CiteULike: jyuh's Zhang

Survival by time of day of hemodialysis in an elderly cohort.

DL Bliwise — 2008-07-03T13:30:00-00:00

JAMA : the journal of the American Medical Association, Vol. 286, No. 21. (5 December 2001), pp. 2690-2694.

CONTEXT: Patients with end-stage renal disease (ESRD) typically undergo hemodialysis (HD) during the morning or afternoon, with time of treatment generally based on space availability or patient preference. No studies have investigated variation in patient survival as a function of the time of day when they receive dialysis. OBJECTIVE: To investigate the association of elderly patients' HD treatment shift with their continued survival, controlling for well-established HD-related mortality risk factors. DESIGN, SETTING, AND PARTICIPANTS: An 11-year follow-up cohort study conducted among 242 ESRD patients aged 60 years or older who underwent HD at 58 dialysis facilities in Georgia either during a morning shift (n = 167) or an afternoon shift (n = 75) and who completed baseline (1988) [corrected] and follow-up (1991) interviews. MAIN OUTCOME MEASURE: Mortality from all causes occurring through July 7, 1999, as verified by death-certificate reviews, and compared by morning vs afternoon-shift HD. RESULTS: Morning-shift HD patients survived significantly longer than afternoon-shift patients (median survival, 941 days vs 470 days; P<.001). A Cox proportional hazards model indicated that the morning shift was protective (relative risk, 0.71; 95% confidence interval, 0.53-0.95) independent of age, race, sex, body mass index, functional status, diabetic ESRD, cardiovascular comorbidity, weekly hours of dialysis, and months of dialysis. CONCLUSIONS: Possible explanations for differential survival in association with morning vs afternoon dialysis include salutary effects of sleep in the morning or less efficient biochemical exchange during afternoon dialysis. Results from this cohort study may warrant prospective observational studies and randomized clinical trials that systematically alter the time of day at which HD is administered.

Total parathyroidectomy combined with partial auto-transplantation for the treatment of secondary hyperparathyroidism.

Q Zou — 2008-07-03T10:54:13-00:00

Chinese medical journal, Vol. 120, No. 20. (20 October 2007), pp. 1777-1782.

BACKGROUND: Drug treatment for secondary hyperparathyroidism caused by chronic renal failure may be available at the early stage of the disease, but it is not as effective for serious patients. The aim of the study was to evaluate the effect of total parathyroidectomy combined with forearm autotransplantation in the uremic patients with secondary hyperparathyroidism. METHODS: From September 1999 through September 2006, parathroidectomy and autotransplantation was performed in 20 patients. The coherence between the results of preoperative parathyroid ultrasonography and surgical exploration were compared. The serum calcium concentration and intact parathyroid hormone (iPTH) were monitored preoperatively, intraoperatively, and postoperatively. RESULTS: A total of 71 hyperplastic parathyroid glands were resected in the 20 patients. The accordance rate of parathyroid localization between B-ultrasonography and intraoperative exploration was 94.4%. The average iPTH value was (110.90 +/- 67.42) ng/L, (433.80 +/- 243.72) ng/L, (48.80 +/- 42.69) ng/L, (229.04 +/- 172.68) ng/L and (232.39 +/- 224.05) ng/L at day 1, 2, 3, 7, 30 after operation respectively. The clinical symptoms were ameliorated and the levels of serum calcium concentration were controlled within the normal range after operation. Recurrent secondary hyperparathyroidism had happened in 1 case, 4 years postoperatively because of the development of autograft hyperplasia, and in another case 2 years postoperatively due to remnant of neck parathyroid glands. The clinical symptoms were all alleviated after re-operation. No surgical complication had occurred in any of the patients. CONCLUSIONS: The total parathyroidectomy with forearm autotransplantation is feasible, safe, and effective for patients with secondary hyperparathyroidism in the short term. The long-term effects should be further investigated.

Role of Wnt-catenin signaling pathway in epithelial-mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1

Jiang — 2007-10-23T23:25:43-00:00

International Journal of Urology, Vol. 14, No. 11. (November 2007), pp. 1034-1039.

