bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine–Induced Prostate Carcinogenesis in CYP1A-Humanized Mice
Authors: Li Guangxun , Wang Hong , Liu Anna B. , Cheung Connie , Reuhl Kenneth R. , Bosland Maarten C. , Yang Chung S. 
Published: May 2012

Abstract
To develop a relevant mouse model for prostate cancer prevention research, we administered a dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), to CYP1A-humanized mice. In comparison with mouse Cyp1a2, human CYP1A2 preferentially activates PhIP to a proximate carcinogen. Following a single oral dose of PhIP (200 mg/kg body weight), we observed inflammation, atrophy of acini, low-grade prostatic intraepithelial neoplasia (PIN; after 20 weeks), and high-grade PIN (HgPIN; after 30 to 50 weeks) in dorsolateral, ventral, and coagulating anterior prostate glands of these mice. These lesions were androgen receptor positive and featured the loss of expression of the basal cell marker p63 and the tumor suppressor PTEN. Similar to human prostate carcinogenesis, glutathione S-transferase P1 (GSTP1) expression was lost or partially lost in HgPIN. E-Cadherin expression was also lost in HgPIN. The expression of DNA methyltransferase 1 was elevated, possibly to enhance promoter hypermethylation for the silencing of GSTP1 and E-cadherin. Prostate carcinogenesis was promoted by a high-fat stress diet, resulting in HgPIN that developed earlier and in advanced lesions displayed features consistent with carcinoma in situ. This dietary carcinogen-induced prostate cancer model, recapitulating important features of early human prostate carcinogenesis, constitutes a new experimental system for prostate cancer research. Cancer Prev Res; 5(7); 963–72. ©2012 AACR.
Antithrombotic Potential of Blockers of Store-Operated Calcium Channels in Platelets
Authors: van Kruchten Roger , Braun Attila , Feijge Marion A. H. , Kuijpers Marijke J. E. , Rivera-Galdos Ronmy , Kraft Peter , Stoll Guido , Kleinschnitz Christoph , Bevers Edouard M. , Nieswandt Bernhard , Heemskerk Johan W. M. 
Published: May 2012

Objective—

Platelet Orai1 channels mediate store-operated Ca
2+
entry (SOCE), which is required for procoagulant activity and arterial thrombus formation. Pharmacological blockage of these channels may provide a novel way of antithrombotic therapy. Therefore, the thromboprotective effect of SOCE blockers directed against platelet Orai1 is determined.

Methods and Results—
Candidate inhibitors were screened for their effects on SOCE in washed human platelets. Tested antagonists included the known compounds, SKF96365, 2-aminoethyl diphenylborate, and MRS1845 and the novel compounds, Synta66 and GSK-7975A. The potency of SOCE inhibition was in the order of Synta66>2-aminoethyl diphenylborate>GSK-7975A>SKF96365>MRS1845. The specificity of the first 3 compounds was verified with platelets from Orai1-deficient mice. Inhibitory activity on procoagulant activity and high-shear thrombus formation was assessed in plasma and whole blood. In the presence of plasma, all 3 compounds suppressed platelet responses and restrained thrombus formation under flow. Using a murine stroke model, arterial thrombus formation was provoked in vivo by transient middle cerebral artery occlusion. Postoperative administration of 2-aminoethyl diphenylborate markedly diminished brain infarct size.

Conclusion—
Plasma-soluble SOCE blockers such as 2-aminoethyl diphenylborate suppress platelet-dependent coagulation and thrombus formation. The platelet Orai1 channel is a novel target for preventing thrombotic events causing brain infarction.
Toll-Like Receptor 4 Deficiency Decreases Atherosclerosis But Does Not Protect Against Inflammation in Obese Low-Density Lipoprotein Receptor–Deficient Mice
Authors: Ding Yilei , Subramanian Savitha , Montes Vince N. , Goodspeed Leela , Wang Shari , Han ChangYeop , Teresa Antonio Sta. , Kim Jinkyu , O’Brien Kevin D. , Chait Alan 
Published: May 2012

Objective—
Obesity is associated with insulin resistance, chronic low-grade inflammation, and atherosclerosis. Toll-like receptor 4 (TLR4) participates in the cross talk between inflammation and insulin resistance, being activated by both lipopolysaccharide and saturated fatty acids. The present study was undertaken to determine whether TLR4 deficiency has a protective role in inflammation, insulin resistance, and atherosclerosis induced by a diabetogenic diet.

