bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor
Authors: Mizuarai Shinji , Yamanaka Kazunori , Itadani Hiraku , Arai Tsuyoshi , Nishibata Toshihide , Hirai Hiroshi , Kotani Hidehito
Published: June 2009

Background

Wee1 is a tyrosine kinase regulating S-G2 cell cycle transition through the inactivating phosphorylation of CDC2. The inhibition of Wee1 kinase by a selective small molecule inhibitor significantly enhances the anti-tumor efficacy of DNA damaging agents, specifically in p53 negative tumors by abrogating S-G2 checkpoints, while normal cells with wild-type p53 are not severely damaged due to the intact function of the G1 checkpoint mediated by p53. Since the measurement of mRNA expression requires a very small amount of biopsy tissue and is highly quantitative, the development of a pharmacodynamic (PD) biomarker leveraging mRNA expression is eagerly anticipated in order to estimate target engagement of anti-cancer agents.

Results

In order to find the Wee1 inhibition signature, mRNA expression profiling was first performed in both p53 positive and negative cancer cell lines treated with gemcitabine and a Wee1 inhibitor, MK-1775. We next carried out mRNA expression profiling of skin samples derived from xenograft models treated with the Wee1 inhibitor to identify a Wee1 inhibitor-regulatory gene set. Then, the genes that were commonly modulated in both cancer cell lines and rat skin samples were extracted as a Wee1 inhibition signature that could potentially be used as a PD biomarker independent of p53 status. The expression of the Wee1 inhibition signature was found to be regulated in a dose-dependent manner by the Wee1 inhibitor, and was significantly correlated with the inhibition level of a direct substrate, phosphorylated-CDC2. Individual genes in this Wee1 inhibition signature are known to regulate S-G2 cell cycle progression or checkpoints, which is consistent with the mode-of-action of the Wee1 inhibitor.

Conclusion

We report here the identification of an mRNA gene signature that was specifically changed by gemcitabine and Wee1 inhibitor combination treatment by molecular profiling. Given the common regulation of expression in both xenograft tumors and animal skin samples, the data suggest that the Wee1 inhibition gene signature might be utilized as a quantitative PD biomarker in both tumors and surrogate tissues, such as skin and hair follicles, in human clinical trials.
Genotyping of TRIM5 locus in northern pig-tailed macaques (Macaca leonina), a primate species susceptible to Human Immunodeficiency Virus type 1 infection
Authors: Kuang Yi-Qun , Tang Xia , Liu Feng-Liang , Jiang Xue-Long , Zhang Ya-Ping , Gao Guangxia , Zheng Yong-Tang
Published: June 2009

Background

The pig-tailed macaques are the only Old World monkeys known to be susceptible to human immunodeficiency virus type 1 (HIV-1) infection. We have previously reported that the TRIM5-Cyclophilin A (TRIMCyp) fusion in pig-tailed macaques (Macaca nemestrina) is dysfunctional in restricting HIV-1, which may explain why pig-tailed macaques are susceptible to HIV-1 infection. Similar results have also been reported by other groups. However, according to the current primate taxonomy, the previously reported M. nemestrina are further classified into three species, which all belong to the Macaca spp. This calls for the need to look into the previous studies in more details.

Results

The local species Northern pig-tailed macaque (M. leonina) was analyzed for the correlation of TRIM5 structure and HIV-1 infection. Eleven M. leonina animals were analyzed, and all of them were found to possess TRIM5-CypA fusion at the TRIM5 locus. The transcripts encoding the dysfunctional TRIM5-CypA should result from the G-to-T mutation in the 3'-splicing site of intron 6. Polymorphism in the putative TRIMCyp recognition domain was observed. The peripheral blood mononuclear cells (PBMCs) of M. leonina were susceptible to HIV-1 infection. Consistent with the previous results, expression of the M. leonina TRIMCyp in HeLa-T4 cells rendered the cells resistant to HIV-2ROD but not to SIVmac239 infection.

Conclusion

The susceptibility of M. leonina to HIV-1 infection is due to the dysfunctional TRIM5-CypA fusion in the TRIM5 locus. This finding should broaden our perspective in developing better HIV/AIDS non-human primate animal models.
Formalin-Induced Behavioural Hypersensitivity and Neuronal Hyperexcitability are Mediated by Rapid Protein Synthesis at the Spinal Level
Authors: Asante Curtis O , Wallace Victoria C , Dickenson Anthony H
Published: June 2009

Background

The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation whose action can be inhibited by the drug rapamycin. Forms of long-term plasticity require protein synthesis and evidence indicates that mRNA in dendrites, axon terminals and cell bodies is essential for long-term synaptic plasticity. Specific to pain, shifts in pain thresholds and responsiveness are an expression of neuronal plasticity and this likely contributes to persistent pain. We investigated this by inhibiting the activity of mTOR with rapamycin at the spinal level, of rats that were subjected to the formalin test, using both behavioural and electrophysiological techniques.

