bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host Cells Reduce Glucose Uptake and Glycogen Deposition in Response to Hepatic Insulin Gene Therapy
Authors: Porter Marty H. , Paveglio Sara A. , Zhang Jin-an , Olson Darin E. , Campbell Adam G. , Thulé Peter M. 
Published: August 2007

Background Hepatic insulin gene therapy (HIGT) restores weight gain and near-normal glycemia in rodent models of insulin- deficient diabetes mellitus. However, the effect of transgenic insulin on endogenous genes and recipient cell function is relatively unexplored. To investigate hepatocellular effects of transgenic insulin expression, we evaluated intermediary glucose metabolism in primary cultured hepatocytes treated with HIGT. Methods Rat hepatocytes were transduced with adenovirus expressing a glucose-responsive human insulin transgene and cultured in high-glucose and high-insulin conditions. We determined glycogen content in cell cultures and intact liver directly. Glycogenolysis was compared using glucose production of cultured cells. Glucose uptake, oxidative, and glycolytic processing were determined by radiotracer analysis or direct end-product assessment. Quantitative real-time reverse transcriptase polymerase chain reaction was used to determine expression of glucose transporter 2 (GLUT2) and glucokinase genes. GLUT2 protein abundance was determined by Western blot analysis. Results HIGT-treated hepatocytes contained significantly less glycogen than either untreated hepatocytes or those treated with an empty virus. Glucose release owing to glycogenolysis remained normal. However, HIGT treatment significantly impaired glucose uptake and processing. Metabolic synthetic processes were not generally inhibited, as indicated by enhanced β-hydroxybutyrate secretion. While preserving cell viability, HIGT treatment diminished expression of both glucokinase and GLUT2. In HIGT-treated streptozocin-treated diabetic rats, total liver glycogen was intermediate between diabetic animals and normal controls. Conclusions These results suggest gene-specific effects in recipient hepatocytes following HIGT treatment and underscore the need for expanded studies examining host cell responses to the transfer of metabolically active transgenes.
Outcomes of National Institutes of Health Peer Review of Clinical Grant Applications
Authors: Kotchen Theodore A. , Lindquist Teresa , Miller Sostek Anita , Hoffmann Raymond , Malik Karl , Stanfield Brent 
Published: August 2007

Purpose We previously reported that National Institutes of Health (NIH) peer review outcomes in 2002 were slightly but significantly less favorable for grant applications for clinical research than for laboratory research. The present analysis was undertaken to determine if factors related to the review process might contribute to this difference. Methods The impact of each of the following factors on median priority scores and funding rates for clinical and nonclinical R01 grant applications was evaluated: (1) the percentage of clinical applications assigned for review to a study section, (2) the requested direct costs, and (3) the clinical research experience of the reviewers. Results Confirming our previous observation, in both 1994 and 2004, median priority scores and funding rates for R01 applications were less favorable for clinical research. In 1994, clinical applications did not fare as well in study sections reviewing relatively low percentages of clinical applications. This was not the case in 2004. Although requested direct costs were greater for clinical than for nonclinical R01 applications, median priority scores within each category were actually more favorable for applications requesting greater funding. Assignment of priority scores was not different for reviewers with or without experience conducting clinical research. Conclusion These data do not support the hypothesis that the less favorable review outcomes for clinical applications are related to these review factors. We suggest that peer review outcomes for clinical research will benefit from the recent refinement of NIH review criteria, emphasizing the unique contributions of clinical investigation, and from increased training opportunities for clinical investigators.
Influence of the Dialysis Membrane on Markers of Tissue Ischemia
Authors: Carrega Louis , Giaime Philippe , Montserrat Colette , Vincente Olivia , Brunet Philippe , Dussol Bertrand , Berland Yvon , Guieu Regis 
Published: August 2007