Methods and Results—
TLR4 and low-density lipoprotein (LDL) receptor double knockout mice and LDL receptor–deficient mice were fed either a normal chow or a diabetogenic diet for 24 weeks. TLR4 and LDL receptor double knockout mice fed a diabetogenic diet showed improved plasma cholesterol and triglyceride levels but developed obesity, hyperinsulinemia, and glucose intolerance equivalent to obese LDL receptor–deficient mice. Adipocyte hypertrophy, macrophage accumulation, and local inflammation were not attenuated in intraabdominal adipose tissue in TLR4 and LDL receptor double knockout mice. However, TLR4 deficiency led to markedly decreased atherosclerosis in obese TLR4 and LDL receptor double knockout mice. Compensatory upregulation of TLR2 expression was observed both in obese TLR4-deficient mice and in palmitate-treated TLR4-silenced 3T3-L1 adipocytes.

Conclusions—
TLR4 deficiency decreases atherosclerosis without affecting obesity-induced inflammation and insulin resistance in LDL receptor–deficient mice. Alternative pathways may be responsible for adipose tissue macrophage infiltration and insulin resistance that occurs in obesity.
Leptin Potentiates Endothelium-Dependent Relaxation by Inducing Endothelial Expression of Neuronal NO Synthase
Authors: Benkhoff Sebastian , Loot Annemarieke E. , Pierson Ina , Sturza Adrian , Kohlstedt Karin , Fleming Ingrid , Shimokawa Hiroaki , Grisk Olaf , Brandes Ralf P. , Schröder Katrin 
Published: May 2012

Objective—
Obesity is associated with hyperleptinemia but it is not clear whether leptin protects vascular function or promotes dysfunction. We therefore studied the consequences of hyperleptinemia in lean mice.

Methods and Results—

Wild-type and endothelial NO synthase (eNOS)
−/−
mice were infused with leptin (0.4 mg/kg per day, 7 days), and endothelium-dependent relaxation was studied in aortic segments. Leptin had no effect on acetylcholine-induced endothelium-dependent relaxation in normal wild-type mice but restored endothelium-dependent relaxation in wild-type mice treated with angiotensin II (0.7 mg/kg per day, 7 days) to induce endothelial dysfunction. Leptin also sensitized aortae from eNOS
−/−
mice to acetylcholine, an effect blocked by neuronal NOS (nNOS) inhibition and not observed in eNOS-nNOS double
−/−
mice. Consistent with these findings, leptin induced nNOS expression in murine and human vessels and human endothelial but not smooth muscle cells. Aortic nNOS expression was also induced in mice by a high-fat diet. Mechanistically, leptin increased endothelial Janus kinase 2 and signal transducer and activator of transcription 3 phosphorylation, and inhibition of Janus kinase 2 prevented nNOS induction in cultured cells and leptin-induced relaxations in eNOS
−/−
mice.

Conclusion—
Leptin induces endothelial nNOS expression, which compensates, in part, for a lack of NO production by eNOS to maintain endothelium-dependent relaxation.
Advance Directives in Community Patients With Heart Failure
Authors: Dunlay Shannon M. , Swetz Keith M. , Mueller Paul S. , Roger Véronique L. 
Published: May 2012

Background—
Although it is recommended that all patients with heart failure (HF) have advance directives (AD) in place before the end of life is imminent, the use of AD in HF has not been well studied.