Results

For in vivo electrophysiology, Sprague Dawley rats were fully anaesthetised and single-unit extracellular recordings were obtained from lamina V wide dynamic range (WDR) dorsal horn spinal neurones at the region where input is received from the hind paw. Neuronal responses from naive rats showed that rapamycin-sensitive pathways were important in nociceptive-specific C-fibre mediated transmission onto WDR neurones as well mechanically-evoked responses since rapamycin was effective in attenuating these measures. Formalin solution was injected into the hind paw prior to which, rapamycin or vehicle was applied directly onto the exposed spinal cord. When rapamycin was applied to the spinal cord prior to hind paw formalin injection, there was a significant attenuation of the prolonged second phase of the formalin test, which comprises continuing afferent input to the spinal cord, neuronal hyperexcitability and an activated descending facilitatory drive from the brainstem acting on spinal neurones. In accordance with electrophysiological data, behavioural studies showed that rapamycin attenuated behavioural hypersensitivity elicited by formalin injection into the hind paw.

Conclusion

We conclude that mTOR has a role in maintaining persistent pain states via mRNA translation and thus protein synthesis. We hypothesise that mTOR may be activated by excitatory neurotransmitter release acting on sensory afferent terminals as well as dorsal horn spinal neurones, which may be further amplified by descending facilitatory systems originating from higher centres in the brain.
Development of a minimization instrument for allocation of a hospital-level performance improvement intervention to reduce waiting times in Ontario emergency departments
Authors: Leaver Chad Andrew , Guttmann Astrid , Zwarenstein Merrick , Rowe Brian H , Anderson Geoff , Stukel Therese , Golden Brian , Bell Robert , Morra Dante , Abrams Howard , Schull Michael J
Published: June 2009

Background

Rigorous evaluation of an intervention requires that its allocation be unbiased with respect to confounders; this is especially difficult in complex, system-wide healthcare interventions. We developed a short survey instrument to identify factors for a minimization algorithm for the allocation of a hospital-level intervention to reduce emergency department (ED) waiting times in Ontario, Canada.

Methods

Potential confounders influencing the intervention's success were identified by literature review, and grouped by healthcare setting specific change stages. An international multi-disciplinary (clinical, administrative, decision maker, management) panel evaluated these factors in a two-stage modified-delphi and nominal group process based on four domains: change readiness, evidence base, face validity, and clarity of definition.

Results

An original set of 33 factors were identified from the literature. The panel reduced the list to 12 in the first round survey. In the second survey, experts scored each factor according to the four domains; summary scores and consensus discussion resulted in the final selection and measurement of four hospital-level factors to be used in the minimization algorithm: improved patient flow as a hospital's leadership priority; physicians' receptiveness to organizational change; efficiency of bed management; and physician incentives supporting the change goal.

Conclusion

We developed a simple tool designed to gather data from senior hospital administrators on factors likely to affect the success of a hospital patient flow improvement intervention. A minimization algorithm will ensure balanced allocation of the intervention with respect to these factors in study hospitals.
Two major gate-keepers in the self-renewal of neural stem cells: Erk1/2 and PLCγ1 in FGFR signaling
Authors: Lee Jin-A , Jang Deok-Jin , Kaang Bong-Kiun
Published: June 2009

Neural stem cells are undifferentiated precursor cells that proliferate, self-renew, and give rise to neuronal and glial lineages. Understanding the molecular mechanisms underlying their self-renewal is an important aspect in neural stem cell biology. The regulation mechanisms governing self-renewal of neural stem cells and the signaling pathways responsible for the proliferation and maintenance of adult stem cells remain largely unknown. In this issue of Molecular Brain [Ma DK et al. Molecular genetic analysis of FGFR1 signaling reveals distinct roles of MAPK and PLCγ1 activation for self-renewal of adult neural stem cells. Molecular Brain 2009, 2:16], characterized the different roles of MAPK and PLCγ1 in FGFR1 signaling in the self-renewal of neural stem cells. These novel findings provide insights into basic neural stem cell biology and clinical applications of potential stem-cell-based therapy.
Molecular genetic analysis of FGFR1 signalling reveals distinct roles of MAPK and PLCγ1 activation for self-renewal of adult neural stem cells
Authors: Ma Dengke K , Ponnusamy Karthikeyan , Song Mi-Ryoung , Ming Guo-li , Song Hongjun
Published: June 2009

Background

Neural stem cells (NSCs) are present in the adult mammalian brain and sustain life-long adult neurogenesis in the dentate gyrus of the hippocampus. In culture, fibroblast growth factor-2 (FGF-2) is sufficient to maintain the self-renewal of adult NSCs derived from the adult rat hippocampus. The underlying signalling mechanism is not fully understood.

Results

In the established adult rat NSC culture, FGF-2 promotes self-renewal by increasing proliferation and inhibiting spontaneous differentiation of adult NSCs, accompanied with activation of MAPK and PLC pathways. Using a molecular genetic approach, we demonstrate that activation of FGF receptor 1 (FGFR1), largely through two key cytoplasmic amino acid residues that are linked to MAPK and PLC activation, suffices to promote adult NSC self-renewal. The canonical MAPK, Erk1/2 activation, is both required and sufficient for the NSC expansion and anti-differentiation effects of FGF-2. In contrast, PLC activation is integral to the maintenance of adult NSC characteristics, including the full capacity for neuronal and oligodendroglial differentiation.

