bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the metabolism of fenretinide by human liver microsomes, cytochrome P450 enzymes and UDP‐glucuronosyltransferases
Authors: Illingworth NA , Boddy AV , Daly AK , Veal GJ 
Published: November 2010

BACKGROUND AND PURPOSEFenretinide (4‐HPR) is a retinoic acid analogue, currently used in clinical trials in oncology. Metabolism of 4‐HPR is of particular interest due to production of the active metabolite 4′‐oxo 4‐HPR and the clinical challenge of obtaining consistent 4‐HPR plasma concentrations in patients. Here, we assessed the enzymes involved in various 4‐HPR metabolic pathways.EXPERIMENTAL APPROACHEnzymes involved in 4‐HPR metabolism were characterized using human liver microsomes (HLM), supersomes over‐expressing individual human cytochrome P450s (CYPs), uridine 5′‐diphospho‐glucoronosyl transferases (UGTs) and CYP2C8 variants expressed inEscherichia coli. Samples were analysed by high‐performance liquid chromatography and liquid chromatography/mass spectrometry assays and kinetic parameters for metabolite formation determined. Incubations were also carried out with inhibitors of CYPs and methylation enzymes.KEY RESULTSHLM were found to predominantly produce 4′‐oxo 4‐HPR, with an additional polar metabolite, 4′‐hydroxy 4‐HPR (4′‐OH 4‐HPR), produced by individual CYPs. CYPs 2C8, 3A4 and 3A5 were found to metabolize 4‐HPR, with metabolite formation prevented by inhibitors of CYP3A4 and CYP2C8. Differences in metabolism to 4′‐OH 4‐HPR were observed with 2C8 variants, CYP2C8*4 exhibited a significantly lowerVmaxvalue compared with *1. Conversely, a significantly higherVmaxvalue for CYP2C8*4 versus *1 was observed in terms of 4′‐oxo formation. In terms of 4‐HPR glucuronidation, UGTs 1A1, 1A3 and 1A6 produced the 4‐HPR glucuronide metabolite.CONCLUSIONS AND IMPLICATIONSThe enzymes involved in 4‐HPR metabolism have been characterized. The CYP2C8 isoform was found to have a significant effect on oxidative metabolism and may be of clinical relevance.
Purine receptor‐mediated endocannabinoid production and retrograde synaptic signalling in the cerebellar cortex
Authors: Kovacs Flora E. , Illes Peter , Szabo Bela 
Published: November 2010

BACKGROUND AND PURPOSEPresynaptic CB1cannabinoid receptors can be activated by endogenous cannabinoids (endocannabinoids) synthesized by postsynaptic neurones. The hypothesis of the present work was that activation of calcium‐permeable transmitter‐gated ion channels in postsynaptic neurones, specifically of P2X purine receptors, can lead to endocannabinoid production and retrograde synaptic signalling.EXPERIMENTAL APPROACHGABAergic inhibitory postsynaptic currents (IPSCs) were recorded with patch‐clamp techniques in Purkinje cells in mouse cerebellar slices. Purine receptors on Purkinje cells were activated by pressure ejection of ATP from a pipette.KEY RESULTSATP evoked an inward current in Purkinje cells, most likely due to P2X receptor activation. The ATP‐evoked currents were accompanied by currents via voltage‐gated calcium channels. ATP suppressed electrical stimulation‐evoked IPSCs and miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin, and these effects were prevented by the CB1antagonist rimonabant and the calcium chelator BAPTA (applied into the Purkinje cell). ATP also suppressed mIPSCs when voltage‐gated calcium channels were blocked by cadmium, and intracellular calcium stores were depleted by thapsigargin. However, ATP failed to suppress mIPSCs when the extracellular calcium concentration was zero.CONCLUSIONS AND IMPLICATIONSATP elicits CB1receptor‐dependent retrograde synaptic suppression, which is probably mediated by an endocannabinod released by the postsynaptic neurone. An increase in intracellular calcium concentration in the postsynaptic neurone is necessary for this retrograde signalling. We propose that ATP increases the calcium concentration by two mechanisms: calcium enters into the neurone via the P2X receptor ion channel and the ATP‐evoked depolarization triggers voltage‐gated calcium channels.
Impaired extinction of fear and maintained amygdala‐hippocampal theta synchrony in a mouse model of temporal lobe epilepsy
Authors: Lesting Jörg , Geiger Matthias , Narayanan Rajeevan T. , Pape Hans‐Christian , Seidenbecher Thomas 
Published: November 2010