Boosted regression trees, multivariate adaptive regression splines and their two-step combinations with multiple linear regression or partial least squares to predict blood-brain barrier passage: a case study.

E Deconinck — 2008-06-30T03:41:42-00:00

Analytica chimica acta, Vol. 609, No. 1. (18 February 2008), pp. 13-23.

The use of some unconventional non-linear modeling techniques, i.e. classification and regression trees and multivariate adaptive regression splines-based methods, was explored to model the blood-brain barrier (BBB) passage of drugs and drug-like molecules. The data set contains BBB passage values for 299 structural and pharmacological diverse drugs, originating from a structured knowledge-based database. Models were built using boosted regression trees (BRT) and multivariate adaptive regression splines (MARS), as well as their respective combinations with stepwise multiple linear regression (MLR) and partial least squares (PLS) regression in two-step approaches. The best models were obtained using combinations of MARS with either stepwise MLR or PLS. It could be concluded that the use of combinations of a linear with a non-linear modeling technique results in some improved properties compared to the individual linear and non-linear models and that, when the use of such a combination is appropriate, combinations using MARS as non-linear technique should be preferred over those with BRT, due to some serious drawbacks of the BRT approaches.

Estimating a weighted average of stratum-specific parameters.

Babette A Brumback — 2008-06-30T03:29:19-00:00

Statistics in medicine (23 June 2008)

This article investigates estimators of a weighted average of stratum-specific univariate parameters and compares them in terms of a design-based estimate of mean-squared error (MSE). The research is motivated by a stratified survey sample of Florida Medicaid beneficiaries, in which the parameters are population stratum means and the weights are known and determined by the population sampling frame. Assuming heterogeneous parameters, it is common to estimate the weighted average with the weighted sum of sample stratum means; under homogeneity, one ignores the known weights in favor of precision weighting. Adaptive estimators arise from random effects models for the parameters. We propose adaptive estimators motivated from these random effects models, but we compare their design-based performance. We further propose selecting the tuning parameter to minimize a design-based estimate of mean-squared error. This differs from the model-based approach of selecting the tuning parameter to accurately represent the heterogeneity of stratum means. Our design-based approach effectively downweights strata with small weights in the assessment of homogeneity, which can lead to a smaller MSE. We compare the standard random effects model with identically distributed parameters to a novel alternative, which models the variances of the parameters as inversely proportional to the known weights. We also present theoretical and computational details for estimators based on a general class of random effects models. The methods are applied to estimate average satisfaction with health plan and care among Florida beneficiaries just prior to Medicaid reform. Copyright (c) 2008 John Wiley & Sons, Ltd.

Antisense, RNAi, and gene silencing strategies for therapy: Mission possible or impossible?

Elizabeth Rayburn — 2008-06-29T05:43:43-00:00

Drug Discovery Today, Vol. 13, No. 11-12. (June 2008), pp. 513-521.

Antisense oligonucleotides can regulate gene expression in living cells. As such, they regulate cell function and division, and can modulate cellular responses to internal and external stresses and stimuli. Although encouraging results from preclinical and clinical studies have been obtained and significant progress has been made in developing these agents as drugs, they are not yet recognized as effective therapeutics. Several major hurdles remain to be overcome, including problems with efficacy, off-target effects, delivery and side effects. The lessons learned from antisense drug development can help in the development of other oligonucleotide-based therapeutics such as CpG oligonucleotides, RNAi and miRNA.

Oral estrogen therapy in postmenopausal women is associated with loss of kidney function.

Sofia B Ahmed — 2008-06-29T04:02:54-00:00

Kidney international (21 May 2008)

Women are generally protected against progressive loss of kidney function; however, this advantage seems to diminish with menopause. Because of conflicting reports on the association between use of hormone therapy and kidney function we studied 5845 women (1459 on hormone therapy and 4386 non-users) who were over 66 years of age and had at least 2 serum creatinine measurements during the 2 year study period. After adjustment for covariates, hormone use (estrogen-only, progestin-only, or both) was associated with a significant loss of estimated GFR as the primary outcome along with an increased risk of rapid loss of kidney function as the secondary outcome compared to non-users. This increased rate of loss was associated with oral but not transvaginal estrogen use. An increased cumulative dose of estrogen was also associated with a greater decline in estimated GFR. Our study shows an independent association in a dose-dependent manner of estrogen use and loss of kidney function in this elderly population.Kidney International advance online publication, 21 May 2008; doi:10.1038/ki.2008.205.