Conclusion

These studies reveal two amino acid residues in FGFR1 with linked downstream intracellular signal transduction pathways that are essential for maintaining adult NSC self-renewal. The findings provide novel insights into the molecular mechanism regulating adult NSC self-renewal, and pose implications for using these cells in potential therapeutic applications.
Tissue-specific variation in DNA methylation levels along human chromosome 1
Authors: De Bustos Cecilia , Ramos Edward , Young Janet M , Tran Robert K , Menzel Uwe , Langford Cordelia F , Eichler Evan E , Hsu Li , Henikoff Steve , Dumanski Jan P , Trask Barbara J
Published: June 2009

Background

DNA methylation is a major epigenetic modification important for regulating gene expression and suppressing spurious transcription. Most methods to scan the genome in different tissues for differentially methylated sites have focused on the methylation of CpGs in CpG islands, which are concentrations of CpGs often associated with gene promoters.

Results

Here, we use a methylation profiling strategy that is predominantly responsive to methylation differences outside of CpG islands. The method compares the yield from two samples of size-selected fragments generated by a methylation-sensitive restriction enzyme. We then profile nine different normal tissues from two human donors relative to spleen using a custom array of genomic clones covering the euchromatic portion of human chromosome 1 and representing 8% of the human genome. We observe gross regional differences in methylation states across chromosome 1 between tissues from the same individual, with the most striking differences detected in the comparison of cerebellum and spleen. Profiles of the same tissue from different donors are strikingly similar, as are the profiles of different lobes of the brain. Comparing our results with published gene expression levels, we find that clones exhibiting extreme ratios reflecting low relative methylation are statistically enriched for genes with high expression ratios, and vice versa, in most pairs of tissues examined.

Conclusion

The varied patterns of methylation differences detected between tissues by our methylation profiling method reinforce the potential functional significance of regional differences in methylation levels outside of CpG islands.
Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells
Authors: Kerros Céline , Cavey Thibault , Sola Brigitte , Jauzac Philippe , Allouche Stéphane
Published: June 2009

Background

opioid and somatostatin receptors (SSTRs) that can assemble as heterodimer were individually reported to modulate malignant cell proliferation and to favour apoptosis. Materials and methods: SSTRs and opioid receptors expression were examined by RT-PCR, western-blot and binding assays, cell proliferation was studied by XTT assay and propidium iodide (PI) staining and apoptosis by annexin V-PI labelling.

Results

almost all human malignant haematological cell lines studied here expressed the five SSTRs. Further experiments were conducted on the human U266 multiple myeloma cells, which express also μ-opioid receptors (MOP-R). XTT assays and cell cycle studies provide no evidence for a significant effect upon opioid or somatostatin receptors stimulation. Furthermore, neither direct effect nor potentiation of the Fas-receptor pathway was detected on apoptosis after these treatments.

Conclusion

these data suggest that SSTRs or opioid receptors expression is not a guaranty for an anti-tumoral action in U266 cell line.
Mechanical ventilation during experimental sepsis increases deposition of advanced glycation end products and myocardial inflammation
Authors: Kneyber Martin CJ , Gazendam Roel P , Niessen Hans WM , Kuiper Jan-Willem , Dos Santos Claudia C , Slutsky Arthur S , Plötz Frans B
Published: June 2009

Introduction

Increasing evidence links advanced glycation end products (AGE) including Nε-(carboxymethyl)lysine (CML) to the development of heart failure. Accumulation of AGE leads to myocardial inflammation, which is considered as one of the possible mechanisms underlying sepsis-induced cardiac dysfunction. We hypothesized that mechanical ventilation (MV) augmented sepsis-induced myocardial CML deposition and inflammation.

Methods

Sepsis was induced using a modified cecal ligation and perforation (CLP) technique in 36 male adult Sprague Dawley rats. Rats were randomized to four hours of MV with low tidal volume (LTV: 6 ml/kg, PEEP 5 cmH2O, n = 10) or high tidal volume (HTV: 15 ml/kg, PEEP 3 cmH2O, n = 10) 24 hours after the induction of sepsis. Eight rats served as septic, non-ventilated controls and eight as non-septic, non-ventilated controls. After 28 hours all rats were killed. The number of extravascular polymorphonuclear (PMN) leucocytes, macrophages, and lymphocytes was measured as the number of positive cells/mm2. The number of CML positive endothelial cells were semi-quantified based upon an intensity score. The CML intensity score was correlated with the number of inflammatory cells to study the association between CML depositions and inflammation.

Results

Gas exchange was comparable between the ventilated groups. Sepsis induced a significant increase in CML deposition in both ventricles that was significantly augmented by MV compared with non-ventilated septic controls (left ventricle 1.1 ± 1.0 vs 0.7 ± 0.1, P = 0.030; right ventricle 2.5 ± 0.5 vs 0.6 ± 0.1, P = 0.037), irrespective of ventilatory strategy. In the right ventricle there was a non-significant tendency towards increased CML deposition in the HTV group compared with septic, non-ventilated controls (1.0 ± 0.1 vs 0.7 ± 0.09, P = 0.07). Sepsis induced a significant increase in the number of macrophages and PMNs compared with non-ventilated septic controls that was augmented by MV, irrespective of ventilatory strategy. CML deposition was significantly correlated with the number of macrophages and PMNs in the heart.