SummaryPurpose:  The relationship between epilepsy and fear has received much attention. However, seizure‐modulated fear and physiologic or structural correlates have not been examined systematically, and the underlying basics of network levels remain unclear to date. Therefore, this project was set up to characterize the neurophysiologic basis of seizure‐related fear and the contribution of the amygdala‐hippocampus system.Methods:  The experimental strategy was composed of the following steps: (1) use of the mouse pilocarpine model of temporal lobe epilepsy (TLE); (2) behavioral analyses of anxiety states in the elevated plus maze test, light–dark avoidance test, and Pavlovian fear conditioning; and (3) probing neurophysiologic activity patterns in amygdala‐hippocampal circuits in freely behaving mice.Results:  Our results displayed no significant differences in basic anxiety levels comparing mice that developed spontaneous recurrent seizures (SRS) and controls. Furthermore, conditioned fear memory retrieval was not influenced in SRS mice. However, during fear memory extinction, SRS mice showed an extended freezing behavior and a maintained amygdala‐hippocampal theta frequency synchronization compared to controls.Discussion:  These results indicate specific alterations in conditioned fear behavior and related neurophysiologic activities in the amygdala‐hippocampal network contributing to impaired fear memory extinction in mice with TLE. Clinically, the nonextinguished fear memories may well contribute to the experience of fear in patients with TLE.
HLA‐B*1511 is a risk factor for carbamazepine‐induced Stevens‐Johnson syndrome and toxic epidermal necrolysis in Japanese patients
Authors: Kaniwa Nahoko , Saito Yoshiro , Aihara Michiko , Matsunaga Kayoko , Tohkin Masahiro , Kurose Kouichi , Furuya Hirokazu , Takahashi Yukitoshi , Muramatsu Masaaki , Kinoshita Shigeru , Abe Masamichi , Ikeda Hiroko , Kashiwagi Mariko , Song Yixuan , Ueta Mayumi , Sotozono Chie , Ikezawa Zenro , Hasegawa Ryuichi ,   for the JSAR research group
Published: November 2010

SummaryStevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life‐threatening severe cutaneous adverse reactions. Recently, strong associations of HLA‐B*1502 with carbamazepine‐induced SJS/TEN have been found in Han Chinese patients. These associations have been confirmed in several Asian populations, excluding Japanese. SJS patients carrying HLA‐B*1508, HLA‐B*1511, or HLA‐B*1521, which are members of the HLA‐B75 type along with HLA‐B*1502, were detected in studies in India and Thailand. In the current study, we genotyped the HLA‐B locus from 14 Japanese typical and atypical SJS/TEN patients in whom carbamazepine was considered to be involved in the onset of adverse reactions. Although there were no HLA‐B*1502 carriers, four patients had HLA‐B*1511. Our data suggest that HLA‐B*1511, a member of HLA‐B75, is a risk factor for carbamazepine‐induced SJS/TEN in Japanese.
Vacuum Erection Devices Revisited: its Emerging Role in the Treatment of Erectile Dysfunction and Early Penile Rehabilitation Following Prostate Cancer Therapy
Authors: Pahlajani Geetu , Raina Rupesh , Jones Stephen , Ali Marwan , Zippe Craig 
Published: November 2010

ABSTRACT

Introduction
Vacuum erection devices (VEDs) are becoming first-line therapies for the treatment of erectile dysfunction and preservation (rehabilitation) of erectile function following treatment for prostate cancer. Currently, there is limited efficacy of the use of phosphodiesterase type 5 inhibitors in elderly patients, or patients with moderate to severe diabetes, hypertension, and coronary artery disease.

Aim
The article aims to study the role of VED in patients following prostate cancer therapy.

Results
Alternative therapies such as VED have emerged as one of the primary options for patients refractory to oral therapy. VED has also been successfully used in combination treatment with oral therapy and penile injections. More recently, there has been interest in the use of VED in early intervention protocols to encourage corporeal rehabilitation and prevention of postradical prostatectomy veno-occlusive dysfunction. This is evident by the preservation of penile length and girth that is seen with early use of the VED following radical prostatectomy. There are ongoing studies to help preserve penile length and girth with early use of VED following prostate brachytherapy and external beam radiation for prostate cancer. Recently, there has also been interest in the use of VED to help maintain penile length following surgical correction of Peyronie’s disease and to increase penile size prior to implantation of the penile prosthesis.