Immunolocalization of Kim-1, RPA-1, and RPA-2 in kidney of gentamicin-, mercury-, or chromium-treated rats: relationship to renal distributions of iNOS and nitrotyrosine.

J Zhang — 2008-06-26T02:48:15-00:00

Toxicologic pathology, Vol. 36, No. 3. (2008), pp. 397-409.

Immunohistochemical studies for kidney injury molecule-1 (Kim-1), renal papillary antigen-1 (RPA-1), and renal papillary antigen-2 (RPA-2) were conducted to explore their relationship to inducible nitric oxide synthase (iNOS) and nitrotyrosine expression. Male Sprague-Dawley rats were exposed to gentamicin (100 mg/kg/day Gen, sc, for 3 days), mercury (0.25 mg Hg/kg, iv, single dose), or chromium (5 mg Cr/kg, sc, single dose) and kidney tissue was examined 24 hours or 72 hours after the last dose of the nephrotoxicant. Another group of kidneys was evaluated 24 hours after rats were administered 3 daily doses (50, 100, 150, 200, or 300 mg/kg/day) of Gen. Gen- and Cr-treated rats exhibited increased immunoreactivity of Kim-1, RPA-1, and RPA-2 largely in the S1/S2 segments and to a lesser extent in the S3 segments of the proximal tubule of the kidney, whereas Hg-treated rats showed increased immunoreactivity of Kim-1, RPA-1, and RPA-2 in the S3 segments. Up-regulation of Kim-1, RPA-1, and RPA-2 expression correlated with injured tubular epithelial cells and also correlated with immunoreactivity of iNOS and nitrotyrosine. It is possible that iNOS activation with nitrotyrosine production in injured nephron segments may be involved in the induction of Kim-1, RPA-1, and RPA-2 following exposure to nephrotoxicants.

Semiparametric Stochastic Mixed Models for Longitudinal Data-spmm.sas

Daowen Zhang — 2008-06-25T15:02:48-00:00

Journal of the American Statistical Association, Vol. 93, No. 442. (1998), pp. 710-719.

We consider inference for a semiparametric stochastic mixed model for longitudinal data. This model uses parametric fixed effects to represent the covariate effects and an arbitrary smooth function to model the time effect. The within-subject correlation is modeled using random effects and a stationary or nonstationary stochastic process. We derive maximum penalized likelihood estimators of the regression coefficients and the nonparametric function. The resulting estimator of the nonparametric...

Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks.

Jun Zhu — 2008-06-18T06:58:33-00:00

Nature genetics (15 June 2008)

A key goal of biology is to construct networks that predict complex system behavior. We combine multiple types of molecular data, including genotypic, expression, transcription factor binding site (TFBS), and protein-protein interaction (PPI) data previously generated from a number of yeast experiments, in order to reconstruct causal gene networks. Networks based on different types of data are compared using metrics devised to assess the predictive power of a network. We show that a network reconstructed by integrating genotypic, TFBS and PPI data is the most predictive. This network is used to predict causal regulators responsible for hot spots of gene expression activity in a segregating yeast population. We also show that the network can elucidate the mechanisms by which causal regulators give rise to larger-scale changes in gene expression activity. We then prospectively validate predictions, providing direct experimental evidence that predictive networks can be constructed by integrating multiple, appropriate data types.

