bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of De Novo Ceramide Synthesis Reverses Diet-Induced Insulin Resistance and Enhances Whole-Body Oxygen Consumption
Authors: Ussher John R. , Koves Timothy R. , Cadete Virgilio J.J. , Zhang Liyan , Jaswal Jagdip S. , Swyrd Suzanne J. , Lopaschuk David G. , Proctor Spencer D. , Keung Wendy , Muoio Deborah M. , Lopaschuk Gary D. 
Published: June 2010

OBJECTIVEIt has been proposed that skeletal muscle insulin resistance arises from the accumulation of intramyocellular lipid metabolites that impede insulin signaling, including diacylglycerol and ceramide. We determined the role of de novo ceramide synthesis in mediating muscle insulin resistance.RESEARCH DESIGN AND METHODSMice were subjected to 12 weeks of diet-induced obesity (DIO), and then treated for 4 weeks with myriocin, an inhibitor of serine palmitoyl transferase-1 (SPT1), the rate-limiting enzyme of de novo ceramide synthesis.RESULTSAfter 12 weeks of DIO, C57BL/6 mice demonstrated a doubling in gastrocnemius ceramide content, which was completely reversed (141.5 ± 15.8 vs. 94.6 ± 10.2 nmol/g dry wt) via treatment with myriocin, whereas hepatic ceramide content was unaffected by DIO. Interestingly, myriocin treatment did not alter the DIO-associated increase in gastrocnemius diacyglycerol content, and the only correlation observed between lipid metabolite accumulation and glucose intolerance occurred with ceramide (R = 0.61). DIO mice treated with myriocin showed a complete reversal of glucose intolerance and insulin resistance which was associated with enhanced insulin-stimulated Akt and glycogen synthase kinase 3β phosphorylation. Furthermore, myriocin treatment also decreased intramyocellular ceramide content and prevented insulin resistance development in db/db mice. Finally, myriocin-treated DIO mice displayed enhanced oxygen consumption rates (3,041 ± 124 vs. 2,407 ± 124 ml/kg/h) versus their control counterparts.CONCLUSIONSOur results demonstrate that the intramyocellular accumulation of ceramide correlates strongly with the development of insulin resistance, and suggests that inhibition of SPT1 is a potentially promising target for the treatment of insulin resistance.
Higher Plasma Soluble Receptor for Advanced Glycation End Products (sRAGE) Levels Are Associated With Incident Cardiovascular Disease and All-Cause Mortality in Type 1 Diabetes
Authors: Nin Johanna W.M. , Jorsal Anders , Ferreira Isabel , Schalkwijk Casper G. , Prins Martin H. , Parving Hans-Henrik , Tarnow Lise , Rossing Peter , Stehouwer Coen D.A. 
Published: June 2010

OBJECTIVE
To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, arterial stiffness, and advanced glycation end products (AGEs).

RESEARCH DESIGN AND METHODS
We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of sRAGE and other biomarkers were measured at baseline. The median follow-up duration was 12.3 years (7.6–12.5).

RESULTS
The incidence of fatal and nonfatal CVD and all-cause mortality increased with higher baseline levels of log-transformed sRAGE (Ln-sRAGE) independently of other CVD risk factors: hazard ratio (HR) 1.90 (95% CI 1.13–3.21) and 2.12 (1.26–3.57) per 1-unit increase in Ln-sRAGE, respectively. Adjustments for estimated glomerular filtration rate (eGFRMDRD), but not or to a smaller extent for markers of endothelial dysfunction, low-grade inflammation, arterial stiffness, and AGEs, attenuated these associations to HR 1.59 (95% CI 0.91–2.77) for fatal and nonfatal CVD events and to 1.90 (1.09–3.31) for all-cause mortality. In addition, in patients with nephropathy, the rate of decline of GFR was 1.38 ml/min/1.73 m2 per year greater per 1-unit increase of Ln-sRAGE at baseline (P = 0.036).