Conclusion
VEDs can be one of the options for penile rehabilitation after prostate cancer therapy.
Mortality attributable to pandemic influenza A (H1N1) 2009 in San Luis Potosí, Mexico
Authors: Comas‐García Andreu , García‐Sepúlveda Christian A. , Méndez‐de Lira José J. , Aranda‐Romo Saray , Hernández‐Salinas Alba E. , Noyola Daniel E. 
Published: November 2010

Please cite this paper as: Comas‐García et al. (2011) Mortality attributable to pandemic influenza A (H1N1) 2009 in San Luis Potosí, Mexico. Influenza and Other Respiratory Viruses 5(2), 76–82.Background  Acute respiratory infections are a leading cause of morbidity and mortality worldwide. Starting in 2009, pandemic influenza A(H1N1) 2009 virus has become one of the leading respiratory pathogens worldwide. However, the overall impact of this virus as a cause of mortality has not been clearly defined.Objectives  To determine the impact of pandemic influenza A(H1N1) 2009 on mortality in a Mexican population.Methods  We assessed the impact of pandemic influenza virus on mortality during the first and second outbreaks in San Luis Potosí, Mexico, and compared it to mortality associated with seasonal influenza and respiratory syncytial virus (RSV) during the previous winter seasons.Results  We estimated that, on average, 8·1% of all deaths that occurred during the 2003–2009 seasons were attributable to influenza and RSV. During the first pandemic influenza A(H1N1) 2009 outbreak, there was an increase in mortality in persons 5–59 years of age, but not during the second outbreak (Fall of 2009). Overall, pandemic influenza A (H1N1) 2009 outbreaks had similar effects on mortality to those associated with seasonal influenza virus epidemics.Conclusions  The impact of influenza A(H1N1) 2009 virus on mortality during the first year of the pandemic was similar to that observed for seasonal influenza. The establishment of real‐time surveillance systems capable of integrating virological, morbidity, and mortality data may result in the timely identification of outbreaks so as to allow for the institution of appropriate control measures to reduce the impact of emerging pathogens on the population.
Processing of Soft Hispanic Cheese (“Queso Fresco”) Using Thermo‐Sonicated Milk: A Study of Physicochemical Characteristics and Storage Life
Authors: Bermúdez‐Aguirre Daniela , Barbosa‐Cánovas Gustavo V. 
Published: November 2010

Abstract:  Queso fresco is a handmade cheese consumed in Latin America and some regions of the United States. However, deficient milk processing has affected its microbial quality and it has an extremely short shelf life and low yield. The objective of this work was to process queso fresco using thermo‐sonicated milk; physicochemical parameters were evaluated, including microbial quality during storage (4 °C). An ultrasonic processor (UP400S, 400 W, 24 kHz, 120 μm) was used to sonicate raw milk. Seven milk systems (500 mL each) were evaluated: 1 untreated, and 6 treated at 63 °C/30 min; 63 °C/10 min + sonication; 63 °C/30 min + sonication; 72 °C/15 s; 72 °C/15 s + sonication; and 72 °C/1 min + sonication. A conventional cheese‐making process was followed for all systems. The effect of sonication on milk was quite noticeable. Curdling times were reduced considerably, cheese yield (20.6%) was almost doubled, and luminosity of cheese was increased (L*). Textural properties and microstructure images matched very well. Queso fresco processed at 63 °C/120 μm/30 min had the best quality. After storage for 23 d at 4 °C mesophilic count was just 4 log; psychrophilic count, 3.5 log; and enterobacteria count, 3 log. The pH and color remained almost constant and a minor degree of syneresis was observed at end of storage. Due to microstructural rearrangement of the milk components such as fat globules and casein micelles, cheese yield was doubled compared to the traditional handmade product. Shelf life was extended considerably and the product had higher quality.Practical Application:  Ultrasound seems to be a viable option for pasteurization of milk and may provide dairy products with specific characteristics. This is an inexpensive and easy nonthermal technology that is affordable for small cheese manufacturers and offers other benefits such as a microbiological safe product, better quality parameters for consumers, and higher cheese yield.
Commentary: Advancing the Research Mission in an Academic Department: The Creation of a Center for Translational Medicine
Authors: Feldman Arthur M. , Force Thomas L. , Whellan David J. , Bray Paul F. , Cheung Joseph Y. , Koch Walter J. 
Published: November 2010