Methods and Results—
We enrolled consecutive Olmsted County residents presenting with HF from October 2007 through October 2011 into a longitudinal study. Information from AD completed before enrollment and hospitalizations in the month before death were abstracted. Among 608 patients (mean age, 74.0 years; 54.9% men; 65.3%; New York Heart Association functional class 3 or 4), 164 (27.0%) patients died after a mean follow-up of 1.8 years. At enrollment, only 249 (41.0%) patients had an AD. Although most AD appointed a proxy decision-maker (90.4%), less than half addressed wishes regarding use of cardiopulmonary resuscitation (41.4%), mechanical ventilation (38.6%), or hemodialysis (10.0%) at the end of life. The independent predictors of AD completion were older age (adjusted odds ratio [OR] per 10-year increase, 1.82; 95% confidence interval [CI], 1.51–2.20), malignancy (OR, 1.58; 95% CI, 1.05–2.37), and renal dysfunction (OR for estimated glomerular filtration rate <60 mL/min 1.55; 95% CI, 1.05–2.29). At the end of life, patients with AD specifying limits in the aggressiveness of care less frequently received mechanical ventilation (OR, 0.26; 95% CI, 0.07–0.88), with a trend toward decreased intensive care unit admission (OR, 0.45; 95% CI, 0.16–1.29).

Conclusions—
Despite a high mortality rate, over half of patients with HF do not have an AD, and existing AD fail to address important end-of-life medical decisions.
Ventricular Assist Device Implantation Corrects Myocardial Lipotoxicity, Reverses Insulin Resistance, and Normalizes Cardiac Metabolism in Patients With Advanced Heart Failure
Authors: Chokshi Aalap , Drosatos Konstantinos , Cheema Faisal H. , Ji Ruiping , Khawaja Tuba , Yu Shuiqing , Kato Tomoko , Khan Raffay , Takayama Hiroo , Knöll Ralph , Milting Hendrik , Chung Christine S. , Jorde Ulrich , Naka Yoshifumi , Mancini Donna M. , Goldberg Ira J. , Schulze P. Christian 
Published: May 2012

Background—
Heart failure is associated with impaired myocardial metabolism with a shift from fatty acids to glucose use for ATP generation. We hypothesized that cardiac accumulation of toxic lipid intermediates inhibits insulin signaling in advanced heart failure and that mechanical unloading of the failing myocardium corrects impaired cardiac metabolism.

Methods and Results—

We analyzed the myocardium and serum of 61 patients with heart failure (body mass index, 26.5±5.1 kg/m
2
; age, 51±12 years) obtained during left ventricular assist device implantation and at explantation (mean duration, 185±156 days) and from 9 control subjects. Systemic insulin resistance in heart failure was accompanied by decreased myocardial triglyceride and overall fatty acid content but increased toxic lipid intermediates, diacylglycerol, and ceramide. Increased membrane localization of protein kinase C isoforms, inhibitors of insulin signaling, and decreased activity of insulin signaling molecules Akt and Foxo were detectable in heart failure compared with control subjects. Left ventricular assist device implantation improved whole-body insulin resistance (homeostatic model of analysis–insulin resistance, 4.5±0.6–3.2±0.5;
P
<0.05) and decreased myocardial levels of diacylglycerol and ceramide, whereas triglyceride and fatty acid content remained unchanged. Improved activation of the insulin/phosphatidylinositol-3 kinase/Akt signaling cascade after left ventricular assist device implantation was confirmed by increased phosphorylation of Akt and Foxo, which was accompanied by decreased membrane localization of protein kinase C isoforms after left ventricular assist device implantation.

Conclusions—
Mechanical unloading after left ventricular assist device implantation corrects systemic and local metabolic derangements in advanced heart failure, leading to reduced myocardial levels of toxic lipid intermediates and improved cardiac insulin signaling.
Distributional Impact of Brain Microbleeds on Global Cognitive Function in Adults Without Neurological Disorder
Authors: Yakushiji Yusuke , Noguchi Tomoyuki , Hara Megumi , Nishihara Masashi , Eriguchi Makoto , Nanri Yusuke , Nishiyama Masanori , Hirotsu Tatsumi , Nakajima Junko , Kuroda Yasuo , Hara Hideo 
Published: May 2012

Background and Purpose—
Brain microbleeds (MBs) are considered to be associated with cognitive decline and can be pathologically and topographically classified as cerebral amyloid angiopathy-related (located in lobar regions) and hypertensive microangiopathy-related (located in deep regions). We examined whether different effects on global cognitive function might be seen with different distributions of MBs.