CONCLUSIONS
Higher levels of sRAGE are associated with incident fatal and nonfatal CVD and all-cause mortality in individuals with type 1 diabetes. sRAGE-associated renal dysfunction may partially explain this association.
Functional Variants inMBL2Are Associated With Type 2 Diabetes and Pre-Diabetes Traits in Pima Indians and the Old Order Amish
Authors: Muller Yunhua L. , Hanson Robert L. , Bian Li , Mack Janel , Shi Xiaolian , Pakyz Ruth , Shuldiner Alan R. , Knowler William C. , Bogardus Clifton , Baier Leslie J. 
Published: June 2010

OBJECTIVEMBL2 encodes the mannose-binding lectin, which is a key player in the innate immune system and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes mellitus. To assess the role of MBL2 in diabetes susceptibility, this gene was analyzed in the Pima Indian population, which has a high prevalence of type 2 diabetes.RESEARCH DESIGN AND METHODSNineteen tag single nucleotide polymorphisms (SNPs) were genotyped in a population-based sample of 3,501 full-heritage Pima Indians, and selected SNPs were further genotyped in independent samples of Native American (n = 3,723) and Old Order Amish (n = 486) subjects.RESULTSTwo variants, a promoter SNP (rs11003125) at −550 bp with a risk allele frequency of 0.77 and a Gly54Asp (rs1800450) with a risk allele frequency of 0.83, were associated with type 2 diabetes in the full-heritage Pima Indians (odds ratio 1.30 per copy of the G allele for rs1103125, P = 0.0007, and 1.30 per copy of the glycine allele for rs1800450, P = 0.002, adjusted for age, sex, birth year, and family membership). These associations replicated in an independent Native American sample (1.19, P = 0.04, for rs11003125) and a Caucasian sample, the Old Order Amish (1.51, P = 0.004, for rs1103125 and 2.38, P = 0.003, for rs1800450). Among Pima Indians with normal glucose tolerance, the diabetes risk allele glycine of Gly54Asp was associated with a decreased acute insulin response to an intravenous glucose bolus infusion (P = 0.004, adjusted for age, sex, percent body fat, glucose disposal under physiological insulin stimulation, and family membership).CONCLUSIONSOur data suggest that the functional variants in MBL2 contribute to type 2 diabetes susceptibility in both Native Americans and the Old Order Amish.
Deficiency of Rac1 Blocks NADPH Oxidase Activation, Inhibits Endoplasmic Reticulum Stress, and Reduces Myocardial Remodeling in a Mouse Model of Type 1 Diabetes
Authors: Li Jianmin , Zhu Huaqing , Shen E , Wan Li , Arnold J. Malcolm O. , Peng Tianqing 
Published: June 2010

OBJECTIVE
Our recent study demonstrated that Rac1 and NADPH oxidase activation contributes to cardiomyocyte apoptosis in short-term diabetes. This study was undertaken to investigate if disruption of Rac1 and inhibition of NADPH oxidase would prevent myocardial remodeling in chronic diabetes.

RESEARCH DESIGN AND METHODS
Diabetes was induced by injection of streptozotocin in mice with cardiomyocyte-specific Rac1 knockout and their wild-type littermates. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. Myocardial hypertrophy, fibrosis, endoplasmic reticulum (ER) stress, inflammatory response, and myocardial function were investigated after 2 months of diabetes. Isolated adult rat cardiomyocytes were cultured and stimulated with high glucose.

RESULTS
In diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly increased in diabetic mice, which were accompanied by elevated expression of pro-fibrotic genes and hypertrophic genes. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. In cultured cardiomyocytes, high glucose–induced ER stress was inhibited by blocking Rac1 or NADPH oxidase.

CONCLUSIONS
Rac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. The role of Rac1 signaling may be associated with ER stress and inflammation. Thus, targeting inhibition of Rac1 and NADPH oxidase may be a therapeutic approach for diabetic cardiomyopathy.
Atrogin-1 Affects Muscle Protein Synthesis and Degradation When Energy Metabolism Is Impaired by the Antidiabetes Drug Berberine
Authors: Wang Huiling , Liu Dajun , Cao Peirang , Lecker Stewart , Hu Zhaoyong 
Published: June 2010

OBJECTIVE
Defects in insulin/IGF-1 signaling stimulate muscle protein loss by suppressing protein synthesis and increasing protein degradation. Since an herbal compound, berberine, lowers blood levels of glucose and lipids, we proposed that it would improve insulin/IGF-1 signaling, blocking muscle protein losses.

