when necessary. After 6 months, satisfaction with care (Satisfaction-With-Stroke-Care-19), was assessed as the primary outcome. Secondary outcomes were quality of life (QoL), disability, handicap, anxiety and depression. Results: 42 patients with a TIA or minor stroke participated in the programme and the follow-up. Of all the participants, 71% were satisfied with the care they have received after discharge. Male patients were more satisfied than female patients. Dissatisfied patients were less able to perform the activities of daily living, had a lower QoL and more depressive symptoms. After regression analysis, only the Barthel Index was independently associated with satisfaction. Conclusions: In this pilot study, our individualised stroke care programme seems to have improved patient satisfaction. Ability to perform daily activities is associated with satisfaction. A randomised controlled trial is needed to confirm the effectiveness of this rehabilitation programme.
Transient Hyperperfusion after Superficial Temporal Artery/Middle Cerebral Artery Bypass Surgery as a Possible Cause of Postoperative Transient Neurological Deterioration
Authors: Kim Jeong Eun , Oh Chang Wan , Kwon O-Ki , Park Sukh Que , Kim Sang Eun , Kim Yu Kyeong
Published: May 2008

Background: This study was designed to investigate the relationship between transient neurological deterioration and changes in cerebral perfusion after superficial temporal artery/middle cerebral artery (STA-MCA) bypass. Methods: Clinical characteristics of the patients with postoperative transient neurological deterioration were analyzed in 120 STA-MCA bypass procedures for ischemic cerebral diseases, such as atherosclerotic disease and moyamoya disease. Serial brain single-photon emission computed tomography (SPECT) was performed on 25 patients before surgery and on the third and tenth postoperative days. The hemispheric perfusion on SPECT was calculated semi-quantitatively using statistical parametric mapping and a probabilistic brain atlas. Results: Among 120 procedures, there were 4 permanent postoperative neurological deficits (3.3%) and 20 postoperative transient neurologic deteriorations with unknown etiology (17%). In 25 patients analyzed for postoperative perfusion changes, cerebral perfusion increased on the third postoperative day and the increased perfusion negatively correlated with preoperative perfusion (correlation coefficient = –0.77; p < 0.001). Temporal changes and the location of transient hyperperfusion on SPECT correlated with the time course and neurological deficits associated with postoperative transient neurological deterioration in 3 patients. Conclusions: Postoperative transient relative hyperperfusion is a common phenomenon and may be one of the causes of postoperative transient neurological deterioration after STA-MCA bypass surgery for ischemic cerebral diseases.
Strong Association between Nutritional Markers and Arterial Stiffness in Continuous Ambulatory Peritoneal Dialysis Patients
Authors: Gu Yue , Cheng Li-Tao , Chen Hui-Min , Sun Xiao-Yan , Tang Li-Jun , Guo Li-Juan , Axelsson Jonas , Wang Tao
Published: May 2008

Background: Malnutrition is a predictor of cardiovascular disease in dialysis patients, but the mechanisms remain unknown. We investigated links between nutritional markers and arterial stiffness in continuous ambulatory peritoneal dialysis patients. Methods: We evaluated the relationship between arterial stiffness evaluated by pulse-wave velocity (PWV) and four estimates of nutritional status (serum albumin, handgrip strength [HGS], subjective global assessment [SGA], and bioelectrical impedance analysis phase angle [PA]) in 124 PD patients. Results: Malnourished patients exhibited a significantly higher PWV than those classified as well-nourished by SGA (p < 0.05). Furthermore, PWV correlated negatively with albumin, HGS and PA (p < 0.001, respectively). PWV was also correlated with age, systolic blood pressure, and C-reactive protein. In multivariate regression analysis, albumin, HGS, SGA and PA were each independently associated with PWV after adjustment. Conclusions: The significant association between each nutritional marker and PWV in PD patients was independent of inflammation and diabetic state, suggesting that malnutrition may contribute to vascular dysfunction.
Head and Neck Cancer Cell Lines Are Resistant to Mitochondrial-Depolarization-Induced Apoptosis
Authors: Zhao Ming , Mydlarz Wojciech K. , Zhou Shaoyu , Califano Joseph
Published: May 2008