AbstractMultidisciplinary research centers have multiplied in academic medical centers over the past decade and several recent reports have described their structure, strengths and limitations, and the difficulties that they may face. However, little attention has been paid to the role of a multidisciplinary center in the context of a single academic department. In 2003, the Department of Medicine at Jefferson Medical College launched the Center for Translational Medicine in order to facilitate multidisciplinary research, optimally utilize space and resources, enhance the educational experience for trainees, link basic investigation with clinical research programs, and develop a program of research excellence.Herein, we describe the structure of the Center and provide evidence of its success. The development of the Center has resulted in increased total funding, an increased number of students and residents pursuing translational research, a more effective utilization of space, the development of multidisciplinary research projects, and a significant increase in the number of individual and programmatic federally funded grants. Though the creation of the Center was not without challenges, the overall benefits for the department and the university have been substantial. The concept of a translational medicine center may be useful for many departments of academic medical centers. Clin Trans Sci 2010; Volume 3: 178–181
Short‐Term Treatment with High‐Dose Atorvastatin Reduces LDL Cholesterol but Shows no Anti‐Inflammatory Effects in Normolipidemic Subjects with Normal CRP Levels
Authors: Millar John S. , Ky Bonnie , Wolfe Megan L. , Pruscino Leticia , Baer Amanda , Rader Daniel J. 
Published: November 2010

AbstractThe benefit in reducing cardiovascular risk with statins has been attributed both to cholesterol lowering and pleiotropic effects. These pleiotropic effects are thought to include attenuation of the inflammatory response due to reduced prenylation of proteins in the inflammatory cascade. We conducted studies in normolipidemic subjects to determine if treatment with high‐dose (80 mg) atorvastatin could reduce circulating levels of inflammatory markers. We also determined whether high‐dose atorvastatin affected the inflammatory response of monocytes stimulated with lipopolysaccharide (LPS) ex vivo. We found that treatment with atorvastatin rapidly and significantly reduced plasma low‐density lipoprotein (LDL) cholesterol levels in subjects treated for 2 weeks. However, statin treatment had no discernible effect on plasma levels of the inflammatory markers high‐sensitivity C‐reactive protein (hsCRP), tumor necrosis factor (TNF)‐α, or interleukin (IL‐6) and no effect on the cytokine response of monocytes following ex vivo stimulation with LPS. High‐dose atorvastatin treatment of normolipidemic subjects with normal C‐reactive protein levels has no effect on the inflammatory response assessed by monocyte stimulation with LPS ex vivo despite significant reductions in LDL cholesterol levels. Clin Trans Sci 2010; Volume 3: 140–146
Combined blockade of thrombin anion binding exosite-1 and PAR4 produces synergistic antiplatelet effect in human platelets
Authors: Wang Wei-Ya , Wei Chien-Kei , Teng Che-Ming , Wu Chin-Chung 
Published: November 2010

SummaryThrombin exosite-1 mediates the specific binding of thrombin with fibrinogen and protease-activated receptor (PAR) 1. Exosite-1 inhibitors have been shown to effectively decrease the clotting activity of thrombin, while their antiplatelet effects are relatively weak. In the present study, the inhibitory effects of two exosite-1 inhibitors, hirugen and HD1, but not the exosite-2 inhibitor HD22, on thrombin-induced platelet aggregation and P-selectin expression were dramatically enhanced by a PAR4 antagonist, YD-3. In contrast, the PAR1 antagonist SCH-79797 did not affect the antiplatelet effects of exosite-1 inhibitors. The exosite-1 inhibitors and YD-3 prevented the Ca2+ spike and the prolonged Ca2+ response in thrombin-stimulated platelets, respectively; and combination of these two classes of agents led to abolishment of Ca2+ signal. Unlike exosite-1 inhibitors, the antiplatelet effects of the active site inhibitor PPACK and the bivalent inhibitor bivalirudin were not significantly enhanced by YD-3. In addition, the platelet-stimulating activity of γ-thrombin, an autolytic product of α-thrombin which lacks exosite-1, was inhibited by YD-3. These results suggest that the synergistic antiplatelet effects of exosite-1 inhibitor and PAR4 antagonist are resulted from combined blockade of PAR1 and PAR4 in platelets. In fibrinogen or plasma clotting assay, YD-3 neither prolonged the clotting time on its own nor enhanced the anticoagulant activity of exosite-1 inhibitors. Therefore, the combined blockade of exosite-1 and PAR4 may offer a potential strategy for improving the balance of benefits and risks of antithrombotic therapy.
Effects of aspirin and desmopressin on platelet reactivity in patients undergoing cardiac surgery with extracorporeal circulation
Authors: Kmitta Eliane , Kueri Sami , Zietak Tomasz , Trenk Dietmar , Keyl Cornelius 
Published: November 2010