The Gut-enriched Kruppel-like Factor (Kruppel-like Factor 4) Mediates the Transactivating Effect of p53 on the p21WAF1/Cip1 Promoter

Weiqing Zhang — 2008-06-24T03:31:29-00:00

J. Biol. Chem., Vol. 275, No. 24. (9 June 2000), pp. 18391-18398.

An important mechanism by which the tumor suppressor p53 maintains genomic stability is to induce cell cycle arrest through activation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 gene. We show that the gene encoding the gut-enriched Kruppel-like factor (GKLF, KLF4) is concurrently induced with p21WAF1/Cip1 during serum deprivation and DNA damage elicited by methyl methanesulfonate. The increases in expression of both Gklf and p21WAF1/Cip1 due to DNA damage are dependent on p53. Moreover, during the first 30 min of methyl methanesulfonate treatment, the rise in Gklf mRNA level precedes that in p21WAF1/Cip1, suggesting that GKLF may be involved in the induction of p21WAF1/Cip1. Indeed, GKLF activates p21WAF1/Cip1 through a specific Sp1-like cis-element in the p21WAF1/Cip1 proximal promoter. The same element is also required by p53 to activate the p21WAF1/Cip1 promoter, although p53 does not bind to it. Potential mechanisms by which p53 activates the p21WAF1/Cip1 promoter include a physical interaction between p53 and GKLF and the transcriptional induction of Gklf by p53. Consequently, the two transactivators cause a synergistic induction of the p21WAF1/Cip1 promoter activity. The physiological relevance of GKLF in mediating p53-dependent induction of p21WAF1/Cip1 is demonstrated by the ability of antisense Gklf oligonucleotides to block the production of p21WAF1/Cip1 in response to p53 activation. These findings suggest that GKLF is an essential mediator of p53 in the transcriptional induction of p21WAF1/Cip1 and may be part of a novel pathway by which cellular responses to stress are modulated. 10.1074/jbc.C000062200

Regression Survival Analysis with an Assumed Copula for Dependent Censoring: A Sensitivity Analysis Approach.

Xuelin Huang — 2008-06-23T07:09:43-00:00

Biometrics (11 February 2008)

In clinical studies, when censoring is caused by competing risks or patient withdrawal, there is always a concern about the validity of treatment effect estimates that are obtained under the assumption of independent censoring. Because dependent censoring is nonidentifiable without additional information, the best we can do is a sensitivity analysis to assess the changes of parameter estimates under different assumptions about the association between failure and censoring. This analysis is especially useful when knowledge about such association is available through literature review or expert opinions. In a regression analysis setting, the consequences of falsely assuming independent censoring on parameter estimates are not clear. Neither the direction nor the magnitude of the potential bias can be easily predicted. We provide an approach to do sensitivity analysis for the widely used Cox proportional hazards models. The joint distribution of the failure and censoring times is assumed to be a function of their marginal distributions. This function is called a copula. Under this assumption, we propose an iteration algorithm to estimate the regression parameters and marginal survival functions. Simulation studies show that this algorithm works well. We apply the proposed sensitivity analysis approach to the data from an AIDS clinical trial in which 27% of the patients withdrew due to toxicity or at the request of the patient or investigator.

Asymptotic theory for the Cox semi-Markov illness-death model

Shu — 2007-03-13T02:54:53-00:00

Lifetime Data Analysis, Vol. 13, No. 1. (March 2007), pp. 91-117.

Summarizing differences in cumulative incidence functions.

Mei-Jie Zhang — 2008-06-22T07:37:34-00:00

Statistics in medicine (18 June 2008)

The cumulative incidence function is widely reported in competing risks studies, with group differences assessed by an extension of the log-rank test. However, simple, interpretable summaries of group differences are not available. An adaptation of the proportional hazards model to the cumulative incidence function is often employed, but the interpretation of the hazard ratio may be somewhat awkward, unlike the usual survival set-up. We propose nonparametric inferences for general summary measures, which may be time-varying, and for time-averaged versions of the measures. Theoretical justification is provided using counting process techniques. A real data example illustrates the practical utility of the methods. Copyright (c) 2008 John Wiley & Sons, Ltd.

Regulatory mechanisms of mitogen-activated kinase signaling.

Y Zhang — 2008-06-17T03:18:06-00:00

Cellular and molecular life sciences : CMLS, Vol. 64, No. 21. (November 2007), pp. 2771-2789.