Background Hemodialysis (HD) is often accompanied by adverse effects, such as tissue ischemia. We have already observed an increase in plasma adenosine (ADO) levels during HD sessions, which may be the result of tissue ischemia. Here we evaluate the influence of the dialysis membrane on two sensitive and early markers of ischemia: ADO and ischemia-modified albumin (IMA). Methods We included in the study 50 patients with end-stage renal failure, 39 hemodialyzed (mean age 61 ± 24 years; 24 male; membranes: 23 synthetic and 16 cellulose based) and 11 undialyzed (mean age 55 ± 12 years; 6 male), and 10 healthy subjects (mean age 47 ± 11 years; 4 male). We compensated for hemoconcentration during HD by measuring either the IMA to albumin (Alb) or the ADO to Alb ratio. Results Under basal conditions, the IMA to Alb ratio was not significantly different in patients and controls and HD did not significantly modify this ratio. Conversely, the ADO to Alb ratio (mean ± SD in μmol/g) was higher in patients before HD compared with either undialyzed patients or controls (before HD: 0.077 ± 0.02; undialyzed patients: 0.026 ± 0.11; controls: 0.022 ± 0.01). During HD, there was a significant increase in the ADO to Alb ratio (before HD: 0.077 ± 0.02; after HD: 0.09 ± 0.029; p < .01). We found no significant difference in the IMA to Alb or ADO to Alb ratio using either synthetic or cellulose-based membranes. Conclusions We concluded that ADO is a more sensitive marker of ischemia than IMA and that, under our HD conditions, the ischemia caused by HD was very weak, independent of the dialysis membrane.
Thiazolidinediones and Progression of Renal Disease in Patients with Diabetes
Authors: Goyal Abhijeet , Crook Errol D. 
Published: August 2007

Objective Thiazolidinediones (TZDs) are used in the treatment of type 2 diabetes mellitus (T2DM) and appear to have beneficial effects on markers of cardiovascular or renal risk that are independent of glycemic control. We examined the effects of TZDs on renal survival in a predominantly black population with T2DM. Methods We performed a retrospective case-control study in patients with T2DM seen in our nephrology clinic in 2001 to 2002. Cases had T2DM and were on a TZD at presentation or for ≥ 6 months over follow-up. Controls were matched for sex, age, duration of T2DM, and initial creatinine. Reaching end-stage renal disease (ESRD) was the primary end point. Results From 387 records, 43 cases (34 blacks, 31 females) and 106 controls (96 blacks, 83 females) were identified. The baseline characteristics were similar for both groups. Both groups had moderate renal disease (estimated glomerular filtration rate ≈ 40-45 mL/min). Cases had lower systolic blood pressure over follow-up (p = .02), but there was no difference in glycemic control or use of insulin. Renal survival was better among cases (age- and gender-adjusted odds ratio for reaching ESRD 0.17 [95% confidence interval 0.03-0.8]; p = .03). When adjusted for systolic blood pressure over follow-up, the tendency for improved renal survival in cases remained but was no longer significant. Conclusion We conclude that TZDs may protect against the progression of renal disease in T2DM. Prospective studies are required to determine the effects of TZDs on renal survival in T2DM.
Inducible Nitric Oxide Synthase Inhibitors Reduce Urinary Markers of Systemic Oxidant Stress in Murine Proliferative Lupus Nephritis
Authors: Njoku Chinedu J. , Patrick Kennerly S. , Ruiz Philip , Oates Jim C. 
Published: August 2007

Background Proliferative lupus nephritis (PLN) is characterized by increased expression of inducible nitric oxide (NO) synthase (iNOS). Inhibition of iNOS with NG-monomethyl L-arginine (L-NMMA) abrogates renal disease in two models of murine PLN, but the mechanism of this effect is unknown. Reactive oxygen species have both direct and indirect pathogenic effects in inflammatory lesions and are therefore potentially an important therapeutic target in PLN. We hypothesized that inhibition of iNOS activity would reduce ROS production in murine PLN. Methods A dose escalation of L-NMMA (0, 20, 100, and 500 mg/kg/day) was performed in New Zealand Black × New Zealand White F1 (NZB/W) mice with active renal disease. Twenty-four-hour urine nitrate + nitrite (NOX) was measured with a chemiluminescence NO analyzer. Twenty-four-hour urine 8-isoprostane F2α (8-iso-PGF2α) was measured by gas chromatography-negative ion chemical ionization mass spectrometry. MRL-MpJFASlpr (MRL/lpr) and NZB/W mice were divided into three groups and given either L-NMMA, L-N6-iminoethyl-lysine (L-NIL), or distilled water for 2 weeks. Urine NOX and 8-iso-PGF2α were determined after 2 weeks. Results L-NMMA reduced both urine NOX and 8-iso-PGF2α levels in a dose-dependent fashion in NZB/W and MRL/lpr mice. Urine NOX and 8-iso-PGF2α levels were highly correlated. Both specific (L-NIL) and nonspecific (L-NMMA) iNOS inhibition reduced urine NOX and 8-iso-PGF2α levels in both models of murine PLN. Conclusion These findings suggest that iNOS activity is a major source of reactive oxidant stress in these models of murine PLN. Future studies will address the pathogenic role of reactive oxygen stress in PLN.
Role of the Mitogen-Activated Protein Kinases in Cytokine-Mediated Inhibition of Insulin Gene Expression
Authors: Chin-Chance Catherine V.T. , Newman Marsha V. , Aronovitz Amy , Blomeier Herman , Kruger Jessica , Lee Eun-Jig , Lowe William L. 
Published: August 2007