Methods—
A total of 1279 adults without neurological disorders were studied prospectively. Subjects were divided into 4 groups: without-MBs group; lobar group; deep group; and with in both areas (diffuse group). The Mini-Mental State Examination was administered to determine global cognitive functions, with scores <27 regarded as subnormal.

Results—
MBs were detected in 98 subjects (8%): 36 subjects (3%) classified as lobar group, 48 subjects (4%) as deep group, and 14 subjects (1%) as diffuse group. Subnormal scores were found in 76 subjects (5.9%), associated with age, education, hypertension, severe white matter hyperintensities, and distribution and number of MBs. In the final model of logistic regression analysis, the deep group (OR, 2.79; 95% CI, 1.14–6.79) was associated with subnormal scores, whereas the lobar group (OR, 0.77; 95% CI, 0.17–3.44) was not. Trend for the diffuse group did not reach the level of significance (OR, 5.01; 95% CI, 0.88–28.41). These trends were also seen in analysis using another cut-off point for subnormal score. Scores for total Mini-Mental State Examination and attention and calculation were significantly lower in the deep group and the diffuse groups compared with the without-MBs group.

Conclusions—
This Japanese cross-sectional study demonstrated that MB-related global cognitive dysfunction seems to occur based on hypertensive pathogenesis rather than on cerebral amyloid angiopathy.
Variation in Prescribing Patterns and Therapeutic Drug Monitoring of Intravenous Busulfan in Pediatric Hematopoietic Cell Transplant Recipients
Authors: McCune Jeannine S. , Baker K. Scott , Blough David K. , Gamis Alan , Bemer Meagan J. , Kelton‐Rehkopf Megan C. , Winter Laura , Barrett Jeffrey S. 
Published: May 2012

AbstractPersonalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8‐fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4‐fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors— group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children.
Sleep Apnea in Children with Laryngomalacia
Authors: Digoy G. Paul , Shukry Mohanad , Stoner Julie A. 
Published: May 2012

ObjectiveThe authors study the contribution of laryngomalacia to obstructive sleep apnea syndrome (OSAS) in children older than 12 months. The clinical and polysomnographic outcomes in patients with OSAS who underwent a supraglottoplasty were also studied.SettingTertiary care children’s hospital.Study DesignA case series with chart review.Subjects and MethodsA review of consecutive pediatric patients diagnosed with both OSAS and state‐dependant laryngomalacia (SDL) between 2005 and 2008. The diagnosis of SDL was made via laryngoscopy under light general anesthesia (sleep endoscopy). All subjects underwent a supraglottoplasty.ResultsA total of 43 patients met inclusion criteria, and 36 patients had complete pre‐ and postoperative data available for review. The apnea‐hypopnea index (AHI) score decreased following supraglottoplasty for 33 (92%; 95% confidence interval [CI], 78%‐98%) of the 36 patients. The mean (SD) change in AHI score (calculated as the postoperative minus the preoperative measure) was −9.2 (11.2), representing a statistically significant reduction (95% CI, −13.0 to −5.5; P <. 0001). The mean (SD) preoperative AHI was 13.3 (12.9). The minimum oxygen saturation increased following supraglottoplasty for 21 (58%; 95% CI, 41%‐74%). The mean (SD) change in the minimum oxygen saturation was 3.5 (8.3), which was a statistically significant increase (95% CI, 0.7‐6.3; P =. 015).ConclusionLaryngomalacia may contribute significantly to OSAS in some children who are 12 months and older. Sleep endoscopy appears to be an effective method in the diagnosis of SDL. When present, a supraglottoplasty can be an effective procedure and may significantly improve symptoms of OSAS.
Effects of sling and voluntary constraint during constraint-induced movement therapy for the arm after stroke: a randomized, prospective, single-centre, blinded observer rated study
Authors: Krawczyk Maciej , Sidaway Marta , Radwańska Anna , Zaborska Joanna , Ujma Renata , Członkowska Anna 
Published: May 2012