Conclusions

Sepsis induces CML deposition in the heart with a predominant right ventricular inflammation that is significantly augmented by MV, irrespective of the ventilatory strategy.
Prospective Minimal Residual Disease Monitoring to Predict Relapse of Acute Promyelocytic Leukemia and to Direct Pre-Emptive Arsenic Trioxide Therapy
Authors: Grimwade David , Jovanovic Jelena V. , Hills Robert K. , Nugent Elizabeth A. , Patel Yashma , Flora Rajinder , Diverio Daniela , Jones Katy , Aslett Hannah , Batson Elaine , Rennie Kristian , Angell Roger , Clark Richard E. , Solomon Ellen , Lo-Coco Francesco , Wheatley Keith , Burnett Alan K.
Published: June 2009

Purpose

Molecular diagnostics and early assessment of treatment response that use methodologies capable of detecting submicroscopic disease can distinguish subgroups of patients with leukemia at differing relapse risk. Such information is being incorporated into risk-stratified protocols; however, there are few data concerning prospective use of sequential minimal residual disease (MRD) monitoring to identify more precisely those patients destined to experience relapse, which would allow more tailored therapies.

Methods

Real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts (ie, PML-RARA, RARA-PML) were used to prospectively analyze 6,727 serial blood and marrow samples from 406 patients with newly diagnosed acute promyelocytic leukemia (APL) who were receiving all-trans-retinoic acid and anthracycline-based chemotherapy.

Results

MRD monitoring according to the recommended schedule successfully identified the majority of patients subject to relapse and provided the most powerful predictor of relapse-free survival (RFS) in multivariable analysis (hazard ratio, 17.87; 95% CI, 6.88 to 46.41; P < .0001); MRD monitoring was far superior to presenting WBC (hazard ratio, 1.02; 95% CI, 1.00 to 1.03; P = .02), which is currently widely used to guide therapy. In patients who were predicted to experience relapse on the basis of MRD monitoring, early treatment intervention with arsenic trioxide prevented progression to overt relapse in the majority, and the RFS rate at 1 year from molecular relapse was 73%. By using this strategy, 3-year cumulative incidence of clinical relapse was only 5% in the Medical Research Council AML15 trial.

Conclusion

Rigorous sequential RQ-PCR monitoring provides the strongest predictor of RFS in APL and, when coupled with pre-emptive therapy, provides a valid strategy to reduce rates of clinical relapse. This provides a model for development of a more individualized approach to management of other molecularly defined subtypes of acute leukemia.
Primary Therapy of Waldenström Macroglobulinemia With Bortezomib, Dexamethasone, and Rituximab: WMCTG Clinical Trial 05-180
Authors: Treon Steven P. , Ioakimidis Leukothea , Soumerai Jacob D. , Patterson Christopher J. , Sheehy Patricia , Nelson Marybeth , Willen Michael , Matous Jeffrey , Mattern John , Diener Jakow G. , Keogh George P. , Myers Thomas J. , Boral Andy , Birner Ann , Esseltine Dixie L. , Ghobrial Irene M.
Published: June 2009

Purpose

We examined the activity of bortezomib, dexamethasone, and rituximab (BDR) in patients with symptomatic, untreated Waldenström macroglobulinemia (WM).

Patients and Methods

A cycle of therapy consisted of bortezomib 1.3 mg/m2 intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m2 on day 11. Patients received four consecutive cycles for induction therapy and then four more cycles, each given 3 months apart, for maintenance therapy. Twenty-three patients received a median of seven cycles of treatment.

Results

Median bone marrow disease involvement declined from 55% to 10% (P = .0004), serum immunoglobulin M levels declined from 4,830 to 1,115 mg/dL (P < .0001), and hematocrit increased from 29.8% to 38.2% (P = .0002) at best response. The overall response rates and major response rates were 96% and 83% with three complete responses, two near complete responses, three very good partial responses, 11 partial responses, and three minor responses. Responses occurred at a median of 1.4 months. With a median follow-up of 22.8 months, 18 of 23 patients remained free of disease progression. Peripheral neuropathy was the most common toxicity, and it resolved to grade ≤ 1 in 13 of 16 patients at a median of 6.0 months. Four of the first seven treated patients developed herpes zoster, resulting in the institution of prophylactic antiviral therapy.

Conclusion

The results demonstrate that BDR produces rapid and durable responses, along with high rates of response and complete remissions in WM. Herpes zoster prophylaxis is necessary with BDR, and reversible peripheral neuropathy was the most common toxicity leading to premature discontinuation of bortezomib in 61% of patients. Exploration of alternative schedules for bortezomib administration that includes weekly dosing should be pursued.
Protective effect of JBP485 on concanavalin A-induced liver injury in mice
Authors: Yang Tao , Wu Jingjing , Wang Changyuan , Liu Qi , Ma Xiaochi , Peng Jinyong , Kaku Taiichi , Liu Kexin
Published: June 2009

Objectives

Cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) was first isolated from Laennec (hydrolysate of human placenta). We thought it valuable to clarify the antihepatitis molecular mechanism of JBP485 to develop a new oral anti-hepatitis drug.

Methods

We investigated the hepatoprotective effect of JBP485 on immune-mediated, concanavalin A (Con A)-induced liver injury in mice. Mice were administered JBP485 before and after injection of Con A (10 mg/kg). Eight hours after Con A, the cytosolic enzyme activity (alanine aminotransferase, lactate dehydrogenase) in serum, and the enzyme activity or concentration (superoxide dismutase, maleic dialdehyde, myeloperoxidase, nitric oxide) in liver homogenate were determined. The liver slices were investigated to observe changes in histology. The effect of JBP485 on level of tumour necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) in liver were detected by immunohistochemistry. Hepatocyte DNA fragmentation was assayed by agarose gel electrophoresis and the transcription of the genes bax and bcl-2 in hepatocytes was determined by reverse transcription-polymerase chain reaction.