MAP kinases (MAPKs) are evolutionarily conserved regulators that mediate signal transduction and play essential roles in various physiological processes. There are three main families of MAPKs in mammals, whose functions are regulated by activators, inactivators, substrates and scaffolds, which together form delicate signaling cascades in response to different extracellular or intracellular stimulation. MAPK signaling is tightly regulated so that optimal biological activities are achieved and health is maintained. However, how the specificity of the signaling flow along each cascade is achieved is still relatively unclear. In this review, we summarize recent advances in understanding the regulation of MAPK cascades and the roles of MAP kinases and their regulators in development and in immune responses.

A SAS macro for estimation of direct adjusted survival curves based on a stratified Cox regression model.

X Zhang — 2008-06-16T04:39:41-00:00

Computer methods and programs in biomedicine, Vol. 88, No. 2. (November 2007), pp. 95-101.

Often in biomedical research the aim of a study is to compare the outcomes of several treatment arms while adjusting for multiple clinical prognostic factors. In this paper we focus on computation of the direct adjusted survival curves for different treatment groups based on an unstratified or a stratified Cox model. The estimators are constructed by taking the average of the individual predicted survival curves. The method of direct adjustment controls for possible confounders due to an imbalance of patient characteristics between treatment groups. This adjustment is especially useful for non-randomized studies. We have written a SAS macro to estimate and compare the direct adjusted survival curves. We illustrate the SAS macro through the examples analyzing stem cell transplant data and Ewing's sarcoma data.

The effect of epoetin dose on hematocrit.

D Cotter — 2008-06-16T03:04:11-00:00

Kidney international, Vol. 73, No. 3. (February 2008), pp. 347-353.

Nearly all dialysis patients receive epoetin therapy to treat anemia. Using the United States Renal Data System, we monitored the 14,001 patients aged 65 and older who started dialysis and epoetin treatment in 2003-2004. We estimated the dose-response relationship for the average epoetin dose and hematocrit during a 3-month initiation and subsequent 3-month maintenance phase using a marginal structural model to adjust for measured time-dependent confounding by indication. During the initiation phase, an S-shaped dose-response relationship for average weekly epoetin dose and hematocrit response was found. Average hematocrit levels rose as the epoetin dose was increased from 9,000 to approximately 22,500 units per week. At higher doses, the effect of increasing epoetin was minimal with average hematocrit levels plateauing at 38.5%, but this was less evident in the maintenance phase. Among patients who reached this phase, doses required to maintain the hematocrit level were lower than those required to achieve similar hematocrit levels in the initiation phase. The dose-response curve found in our study suggests that published recommendations for starting dose are appropriate, and a starting dose of 7,500-15,000 units per week can maintain the hematocrit level in the desired target range of 33-36%.

Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.

BM Brenner — 2008-06-14T06:11:53-00:00

The New England journal of medicine, Vol. 345, No. 12. (20 September 2001), pp. 861-869.

BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy. METHODS: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease. RESULTS: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo). CONCLUSIONS: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.

Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study.

Z Zhang — 2008-06-14T05:48:40-00:00

Journal of the American Society of Nephrology : JASN, Vol. 16, No. 6. (June 2005), pp. 1775-1780.

A key issue in the analysis of outcome trials is the adjustment for baseline covariates that influence the primary outcome. Imbalance of an important covariate between treatment groups at baseline is of considerable concern if one treatment group is favored over another with respect to the hypothesis testing outcome. With the use of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study database as an example, the influence of baseline proteinuria on the primary composite endpoint, ESRD, and ESRD or death after adjusting for baseline proteinuria as a continuous covariate was examined. Increasing baseline proteinuria was associated with increased risk for renal events, confirming that proteinuria is an important covariate for renal outcomes. When the randomization was stratified according proteinuria <2000 mg/g or >/=2000 mg/g, within the higher proteinuria stratum (>/=2000 mg/g), patients in the losartan group had a higher baseline mean proteinuria value. When the imbalance was adjusted, an increase in the magnitude and the significance of the risk reduction with losartan for each outcome was observed. No apparent interaction between treatment effect and baseline proteinuria was found, and there was no heterogeneity in the treatment response in patients with different baseline proteinuria levels. After proteinuria was adjusted as a continuous variable, greater treatment effects were observed in the RENAAL study. This effect was due solely to the imbalance in baseline proteinuria. Considering the importance of proteinuria as a risk factor, adjustment for baseline proteinuria as a continuous covariate should be prespecified in the design and analysis of clinical trials involving renal outcomes, even when patients are stratified on the basis of level of proteinuria.