Objective: To determine whether a combination of constraint-induced movement therapy and physiotherapy in stroke patients using different constraint regimens (sling versus voluntary constraint) changes or reduces motor deficits, the amount of functional use of the arm and whether the effects of treatment continue after 12 months. Design: Forty-seven stroke patients were stratified and randomly divided into intensive physiotherapy programmes focused on regaining arm functions. Setting: Neurorehabilitation Unit of IInd Department of Neurology at Institute of Psychiatry and Neurology in Warsaw. Subject: Patients were randomly allocated to: the sling-constraint group ( n = 24) or to the voluntary-constraint group ( n = 23). Interventions: Massed practice with the paretic arm (5 hours/day for 15 consecutive working days). Sling-constraint group had their arm immobilized in a hemi-sling during therapy. In addition, individual, 1-hour physiotherapy sessions were conducted in both groups. Main measures: Rivermead Motor Assessment (RMA) Arm scale, (0–15), Motor Activity Log – Quality of Movement (MAL-QOM) (0–5 for 30 daily tasks). Results: There was no significant difference between groups after therapy (MAL-QOM mean change for sling group 0.78, SD = 0.46 and for voluntary-constraint group 0.84, SD = 0.48; P = 0.687). All treated patients retained mean gains in real-world arm use (MAL-QOM) mean scores after 12 months follow-up compared with posttreatment values but there was no significant difference between groups (comparison of estimated mean change of MAL-QOM stated 0.23. 95% confidence interval = −0.04–0.50). Conclusion: Voluntary activity constraint in the intact arm is equivalent to sling, standard constraint during massed practice of paretic arm.
Suture-Only Fixation Technique Leads to a Higher Degree of Extrusion Than Bony Fixation in Meniscal Allograft Transplantation
Authors: Abat Ferran , Gelber Pablo Eduardo , Erquicia Juan Ignacio , Pelfort Xavier , Gonzalez-Lucena Gemma , Monllau Juan Carlos 
Published: May 2012

Background: Most of the published series of transplanted menisci have consistently shown some degree of allograft extrusion. The speculation is that this meniscal extrusion may be caused by the soft tissue technique used to fix the allograft. Hypothesis: The percentage of extruded meniscal graft would be higher if the allograft were only fixed with sutures rather than with associated bony fixation. Study Design: Cohort study; Level of evidence, 2. Methods: We performed a prospective series of 88 meniscal allograft transplantations. Thirty-three of the grafts were fixed with the suture-only technique (group A). The remaining 55 cases were performed with the bone plug method (group B). All patients were studied with magnetic resonance imaging (MRI) at a minimum 3 years’ follow-up to determine the degree of meniscal extrusion. The time between surgery and MRI evaluation was 40 months (range, 36-48 months) in both groups. Meniscal extrusion was measured on coronal MRI. The percentage of the meniscal body width that was extruded was calculated. The average percentage of extrusion for each group was compared. The Lysholm score was analyzed in relation to the fixation method and degree of meniscal extrusion. Tears of the allograft that required surgical intervention were also reported. Results: The average percentage of meniscal tissue extruded in group A was 36.3% ± 13.7% without differences between the medial (35.9% ± 18.1%) and lateral (38.3% ± 14.4%) compartments ( P = .84). Group B had a mean 28.13% ± 12.2% of the meniscal body extruded without differences between the medial (25.8% ± 16.2%) and lateral (30.14% ± 13.5%) compartments. A higher percentage of extruded meniscal tissue was found in group A than in group B ( P < .001). No association between the degree of meniscal extrusion and the functional score was observed ( P = .4). Graft tears were observed in 21.4% of the cases in group A and in 7.3% of the cases in group B ( P = .09). Conclusion: A meniscal allograft fixed with the suture-only technique showed a significantly higher degree of extruded meniscal body than that fixed with the bony fixation method, with no influence on the functional outcome. There was also a considerably higher rate of graft tears observed in those menisci fixed only with sutures, although this difference was not statistically significant with the numbers available.