Key findings

Con A increased the cytosolic and liver homogenate enzyme activity, and the concentrations of ICAM-1 and TNF-α, which were significantly inhibited by JBP485 administration. Also, the increase in DNA fragmentation and decrease in bcl-2/bax mRNA induced by Con A administration were significantly inhibited by JBP485.

Conclusions

These results indicated that immune-mediated liver damage can be prevented by JBP485, and that this is mainly associated with immunomodulatory effects on T cells and adhesion molecules, antioxidation, and inhibition of apoptosis.
Synergistic action of statins and nitrogen-containing bisphosphonates in the development of rhabdomyolysis in L6 rat skeletal myoblasts
Authors: Matzno Sumio , Nishiguchi Tomoko , Akiyoshi Takeshi , Anami Setsuko , Nakabayashi Toshikatsu , Matsuyama Kenji
Published: June 2009

Objectives

Nitrogen-containing bisphosphonates, which are widely used to treat osteoporosis, act as inhibitors of farnesyl pyrophosphate synthase, one of the key enzymes of the mevalonate pathway, and thus may have the potential to enhance the effect of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase). In this study, we evaluated the synergistic effect of two nitrogen-containing bisphosphonates, alendronate and risedronate, in statin-induced apoptosis in rat skeletal L6 myoblasts.

Methods

L6 rat myoblasts were differentiated with drugs. DNA fragmentation was measured and small GTPase was detected by immunoblotting.

Key findings

Alendronate and risedronate caused dose-dependent apoptosis of L6 myoblasts. Risedronate induced detachment of rho GTPase from the cell membrane, followed by activation of the caspase-8-related cascade. Risedronate-induced apoptosis was synergistically enhanced with atorvastatin and significantly reduced by addition of geranylgeraniol. By contrast, alendronate did not reduce membrane GTPases and the apoptosis was caspase independent.

Conclusions

These results suggest that risedronate-induced apoptosis is related to geranylgeranyl pyrophosphate depletion followed by rho detachment, whereas alendronate affects are independent of rho. Our results suggest a risk of synergistic action between nitrogen-containing bisphosphonates and statins in the development of rhabdomyolysis when treating osteoporosis in women with hyperlipidaemia.
Protective effects of water-soluble low-molecular-weight β-(1,3-1,6)D-glucan purified from Aureobasidium pullulans GM-NH-1A1 against UFT toxicity in mice
Authors: Kimura Yoshiyuki , Sumiyoshi Maho , Suzuki Toshio
Published: June 2009

Objectives

5-Fluorouracil and its derivatives are widely used in the treatment of a variety of tumours. However, their use is associated with gastrointestinal toxicity, myelotoxicity and immune toxicity. In this study, we examined the protective effects of low-molecular-weight β-glucan isolated from Aureobasidium pullulans GM-NH-1A1 against toxicity of UFT (combination of tegafur (1-(2-tetrahydrofuryl)-5-fluorouracil) and uracil) in mice bearing colon 26 tumours.

Methods

UFT was administered orally at 50 mg/kg once daily for 14 days alone or with orally administered low-molecular-weight β-glucan, 25, 50 and 100 mg/kg twice daily.

Key findings

Tumour growth was inhibited equally in all treatment groups. Onset of diarrhoea, which started on day 9 of UFT administration, was delayed by concomitant administration of the β-glucan (50 and 100 mg/kg twice daily). Histological analysis showed that damage to small-intestine villi by UFT was inhibited by the orally administered β-glucan.

Conclusions

Oral administration of low-molecular-weight β-glucan prevents gastrointestinal mucositis associated with UFT therapy without interfering with its anti-tumour activity.
Effect of hesperidin on the oral pharmacokinetics of diltiazem and its main metabolite, desacetyldiltiazem, in rats
Authors: Cho Young-Ah , Choi Dong-Hyun , Choi Jun-Shik
Published: June 2009

Objectives

This study was to investigate the effect of hesperidin, an antioxidant, on the bioavailability and pharmacokinetics of diltiazem and its active major metabolite, desacetyldiltiazem, in rats.

Methods

A single dose of diltiazem was administered orally (15 mg/kg) in the presence or absence of hesperidin (1, 5 or 15 mg/kg), which was administered 30 min before diltiazem.

Key findings

Compared with the control group (given diltiazem alone), hesperidin (5 or 15 mg/kg) significantly altered the pharmacokinetic parameters of diltiazem, except for 1 mg/kg hesperidin. The area under the plasma concentration-time curve from time 0 h to infinity (AUC0-∞) was significantly (5 mg/kg, P < 0.05; 15 mg/kg, P < 0.01) increased by 48.9–65.3% and the peak plasma concentration (Cmax) was significantly (P < 0.05) increased by 46.7–62.4% in the presence of hesperidin (5 or 15 mg/kg). Consequently, the absolute bioavailability (F) of diltiazem with hesperidin was significantly (5 mg/kg, P < 0.05; 15 mg/kg, P < 0.01) higher than that in the control group. Hesperidin (5 or 15 mg/kg) significantly (P < 0.05) increased the AUC0-∞ and 15 mg/kg of hesperidin significantly (P < 0.05) increased the Cmax of desacetyldiltiazem. However, the metabolite-parent ratio (MR) of desacetyldiltiazem was not significantly changed in the presence of hesperidin.