Background Following islet transplant, inflammatory cells in the vicinity of the transplant graft elaborate cytokines that contribute to islet graft dysfunction. To better understand the mechanism for this effect of cytokines on graft function, we examined the impact of cytokines on intracellular signaling and insulin promoter activity in pancreatic beta cells. Methods Two pancreatic beta cell lines, RINm5F and MIN6 cells, were transfected with a rat insulin promoter (RIP) luciferase fusion gene and treated with a combination of cytokines, including 5 ng/mL interleukin-1β + 10 ng/mL tumor necrosis factor α + 25 ng/mL interferon-γ. The effect of cytokines on beta cell transcription factors and signaling pathways was analyzed by real-time reverse transcriptase polymerase chain reaction and Western blotting. Results Treatment for 48 hours with the combination of cytokines decreased insulin 1 messenger ribonucleic acid (mRNA) levels to 51% and 38% and RIP1 activity to 16% and 30% of control levels in RINm5F and MIN6 cells, respectively. The level of mRNAs encoding transcription factors important for insulin gene expression and beta cell function, including MafA, PDX-1, Nkx6.1, and Pax6, was also decreased by cytokine treatment. Cytokines increased phosphorylation of ERK and c-Jun NH2-terminal kinase (JNK) in RINm5F and MIN6 cells but had no effect on p38 kinase phosphorylation. Neither JNK nor ERK inhibition had a significant effect on cytokine-mediated inhibition of RIP1 activity. Conclusion Beyond modulating beta cell survival, cytokines inhibit insulin promoter activity, which likely contributes to islet dysfunction following islet transplant. This effect appears to be mediated, in part, via altered expression of transcription factors important for insulin gene expression.
Intradermal Capsaicin Causes Dose-Dependent Pain, Allodynia, and Hyperalgesia in Humans
Authors: Scanlon Graham C. , Wallace Mark S. , Ispirescu Sorin J. , Schulteis Gery 
Published: August 2007

Background Intradermal capsaicin is a human pain model that produces reliable pain and sensitization. This model facilitates controlled testing of analgesic efficacy via a crossover design while minimizing confounding variables in clinical pain states and retaining sufficient power with small samples. Methods To determine the lowest dose of capsaicin that produces consistent neurosensory measures, we administered 0.1, 1, 10, or 100 μg to healthy volunteers in a blinded manner ( N = 19). Pain scores were recorded at 0, 5, 10, 15, and 60 minutes on a visual analog scale from 0 to 100. Areas and intensities of mechanical allodynia (foam brush stimulus) and pinprick hyperalgesia (von Frey test) were quantified at 15 and 60 minutes, as were flare areas. Results Capsaicin produced dose-dependent increases in spontaneous pain ( p = .013), the area and intensity of mechanical allodynia ( p = .006 and p < .001, respectively), the area and intensity of pinprick hyperalgesia ( p = .010 and p = .014, respectively), and the flare area ( p = .010). The 10 μg dose produced greater spontaneous pain than the 1 μg dose ( p = .017). The 100 μg dose produced greater spontaneous pain than the 10 μg, but the difference was not statistically significant. Conclusion The 10 and 100 μg capsaicin doses produced robust pain measures across a range of modalities, and lower doses produced minimal effects. Whereas most studies use 100 μg, using a lower dose is reasonable and may facilitate detection of subtle analgesic effects—particularly with nonopioid analgesics—and drugs can be tested in lower doses, minimizing adverse side effects.
Diagnosis and Treatment of Peripheral Arterial Disease Compared with Other Atherosclerotic Vascular Diseases in a University Primary Care Clinic
Authors: Ismail Hassan M. , Jackson Kyoo , Smith Daniel 
Published: August 2007