RESEARCH DESIGN AND METHODS
We evaluated whether berberine ameliorates muscle atrophy in db/db mice, a model of type 2 diabetes, by measuring protein synthesis and degradation in muscles of normal and db/db mice treated with or without berberine. We also examined mechanisms for berberine-induced changes in muscle protein metabolism.

RESULTS
Berberine administration decreased protein synthesis and increased degradation in muscles of normal and db/db mice. The protein catabolic mechanism depended on berberine-stimulated expression of the E3 ubiquitin ligase, atrogin-1. Atrogin-1 not only increased proteolysis but also reduced protein synthesis by mechanisms that were independent of decreased phosphorylation of Akt or forkhead transcription factors. Impaired protein synthesis was dependent on a reduction in eIF3-f, an essential regulator of protein synthesis. Berberine impaired energy metabolism, activating AMP-activated protein kinase and providing an alternative mechanism for the stimulation of atrogin-1 expression. When we increased mitochondrial biogenesis by expressing peroxisome proliferator–activated receptor γ coactivator-1α, berberine-induced changes in muscle protein metabolism were prevented.

CONCLUSIONS
Berberine impairs muscle metabolism by two novel mechanisms. It impairs mitochonidrial function stimulating the expression of atrogin-1 without affecting phosphorylation of forkhead transcription factors. The increase in atrogin-1 not only stimulated protein degradation but also suppressed protein synthesis, causing muscle atrophy.
Christian Orientals in Conversation with Islam: Two Examples from German Mission History in the Late Nineteenth and Early Twentieth Centuries
Authors: Tamcke Martin 
Published: June 2010

Abstract: The writer describes experiences of Oriental Christians belonging to German missions dealing with Syriac-speaking Muslims in the late nineteenth and early twentieth centuries. Using the example of two prime Missions in the Urmia-region of Iran—the German Mission to the Orient and the Hermannsburger Mission—he establishes the difference between formally schooled, European-trained Christian rhetoricians, whose forum for debate was public and published, and the less flamboyant, native-born Christians in unpublished discussion with their fellow countrymen. Focus is on two types of encounter: a several-weeks-long published controversy, backed by Turkish political editor Edhem Ruhi but centred on the preaching and writing of Turkish Christian convert John Awetaranian; and the on-the-ground lessons learned by Pera Johannes and his associates at the Hermannsburg Mission in Wasirabad, as they engaged in tentative, non-inflammatory discussion with Muslims of a common cultural background. Both examples show the significance of political involvement, since, on the one hand, Ruhi's newspaper was a forum for his views and thus set into motion as well as called a halt to the Awetaranian-Islam debate, and on the other, the horror stories of the Hermannsburg Mission ultimately showed up the futility and perhaps foolhardiness of combatting culture, even as members of a tolerated minority. On the surface, Awetarian represents the product of self-assured literary activity engaging in open controversy in mission work; and Pera Johannes with the Hermannsburger demonstrates the relatively unlettered, despised native group of Christians in a tenuous situation. The two examples meet, historically, in their encountering realities of politics that could make or break their project.
Neurosurgeons' perspectives on psychosurgery and neuroenhancement: a qualitative study at one center
Authors: Mendelsohn Daniel , Lipsman Nir , Bernstein Mark 
Published: June 2010

Object
Advances in the neurosciences are stirring debate regarding the ethical issues surrounding novel neurosurgical interventions. The application of deep brain stimulation (DBS) for treating refractory psychiatric disease, for instance, has introduced the prospect of altering disorders of mind and behavior and the potential for neuroenhancement. The attitudes of current and future providers of this technology and their position regarding its possible future applications are unknown. The authors sought to gauge the opinions of neurosurgical staff and trainees toward various uses of neuromodulation technology including psychosurgery and neuroenhancement.

Methods
The authors conducted a qualitative study involving in-depth interviews with 47 neurosurgery staff, trainees, and other neuroclinicians at a quaternary care center.

Results
Several general themes emerged from the interviews. These included universal support for psychosurgery given adequate informed consent and rigorous scientific methodology, as well as a relative consensus regarding the priority given to patient autonomy and the preservation of personal identity. Participants' attitudes toward the future use of DBS and other means of neuromodulation for cognitive enhancement and personality alteration revealed less agreement, although most participants felt that alteration of nonpathological traits is objectionable.