Conclusions

Hesperidin significantly enhanced the oral bioavailability of diltiazem in rats. It might be considered that hesperidin increased the intestinal absorption and reduced the first-pass metabolism of diltiazem in the intestine and in the liver via an inhibition of cytochrome P450 3A or P-glycoprotein.
Novel approach to initial blank design in deep drawing using artificial neural network
Authors: Haddadzadeh M , Razfar M R , Mamaghani M R M
Published: June 2009

In the deep drawing process, the initial blank has a simple shape but its perimeter shape becomes very complex after drawing. If the initial blank shape is designed in such a way that it is formed directly into the desired shape by the drawing process, this will lead to a reduction in the trimming process and a decrease in the drawing force and raw material. The present paper proposes a novel approach to the initial blank optimization in deep drawing by using an artificial neural network (ANN) to obtain the shape of the initial blank in one step. The finite element method (FEM) is employed for simulating the deep drawing process to provide training data for the ANN. The aim of the neural network is to predict the initial blank shape for the desired final shape. Results from sensitivity analysis and experimental tests were compared. The FEM results were verified through experiment.
Reducing the rail component of rolling noise by vibration absorber: theoretical prediction
Authors: Wu T X , Liu H P
Published: June 2009

A compound track—absorber model is employed to study the performance of a rail vibration absorber in reducing the rail component of rolling noise. The rail vibration and radiation due to a roughness excitation are calculated with the use of the absorber. Different types of rail absorber and installation locations are considered in calculations to investigate their influence on the absorber's performance. The theoretical predictions show that the rail-radiated noise can be reduced by about 6—8 dB(A) using the rail absorber for the situation modelled here. The most appropriate installation place for a discrete absorber is at mid-span between sleepers because the vibration response there is large. As the rail vibration amplitude is small at sleepers, they are not the appropriate installation place for a discrete absorber to reduce rail radiation via energy dissipation. It should be noticed that the performance of the rail absorber is predicted under idealized conditions, and the noise reduction that can be achieved using the absorber is dependent on some practical factors, which are not further studied in this work.
Preclinical testing on insects predicts human haematotoxic potentials
Authors: Berger Josef
Published: June 2009

The substitution of insects for laboratory animals in toxicity testing is likely to become a reality in the framework of prescreening. Haematotoxicological studies of newly developed chemicals, such as food components, drugs, etc. performed on insects can offer advantages in, for example, environmental toxicology. Reliable routine predictions should produce an increase in our knowledge of haemocyte physiology. Although the differences between human physiology and morphology and those of insects are great, the basic functions of insect haemocytes and mammalian leukocytes appear not to have changed during evolution. The use of insects in haematotoxicity assays represents a preclinical testing strategy which will lower costs, accelerate screening and offer ethical benefits.
The impact of light, noise, cage cleaning and in-house transport on welfare and stress of laboratory rats
Authors: Castelhano-Carlos M J , Baumans V
Published: June 2009

Human interaction and physical environmental factors are part of the stimuli presented to laboratory animals everyday, influencing their behaviour and physiology and contributing to their welfare. Certain environmental conditions and routine procedures in the animal facility might induce stress responses and when the animal is unable to maintain its homeostasis in the presence of a particular stressor, the animal's wellbeing is threatened. This review article summarizes several published studies on the impact of environmental factors such as light, noise, cage cleaning and in-house transport on welfare and stress of laboratory rats. The behaviour and physiological responses of laboratory rats to different environmental housing conditions and routine procedures are reviewed. Recommendations on the welfare of laboratory rats and refinements in experimental design are discussed and how these can influence and improve the quality of scientific data.
Spontaneous thymic lymphomas in the non-obese diabetic/Shi-scid, IL-2Rγnull mouse
Authors: Kato Chie , Fujii Etsuko , Chen Yu Jau , Endaya Berwini B , Matsubara Koichi , Suzuki Masami , Ohnishi Yasuyuki , Tamaoki Norikazu
Published: June 2009

The NOD/Shi- scid, IL-2R γnull (NOG) mouse is a severely immunodeficient mouse used for the engraftment of human tissues and cells. In this study, 2406 mice (8–62 weeks old, 503 males and 1903 females) were subcutaneously engrafted with human tissues. In 16 mice (12–26 weeks old, 1 male and 15 females), a mass was seen in the anteroventralis of the thorax on gross examination with an incidence of 0.7%. Histologically, the masses were composed of sheets of lymphoblastic cells. A ‘starry sky’ pattern was observed with numerous mitoses. Immunohistochemically the lymphoblastic cells were positive for Thy 1. The lymphoblastic cells were also seen in the spleen, lung, liver, kidney and heart. The gross and histopathological findings led to the diagnosis of spontaneous thymic lymphoma in NOG mice.
Introduction: Applications of Management Science and Operations Research Models and Methods to Problems in Health Care
Authors: Carter Michael W. , Golden Bruce L. , Wasil Edward A.
Published: June 2009

Over the last decade or so, the health-care industry in the United States, Canada, and around the world has started to solve important problems using traditional management science and operations research (MS/OR) models and methods, such as mathematical programming, simulation, queueing theory, and decision analysis. In recent years, the results of modeling efforts have been significant and have begun to positively affect the delivery of health care. This special issue documents eight successful applications of MS/OR methods to solving actual problems in health care.
Predictors of STDs Among Asian and Pacific Islander Young Adults
Authors: Hahm Hyeouk Chris , Lee Jieha , Ozonoff Al , Amodeo Maryann
Published: June 2009

CONTEXT:  Limited information is available on factors associated with STDs among Asian and Pacific Islander young adults. Such information is vital to developing effective interventions to reduce STDs within this group.