Background Despite the fact that peripheral arterial disease (PAD) significantly increases the risk of cardiovascular mortality, it is significantly underdiagnosed and undertreated. The purpose of this study was to evaluate the practice at a northeast Tennessee university primary care clinic regarding the diagnosis and treatment of PAD. Methods A retrospective medical record survey was conducted to evaluate practice patterns in diagnosing and treating PAD in a university primary care clinic. A clinic population of 711 patients was selected using International Classification of Diseases-9 codes for coronary artery disease (CAD), cerebovascular disease (CVD), and/or PAD. A sample of 180 patients (25.3%) was randomly selected using a systematic statistical method. Of these, 125 patients met the diagnostic criteria for CAD, CVD, and/or PAD. The study covered a 3-year period, from July 2001 until June 2004. Demographic and other data, including the use of antiplatelet therapy, were collected. Results One hundred ten patients met all of the inclusion and exclusion criteria. Thirty-nine percent were males, and 61% were females. Overall, 79% had CAD, 53% had CVD, and 25% had PAD. Almost half of the patients had some combination of these. Only about 2% had PAD only compared with 36% with CAD only and 17% with CVD only. Although the prevalence of CAD and CVD (among other atherosclerotic vascular diseases) in our clinic was comparable to national figures, the prevalence of PAD was significantly lower ( p = .004). The overall use of any antiplatelet agent was 84.2% for patients with only CAD and 80% for only CVD. There was not an adequate number of patients with only PAD to evaluate the use of antiplatelet therapy in this group. Conclusion The low prevalence of PAD only (most PAD patients had coexisting CAD and CVD) indicates that PAD is underdiagnosed at our clinic. There was suboptimal use of aspirin and other antiplatelet drugs among patients with atherosclerotic vascular disease.
Prevalence of Hyperlipidemia and Its Risk Factors for the Middle-Aged and Elderly in the Guangxi Hei Yi Zhuang and Han Populations
Authors: Ruixing Yin , Fengping He , Shangling Pan , Dezhai Yang , Weixiong Lin , Tangwei Liu , Yuming Chen , Jinzhen Wu , Limei Yao , Jiandong Huang 
Published: August 2007

Background Han is the largest and Zhuang is the second largest among the 56 nationalities in China. Geographically and linguistically, Zhuang can be classified into 43 ethnic subgroups, among which Hei Yi (which means “black worship” and “black dressing”) Zhuang is the most conservative group, according to its unique culture and customs. Little is known about the lipid profiles and corresponding risk factors of hyperlipidemia in this population. Therefore, the aim of this study was to compare the effects of demographic characteristics, health-related behaviors, and lifestyle factors on the prevalence of hyperlipidemia for the middle-aged and elderly in the Guangxi Hei Yi Zhuang and Han populations. Methods A sample of 657 people of Hei Yi Zhuang aged 40 years and over was randomly selected from 7 villages in Napo County, Guangxi, China. Information on demographic characteristics, health-related behaviors, and lifestyle factors was collected by questionnaire. Blood pressure, height, weight, waist circumference, and serum lipid and apolipoprotein (apo) levels were measured, and body mass index (BMI) was calculated as a measure of weight relative to height. The results were compared with those in 520 people of Han living in the same region. Results The prevalence of hyperlipidemia in the Hei Yi Zhuang was significantly lower than that in the Han (36.2% vs 42.3%; p < .05). The levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and apo B in Hei Yi Zhuang were also significantly lower than those in the Han (p < .05 to .001), but the levels of high-density lipoprotein cholesterol and the ratio of apo A-I to apo B in the Hei Yi Zhuang were significantly higher than those in the Han (p < .01 and < .001, respectively). There were no significant differences in apo A-I levels between the two ethnic groups (p > .05). The prevalence of hyperlipidemia was positively correlated with BMI and blood pressure in the Hei Yi Zhuang. Hyperlipidemia was positively associated with age, BMI, and blood pressure and negatively associated with gender (female higher) in the Han. Conclusions In the present study of the middle-aged and elderly population, the Hei Yi Zhuang have a more favorable lipid profile and a lower prevalence of hyperlipidemia than do the Han, and there is also a significant difference in the risk factors for hyperlipidemia between the two ethnic groups, which might result from the effects of different demographic characteristics, health-related behaviors, and lifestyle factors.
Prostate-Specific Antigen ‘Velocity’ as a Diagnostic Test for Prostate Cancer
Authors: Concato John , Wells Carolyn K. 
Published: August 2007