Conclusions
There is support in the neurosurgical community for the surgical management of refractory psychiatric disease. The use of neuromodulation for the alteration of nonpathological traits is morally and ethically dubious when it is out of sync with the values of society at large. Both DBS and neuromodulation will have far-reaching and profound public health implications.
Treatment with Angiotensin II Inhibitors and Residual Renal Function in Peritoneal Dialysis Patients
Authors: Kolesnyk Inna , Noordzij Marlies , Dekker Friedo W. , Boeschoten Elisabeth W. , Krediet Raymond T. 
Published: June 2010

Background Many studies have shown the renoprotective effect of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) in patients with chronic kidney disease stages I–IV. Two randomized controlled trials (RCTs) showed a positive effect of AII inhibitors on residual glomerular filtration rate (rGFR) in peritoneal dialysis (PD) patients. However, these studies were small and were performed in a highly selected group of PD patients. Our aim was to confirm the above findings in a larger number of prospectively followed PD patients. Methods First we analyzed the time course of decline of rGFR in 452 incident PD patients that were not anuric at the start of dialysis and that had structured follow-up data, with measurements at 3, 6, 12, 18, 24, 30, and 36 months after the start of dialysis. Changes in rGFR over time were analyzed with a linear mixed model for repeated measures. In addition, Cox regression models were used to estimate the risk of developing anuria. In a second approach, we aimed to repeat the above analyses in a selected group of patients that theoretically could have been randomized and therefore resembled the population studied in the 2 mentioned RCTs. In this group the follow-up was restricted to 1 year. Results 201 patients were treated with ACEi/ARBs and 251 did not take these drugs at the start of PD. More patients from the treated group had diabetes and used more antihypertensive medications. The time course of decline of rGFR was not different between the 2 groups over the 3 years of PD treatment ( p = 0.52). Less than 25% of patients from each group became anuric and there was no difference in time to development of complete anuria between the treated and untreated groups. In the second approach, 130 patients were included: 37 were treated with ACEi/ARBs and 93 were not. Again, no difference was found between the 2 groups with respect to the rate of decline of rGFR and time of anuria development. Conclusion Our findings are not in line with the results of previous RCTs. The biggest limitation of observational studies is the inability to avoid confounding by indication. However, a RCT in such a setting also does not give a reliable answer. Given all the benefits of ACEi/ARBs, the medications should not be withheld from PD patients. However, their renoprotective effects may often be overruled by other factors influencing the time course of rGFR.
High Water Evaporation Rate is Associated with Low Blood Pressure in Chronic Peritoneal Dialysis Patients
Authors: Hwang Jyh-Chang , Kan Wei-Chih , Wang Charn-Ting 
Published: June 2010

Background The relationship between water evaporation rate (WER) and blood pressure (BP) in continuous ambulatory peritoneal dialysis (CAPD) patients has not been addressed before. This study was undertaken to evaluate the effects of WER on the BP and body weight (BW) of end-stage renal disease patients treated with CAPD. Methods Based on mean WER of each month, the year 2005 was divided into “high WER” and “low WER” stages. This study enrolled 66 CAPD patients at our center during 2005. The BP and BW of each patient were collected monthly. WER was measured with a class A evaporation pan. Results Compared to the high WER stage, CAPD patients had higher BP (systolic: 142 ± 29 vs 134 ± 27 mmHg, p < 0.001; diastolic: 86 ± 17 vs 84 ± 16 mmHg, p < 0.001) and BW (56.8 ± 10.2 vs 56.1 ± 10.2 kg, p < 0.001) in the low WER stage. Ambient temperature was significantly higher in the high WER stage ( p = 0.004) and it was also positively correlated with WER ( r = 0.82, p = 0.0012). Both mean BP ( r = –0.72, p = 0.0089) and BW ( r = –0.79, p = 0.002) showed inverse relationships to the WER. Moreover, both mean BP ( r = –0.95, p < 0.001) and BW ( r = –0.90, p < 0.001) also showed negative linear regressions to ambient temperature. There was a positive linear regression between mean BP and BW ( r = 0.85, p = 0.0004). Multiple linear regression analysis found that WER (β = –0.672, p = 0.026) was an independent factor correlated to patients’ mean BP. Conclusions CAPD patients had lower BP and BW in the high WER stage. These decreases were associated with higher ambient temperature and WER. We hypothesize that increased insensible salt and fluid loss secondary to high WER during hot seasons, especially in subtropical areas, ameliorates the hypervolemia and hypertension in CAPD patients.
Peritoneal Dialysis is not Associated with Myocardial Stunning
Authors: Selby Nicholas M. , McIntyre Christopher W. 
Published: June 2010