METHODS:  Data were derived from the National Longitudinal Study of Adolescent Health, Wave 3; the sample consisted of 605 female and 578 male Asian and Pacific Islander young adults. Logistic regression analysis was used to assess factors associated with ever having had an STD.

RESULTS:  Thirteen percent of females and 4% of males had ever had an STD. Among those who had had an STD, 75% were female, 9% had ever been paid for sex, 31% had had sex before age 15 and 55% had had multiple sex partners in the previous 12 months. Being female (odds ratio, 4.1), being Indian (compared with being Filipino; 4.8), having ever been paid money for sex (4.7) and having had more than one sex partner in the past 12 months (2.5) were associated with increased odds of having had an STD diagnosis. The more respondents believed that STDs were responsive to treatment, the greater their odds of having had an STD (2.3); the more they believed that STDs had negative consequences for a relationship, the lower their odds of having had an STD (0.7).

CONCLUSIONS:  Asian and Pacific Islander women and Indians are priority groups for both research and clinical attention; prevention efforts to reduce STDs should be tailored to these groups. Clinicians working with Asians and Pacific Islanders need to focus on clients’ number of sexual partners and health‐related beliefs.
Timing of Sexual Debut and Initiation of Postsecondary Education by Early Adulthood
Authors: Spriggs Aubrey L , Halpern Carolyn Tucker
Published: June 2009

CONTEXT:  Although sexual debut has been negatively associated with adolescent educational performance and aspirations, it is not clear whether such relationships continue beyond adolescence.

METHODS:  Initiation of postsecondary education by young adulthood was assessed among 3,965 participants in the National Longitudinal Study of Adolescent Health who had not experienced sexual intercourse at baseline. Associations between age at sexual debut and educational progress were examined in bivariate and multivariable Poisson regression analyses.

RESULTS:  Most respondents experienced sexual debut during adolescence: 15% before age 16 (early) and 53% at ages 16–18 (typical). Sixty‐five percent of respondents initiated postsecondary education by early adulthood; however, the proportion was significantly lower among those who had had an early (49%) or typical sexual debut (63%) than among those who debuted late (78%). In unadjusted analyses, early and typical debut were associated with a reduced likelihood of initiation of postsecondary education for both females (relative risk ratios, 0.6 and 0.8, respectively) and males (0.7 and 0.8). However, in adjusted analyses, the associations were attenuated for females (0.8 and 0.9) and were at best marginally significant for males. Childbearing was a significant mediator of this relationship.

CONCLUSIONS:  Adolescent sexual debut appears to be modestly negatively associated with early adult postsecondary education initiation, particularly for females. Targeting mediators of the sexual debut–education relationship, such as early childbearing, could lead to effective interventions.
Implementing an Advance Emergency Contraception Policy: What Happens in the Real World?
Authors: Whittaker Paul G. , Armstrong Kay A. , Adams Janet
Published: June 2009

CONTEXT:  Advance provision of emergency contraception increases the likelihood of its use, yet little is known about the factors that influence successful implementation of an advance provision policy in publicly funded family planning clinics.

METHODS:  Data on knowledge of, attitudes toward and use of emergency contraception were collected from 211 patients attending four Title X–funded clinics in Pennsylvania in 2001–2002. In addition, 22 staff from the four clinics were interviewed regarding barriers to and facilitators of advance provision in 2004–2005, and 111 staff from 46 clinics completed related surveys in 2005. Qualitative data underwent content analysis, and frequencies and bivariate associations between variables were calculated for the survey data.

RESULTS:  Most patients said they would use emergency contraception (80%) and believed it should be easy to obtain (93%), although 46% thought it is a form of abortion. Patients’ familiarity with the method, attitudes toward it and self‐efficacy regarding its use were not associated with most demographic or reproductive health characteristics. While nearly all interviewed staff endorsed routine advance provision, only about half of survey respondents offered it “very often” at patients’ initial or annual visits. Barriers to advance provision included staff prejudgment of patients’ needs and ability to use the method, time constraints and inefficiencies in clinic procedures.

CONCLUSIONS:  Strategies that may facilitate advance provision of emergency contraception include emphasizing the need for staff to offer it during all patient visits, providing patient‐friendly information and streamlining clinic procedures.
STDs Among Sexually Active Female College Students: Does Sexual Orientation Make a Difference?
Authors: Lindley Lisa L. , Barnett Corrie L. , Brandt Heather M. , Hardin James W. , Burcin Michelle
Published: June 2009

CONTEXT:  Research addressing sexual health or STD risk among lesbian and bisexual college women is scarce.

METHODS:  Data on 29,952 sexually active females aged 18–24 who completed the 2006 National College Health Assessment were examined to assess differences in sexual risk factors and recent STD incidence by sexual orientation. Comparisons were analyzed at the bivariate level and through multivariate logistic regression.

RESULTS:  Bisexual students were the most likely to have had an STD during the past year (9%); lesbians were the least likely (2%). However, lesbians were also the least likely to have had a routine gynecologic examination (46%, compared with 64–73% of others). Among students who had had multiple partners in the past year, those who had had partners of both sexes were more likely to have had an STD (16%) than were students who had had only male partners (9%) or only female partners (6%). Students who had binged on alcohol the last time they partied, had had multiple partners or had had a routine gynecologic examination in the past year, had been tested for HIV or had not used condoms at last vaginal intercourse were at increased odds of having had an STD (odds ratios, 1.3–4.0).