Purpose: Mitochondrial dysfunction has been linked to defects in the apoptotic pathway, and solid tumors, including head and neck squamous cell carcinoma (HNSCC), exhibit defects in apoptosis. Loss of mitochondrial membrane potential (ΔΨm) is an early initiating event in the mitochondrial apoptotic pathway. We investigated the apoptotic response of 3 head and neck cancer cell lines treated with a mitochondrial-membrane-depolarizing agent, valinomycin, and studied the ability of depolarization to induce release of cytochrome c in these cell lines. Experimental Design: HNSCC cell lines JHU-011, -012 and -019, and a leukemia control cell line HL-60 were assayed for ΔΨm after valinomycin treatment by staining with mitochondrial-membrane-potential-specific probe JC-1 and stained with apoptosis-specific probe annexin-V to measure their rate of apoptosis by FACS. Western blotting was also applied to detect cytoplasmic cytochrome c release. Results: ΔΨm in head and neck cell lines started to show slight loss of ΔΨm, while HL-60 showed significant loss of ΔΨm after 30 min of treatment. All cell lines demonstrated complete mitochondrial depolarization within 24 h, however, only the control cell line HL-60 underwent apoptosis. In addition, HNSCC cell lines did not demonstrate cytoplasmic cytochrome c release despite significant mitochondrial membrane depolarization, while HL-60 cell initiated apoptosis and cytochcrome c release after 24 h of treatment. Conclusions: Head and neck cancer cell lines exhibit defects in mitochondrial-membrane-depolarization-induced apoptosis as well as impaired release of cytochrome c despite significant mitochondrial membrane depolarization. Proximal defects in the mitochondrial apoptosis pathway are a feature of HNSCC.
A primate transfer RNA gene cluster and the evolution of human chromosome 1
Authors: Buckland R.A.
Published: May 2008

The localisation of tRNAAsn gene clusters in the karyotypes of primates has been studied by means of in situ hybridisation. In the human and orangutan (Pongo pygmaeus) karyotypes there are two such gene clusters, one each on the long and short arms of chromosome 1. Old World monkeys, however, contain both gene clusters on their equivalent of the human chromosome 1 short arm, which can be explained by a pericentric inversion which (amongst other chromosome changes) distinguishes the human and Old World monkey chromosomes 1. The capuchin (Cebus appella), however, a New World monkey, has only one tRNAAsn gene cluster, at least on the elements equivalent to human chromosome 1. This cluster is located proximal to the centromere on a chromosome that has been tentatively identified (by others) as the equivalent of the long arm of human chromosome 1. Should this prove to be correct, it would indicate that the large primate metacentric came into being in the form found today in the great apes, rather than in the form currently found in Old World monkeys. These data further show that the tRNAAsn gene cluster has been split in two since before the Old World monkeys and hominids diverged, i.e., over 30 million years ago, and also that the original transfer of these genes from one arm of chromosome 1 to the other was unlikely to have involved a pericentric inversion but, rather, some form of replicative transposition.
Synapsis, recombination, and meiotic segregation in the mesquite lizard, Sceloporus grammicus, complex
Authors: Reed K.M. , Sites, Jr. J.W. , Greenbaum I.F.
Published: May 2008

Somatic and meiotic chromosomal and synaptonemal complex techniques were used to characterize the chromosomal complement and to study the fission heteromorphism of chromosome 4 in the FM2 cytotype of Sceloporus grammicus. Analysis of silver-stained somatic metaphases revealed that the nucleolar organizer region in this cytotype is located at the distal end of a pair of medium-sized acrocentric chromosomes, rather than on the largest acrocentric chromosomal pair, as previously reported. This condition is hypothesized to be the result of at least two sequential rearrangements. Analysis of surface-spread zygotene and pachytene nuclei indicated that the components of the chromosome 4 trivalent initiated synapsis at their distal telomeric regions. Although synapsis of the fission trivalent was synchronous with that of the homomorphic autosomal pairs, completion of synapsis was delayed in the trivalent. Associations between the fission trivalent and other autosomal or sex-chromosomal elements occurred in approximately one third of the pachytene nuclei examined. Analysis of secondary spermatocytes (metaphase II configurations) revealed low levels of nondisjunction in fission heterozygotes. These analyses indicate that FM2 individuals heterozygous for the fission rearrangement of chromosome 4 suffer no meiotic deficit.