Background Hemodynamic changes during hemodialysis can precipitate subclinical myocardial ischemia, which over time contributes to the development of cardiac failure and is associated with a poor prognosis. Peritoneal dialysis (PD) is also associated with acute changes in systemic hemodynamics and a similarly high incidence of cardiovascular disease; we therefore sought to examine whether the hemodynamic effects of a PD exchange would be sufficient to induce subclinical myocardial ischemia. Methods 10 patients on PD entered a prospective observational study to determine whether left ventricular (LV) regional wall motion abnormalities (RWMAs) developed following a dialysate exchange. Serial echocardiography with quantitative analysis was used to assess ejection fraction and regional systolic LV function (shortening fraction). Blood pressure (BP) and hemodynamic variables were measured using continuous pulse wave analysis. Results We observed a very low frequency of RWMA development (5/100 regions). Only 1 patient had more than 1 RWMA and 6 patients were entirely unaffected. Overall mean shortening fraction increased when comparing pre and post values for both 2-chamber (from 3.06% ± 1.5% to 4.26% ± 1.3%, p = 0.001) and 4-chamber (from 3.00% ± 0.7% to 3.67% ± 0.9%, p = 0.021) analyses. Mean arterial pressure fell by a small degree during drainage of dialysate, with a larger rise in BP observed during instillation. These changes were driven by changes in peripheral resistance that fell during drainage and rose during instillation. Conclusions In contrast to hemodialysis, the acute effects of PD do not result in subclinical myocardial ischemia.
Pharmacokinetics of once-daily Etravirine without and with Once-daily Darunavir/ritonavir in Antiretroviral-Naive HIV type-1-Infected Adults
Authors: DeJesus Edwin , Lalezari Jacob P , Osiyemi Olayemi O , Ruane Peter J , Ryan Robert , Kakuda Thomas N , Witek James 
Published: June 2010

Background A pharmacokinetic trial was conducted to evaluate the potential for once-daily etravirine in anti-retroviral regimens without and with darunavir/ritonavir. Methods During this multicentre, open-label, Phase IIa trial, treatment-naive patients aged ≥18 years with HIV type-1 (HIV-1) received etravirine 400 mg once daily with tenofovir disoproxil fumarate/emtricitabine 300/200 mg once daily from days 1–14; on days 15–28, darunavir/ritonavir 800/100 mg once daily was added. On day 29, etravirine was discontinued and patients continued with the other medications to day 42. Serial blood sampling for etravirine pharmacokinetics was performed over 24 h on day 14 and 28; patients fasted for ≥10 h prior to these visits. Results Of 23 enrolled patients (male 87%, Caucasian 39%), pharmacokinetic profiles for etravirine were available for 21 and 20 patients on day 14 and 28, respectively. The plasma concentration–time profile and pharmacokinetics for etravirine were unchanged with or without darunavir/ritonavir. The mean maximum plasma concentration (Cmax) was reached 4 h after administration and was 790 and 801 ng/ml on day 14 and 28, respectively; mean area under the plasma concentration–time curve (AUC) from before administration to 24 h after administration was 10,410 ng•h/ml on day 14 and 10,720 ng•h/ml on day 28. In a post-hoc analysis, etravirine Cmax was higher, minimum plasma concentration was lower and AUC was similar when compared with etravirine 200 mg twice daily. Conclusions Addition of darunavir/ritonavir to etravirine, all dosed once daily, did not have a clinically significant effect on the pharmacokinetics of etravirine. Findings support further investigation of etravirine 400 mg once daily in HIV-1-infected patients. (Trial registration number NCT00534352.)