CONCLUSIONS:  Sexual health programs targeting female college students, regardless of sexual orientation, must focus on behavioral risks associated with STDs. In addition, the importance of regular gynecologic exams should be emphasized, especially among lesbians. Further research is needed on risk‐taking among female college students who are sexually active with both sexes.
Second Births to Teenage Mothers: Risk Factors For Low Birth Weight and Preterm Birth
Authors: Partington Susan N. , Steber Dale L. , Blair Kathleen A. , Cisler Ron A.
Published: June 2009

CONTEXT: Teenagers are more likely than older women to have a low‐birth‐weight infant or a preterm birth, and the risks may be particularly high when they have a second birth. Identifying predictors of these outcomes in second teenage births is essential for developing preventive strategies.

METHODS: Birth certificate data for 1993–2002 were linked to identify second births to Milwaukee teenagers. Predictors of having a low‐birth‐weight second infant or a preterm second birth were identified using logistic regression.

RESULTS: The same proportion of first and second infants were low‐birth‐weight (12%), but second births were more likely than first births to be preterm (15% vs. 12%). In analyses that adjusted for demographic, pregnancy and behavioral characteristics, the odds that a second infant was low‐birth‐weight or preterm were elevated if the mother smoked during pregnancy (odds ratios, 2.2 and 1.9, respectively), had inadequate prenatal weight gain (1.8 and 1.4), had an interpregnancy interval of less than 18 months (1.6–2.9 and 1.4–2.3) or was black (2.7 and 1.7). Women who had received an adequate level of prenatal care had reduced odds of both outcomes (0.6 and 0.4). Women younger than 16 also had increased odds of having a low‐birth‐weight second infant. Further adjustment for socioeconomic characteristics yielded largely the same results. In addition, women who were unmarried or did not identify a father were at increased risk of both outcomes (1.5 for each), and poor women were at risk of having a low‐birth‐weight infant (1.3).

CONCLUSIONS: Predictors of poor birth outcomes include modifiable behaviors. Prenatal interventions addressing these behaviors could help improve outcomes.
Barriers to Adolescents' Getting Emergency Contraception Through Pharmacy Access in California: Differences by Language and Region
Authors: Sampson Olivia , Navarro Sandy K. , Khan Amna , Hearst Norman , Raine Tina R. , Gold Marji , Miller Suellen , De Bocanegra Heike Thiel
Published: June 2009

CONTEXT: In California, emergency contraception is available without a prescription to females younger than 18 through pharmacy access. Timely access to the method is critical to reduce the rate of unintended pregnancy among adolescents, particularly Latinas.

METHODS: In 2005–2006, researchers posing as English‐ and Spanish‐speaking females—who said they either were 15 and had had unprotected intercourse last night or were 18 and had had unprotected sex four days ago—called 115 pharmacy‐access pharmacies in California. Each pharmacy received one call using each scenario; a call was considered successful if the caller was told she could come in to obtain the method. Chi‐square tests were used to assess differences between subgroups. In‐depth interviews with 22 providers and pharmacists were also conducted, and emergent themes were identified.

RESULTS: Thirty‐six percent of all calls were successful. Spanish speakers were less successful than English speakers (24% vs. 48%), and callers to rural pharmacies were less successful than callers to urban ones (27% vs. 44%). Although rural pharmacies were more likely to offer Spanish‐language services, Spanish‐speaking callers to these pharmacies were the least successful of all callers (17%). Spanish speakers were also less successful than English speakers when calling urban pharmacies (30% vs. 57%). Interviews suggested that little cooperation existed between pharmacists and clinicians and that dispensing the method at clinics was a favorable option for adolescents.

CONCLUSIONS: Adolescents face significant barriers to obtaining emergency contraception, but the expansion of Spanish‐language services at pharmacies and greater collaboration between providers and pharmacists could improve access.
Minors' Behavioral Responses to Parental Involvement Laws: Delaying Abortion Until Age 18
Authors: Colman Silvie , Joyce Ted
Published: June 2009

CONTEXT: Prior research on the effect of laws mandating parental involvement in minors' abortions has failed to examine an important behavioral response to such laws: Older teenagers may delay an abortion until age 18; for some, this may mean terminating a pregnancy after the first trimester.

METHODS: Statewide data were obtained on abortions in Texas in 1997–2003. Analysis of relative rate ratios with narrowly defined comparison groups was used to evaluate the association between Texas's parental notification law and the occurrence of second‐trimester abortions among minors who have responded to the law by delaying abortion until age 18.

RESULTS: : In the four years after the law went into effect, the proportion of abortions obtained at age 18 increased by six percentage points among minors who conceived at age 17 years and eight months, and by 13 points among those who did so at 17 years and nine months. As a result, the second‐trimester abortion rate of these groups combined increased by 21%; by contrast, there was no evidence of an increase in this rate among younger minors, for whom delaying the abortion until age 18 was not feasible.

CONCLUSIONS: Some minors postpone abortion until the second or even third trimester of pregnancy to circumvent parental notification requirements. Given the greater costs of and medical risks associated with late‐term abortions, policymakers should not ignore this behavior.