SummaryThe effect of desmopressin on platelet function in patients with continued antiplatelet therapy undergoing cardiac surgery is discussed controversially. We assessed platelet reactivity in 86 patients undergoing elective coronary artery bypass grafting (CABG) under extracorporeal circulation. Twenty-nine of these patients were without preoperative antiplatelet therapy (group A), while 57 were treated with acetylsalicylic acid (ASA) 100 mg qd up to the day of surgery. Out of this cohort, 24 patients received no desmopressin perioperatively (group B), whereas 33 patients were treated with desmopressin 0.4 μg/kg after administration of protamine due to increased bleeding tendency (group C). Multiple electrode platelet aggregometry with arachidonic acid as agonist showed a marked decrease of platelet reactivity in patients without antiplatelet therapy immediately after extracorporeal circulation compared to preoperative control (375 ± 227 vs. 749 ± 330 AU*min, p<0.001). Platelet reactivity recovered to preoperative controls in group A at 24 hours after protamine administration (662 ± 295 AU*min). Platelet reactivity in patients on ASA was not decreased further after extracorporeal circulation (group B: 197 ± 126 vs. 251 ± 203 AU*min, p=0.14; group C: 212 ± 100 vs. 245 ± 248 AU*min, p=0.43) and improved significantly within 24 hours. A statistically significant effect of desmopressin, however, could not be determined (group B: 392 ± 223 AU*min; group C: 439 ± 324 AU*min at 24 hours after protamine, p=0.63 for between-subjects contrast). Our data suggest that desmopressin does not affect platelet reactivity in patients on ASA undergoing CABG and is, therefore, not useful in this clinical setting.
Human Placental Pericytes Poorly Stimulate and Actively Regulate Allogeneic CD4 T Cell Responses
Authors: Maier Cheryl L. , Pober Jordan S. 
Published: November 2010

Objective—
Cell-mediated immune responses in peripheral tissues begin with T cell infiltration through endothelial cell (EC) microvessels and accumulation in the perivascular space occupied by pericytes (PC). Here, we investigate how human T cells interact with PC.

Methods and Results—

We compared human placental PC with autologous umbilical vein EC. Cultured PC express lower levels of major histocompatibility complex (MHC) and positive costimulatory molecules but higher levels of negative costimulatory molecules than do EC. Unlike EC, interferon-γ-treated MHC class II–positive PC (PC
+
) cannot stimulate resting allogeneic CD4 T cell proliferation or cytokine production. Instead, coculture of resting CD4 T cells with PC
+
induces CD25 expression and renders T cells unresponsive to restimulation by EC
+
from the same donor. PC cultured across a semi-permeable membrane decrease alloreactive CD4 T cell proliferation to EC
+
, an effect enhanced by pretreatment of PC with interferon-γ and partially reversed by interleukin-10 and transforming growth factor-β neutralization, but do not induce anergy.

Conclusion—
Human placental PC are poorly immunogenic and negatively regulate CD4 T cell responses through contact-dependent and contact-independent mechanisms.
Induction of MicroRNA-1 by Myocardin in Smooth Muscle Cells Inhibits Cell Proliferation
Authors: Chen Jie , Yin Hao , Jiang Yulan , Radhakrishnan Sarvan Kumar , Huang Zhan-Peng , Li Jingjing , Shi Zhan , Kilsdonk Elisabeth P.C. , Gui Yu , Wang Da-Zhi , Zheng Xi-Long 
Published: November 2010

Objective—
Myocardin is a cardiac- and smooth muscle–specific transcription co-factor that potently activates the expression of downstream target genes. Previously, we demonstrated that overexpression of myocardin inhibited the proliferation of smooth muscle cells (SMCs). Recently, myocardin was reported to induce the expression of microRNA-1 (miR-1) in cardiomyocytes. In this study, we investigated whether myocardin induces miR-1 expression to mediate its inhibitory effects on SMC proliferation.

Methods and Results—
Using tetracycline-regulated expression (T-REx) inducible system expressing myocardin in human vascular SMCs, we found that overexpression of myocardin resulted in significant induction of miR-1 expression and inhibition of SMC proliferation, which was reversed by miR-1 inhibitors. Consistently, introduction of miR-1 into SMCs inhibited their proliferation. We isolated spindle-shaped and epithelioid human SMCs and demonstrated that spindle-shaped SMCs were more differentiated and less proliferative. Correspondingly, spindle-shaped SMCs had significantly higher expression levels of both myocardin and miR-1 than epithelioid SMCs. We identified Pim-1, a serine/threonine kinase, as a target gene for miR-1 in SMCs. Western blot and luciferase reporter assays further confirmed that miR-1 targeted Pim-1 directly. Furthermore, neointimal lesions of mouse carotid arteries displayed downregulation of myocardin and miR-1 with upregulation of Pim-1.

Conclusion—
Our data demonstrate that miR-1 participates in myocardin-dependent of SMC proliferation inhibition.