Background Prostate-specific antigen “velocity” (slope) is promoted as a diagnostic test for prostate cancer, but its clinical usefulness is uncertain. Accordingly, we evaluated the sensitivity of prostate-specific antigen (PSA) velocity among men who are diagnosed subsequently with prostate cancer. Methods Among 64,545 men receiving primary care at any of nine Veterans Affairs Medical Centers during 1989-1990, 1,313 men at least 50 years old had an incident diagnosis of prostate cancer during 1991-1995. PSA velocity values obtained prior to diagnosis (“test”) were compared with results from prostate biopsies (“truth”). Results Among men ( n = 493) with at least two tests before diagnosis, the sensitivity of PSA velocity ≥ 0.75 ng/mL/yr was 75.5% (95% confidence interval [CI] 71.7-79.3) overall and 48.1% (95% CI 34.8-61.5) among men with normal values of PSA (< 4.0 ng/mL). Based on published data for specificity and prevalence, the estimated positive predictive value of PSA velocity ≥ 0.75 ng/mL/yr is as low as 5%. Conclusion PSA velocity may have limited usefulness as a diagnostic test for prostate cancer.
Relationship between A2A Adenosine Receptor Expression and Intradialytic Hypotension during Hemodialysis
Authors: Giaime Philippe , Carrega Louis , Fenouillet Emmanuel , Mercier Laurence , Gerolami Victoria , Ruf Jean , Sauze Nicole , Brunet Philippe , Saadjian Alain , Berland Yvon , Dussol Bertrand , Guieu Regis 
Published: August 2007

BackgroundIntradialytic hypotension (IDH) is a common complication of hemodialysis sessions (HDSs). Adenosine may contribute to the drop in blood pressure during IDH events because it has hypotensive effects. As A2Aadenosine receptor expression is essential for blood pressure control, we compared the expression of A2Areceptors (Bmax, KD, and messenger ribonucleic acid [mRNA] levels) in peripheral blood mononuclear cells from IDH and non-IDH patients and from controls. We also evaluated adenosine plasma levels (APLs).MethodsWe included 10 hemodialyzed patients with at least three IDH events per month. We also included 11 hemodialyzed patients with no history of IDH events and 10 healthy subjects as controls.ResultsIDH patients had higher Bmax values than non-IDH patients (mean before HDS, +86%; after HDS, +112%), whereas non-IDH patients had lower Bmax values than controls (mean −72%). KDvalues were not significantly different between patients and controls. The levels of mRNA increased significantly during HDS but without an increase in receptor expression on the cell membranes. APLs were higher in hemodialyzed patients than in controls.ConclusionWe found that A2Areceptors are more expressed in IDH patients than in non-IDH patients, whereas APL was high in all patients. Both high APL and a relative increase in A2Areceptor expression may favor IDH events.
Search for Microbial Signatures within Human and Microbial Calcifications Using Soft X-Ray Spectromicroscopy
Authors: Benzerara Karim , Miller Virginia M. , Barell Gerard , Kumar Vivek , Miot Jennyfer , Brown Gordon E. , Lieske John C. 
Published: August 2007

Background The origin of advanced arterial and renal calcification remains poorly understood. Self-replicating, calcifying entities have been detected and isolated from calcified human tissues, including blood vessels and kidney stones, and are referred to as nanobacteria. However, the microbiologic nature of putative nanobacteria continues to be debated, in part because of the difficulty in discriminating biomineralized microbes from minerals nucleated on anything else (eg, macromolecules, cell membranes). To address this controversy, the use of techniques capable of characterizing the organic and mineral content of these self-replicated structures at the submicrometer scale would be beneficial. Methods Calcifying gram-negative bacteria ( Caulobacter crescentus, Ramlibacter tataouinensis) used as references and self-replicating calcified nanoparticles cultured from human samples of calcified aneurysms were examined using a scanning transmission x-ray microscope (STXM) at the Advanced Light Source at Lawrence Berkeley National Laboratory. This microscope uses a monochromated and focused synchrotron x-ray beam (80-2,200 eV) to yield microscopic and spectroscopic information on both organic compounds and minerals at the 25 nm scale. Results High-spatial and energy resolution near-edge x-ray absorption fine structure (NEXAFS) spectra indicative of elemental speciation acquired at the C K-edge, N K-edge, and Ca L2,3-edge on a single-cell scale from calcified C. crescentus and R. tataouinensis displayed unique spectral signatures different from that of nonbiologic hydroxyapatite (Ca10(PO4)6(OH)2). Further, preliminary NEXAFS measurements of calcium, carbon, and nitrogen functional groups of cultured calcified nanoparticles from humans revealed evidence of organics, likely peptides or proteins, specifically associated with hydroxyapatite minerals. Conclusion Using NEXAFS at the 25 nm spatial scale, it is possible to define a biochemical signature for cultured calcified bacteria, including proteins, polysaccharides, nucleic acids, and hydroxyapatite. These preliminary studies suggest that nanoparticles isolated from human samples share spectroscopic characteristics with calcified proteins.