CellFrame: A Data Structure for Abstraction of Cell Biology Experiments and Construction of Perturbation Networks

Yunchen Gong — 2007-11-19T21:29:54-00:00

Annals of the New York Academy of Sciences, Vol. 1115, No. 1. (December 2007), pp. 249-266.

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3

Mark Kleinman — 2008-03-27T04:35:18-00:00

Nature (26 March 2008)

Improving Efficiency of Inferences in Randomized Clinical Trials Using Auxiliary Covariates.

Min Zhang — 2008-06-09T12:33:16-00:00

Biometrics (11 January 2008)

The primary goal of a randomized clinical trial is to make comparisons among two or more treatments. For example, in a two-arm trial with continuous response, the focus may be on the difference in treatment means; with more than two treatments, the comparison may be based on pairwise differences. With binary outcomes, pairwise odds ratios or log odds ratios may be used. In general, comparisons may be based on meaningful parameters in a relevant statistical model. Standard analyses for estimation and testing in this context typically are based on the data collected on response and treatment assignment only. In many trials, auxiliary baseline covariate information may also be available, and it is of interest to exploit these data to improve the efficiency of inferences. Taking a semiparametric theory perspective, we propose a broadly applicable approach to adjustment for auxiliary covariates to achieve more efficient estimators and tests for treatment parameters in the analysis of randomized clinical trials. Simulations and applications demonstrate the performance of the methods.

Development of formulae for accurate measurement of the glomerular filtration rate by renal dynamic imaging.

Q Li — 2008-06-09T03:06:34-00:00

Nuclear medicine communications, Vol. 28, No. 5. (May 2007), pp. 407-413.

AIM: Currently, the widely adopted renal dynamic imaging in clinical practice uses Gates' method to calculate the glomerular filtration rate (GFR), but many researchers have proven that Gates' method may result in bias. Thus, this article explores alternative improved formulae to calculate GFR by renal dynamic imaging. METHODS: Three hundred and sixty-seven patients were selected and their GFR values were measured using renal dynamic imaging and the two-plasma method with 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) as the imaging agent. With the two-plasma GFR as reference value, two equations were obtained from linear and non-linear regression analyses between the renal uptake percentage and two-plasma GFR. The 367 patients were divided into two random groups, with the first group used to derive the regression formulae and the second to verify the formulae. Finally, all patients were studied to derive the formulae to calculate GFR. The comparison of our formulae with the commonly used Gates' formula was conducted by the Bland-Altman method. RESULTS: The linear and non-linear GFR formulae were as follows: GFR (ml/min/1.73 m2)=(631.633 x renal uptake percentage - 2.040) x 1.73/BSA (BSA, body surface area) and GFR (ml/min/1.73 m2)=(-1996.585 x renal uptake percentage2 + 1013.526 x renal uptake percentage - 12.739) x 1.73/BSA, respectively. The biases of the GFR values calculated using the linear and non-linear formulae and Gates' formula relative to the two-plasma GFR were -2.5 +/- 19.1 ml/min/1.73 m2, -2.0 +/- 19.3 ml/min/1.73 m2 and 3.4 +/- 19.4 ml/min/1.73 m2, respectively. CONCLUSIONS: The GFR values calculated using our new formulae correlate better with the reference GFR value than does GFR calculated by Gates' formula, and the GFR values measured using the non-linear formula are more accurate than those obtained using the linear formula.

Optimal waist circumference cutoffs for abdominal obesity in Chinese.

Yuqian Bao — 2008-06-06T03:39:38-00:00

Atherosclerosis (18 March 2008)

OBJECTIVE: To determine the appropriate cutoffs for visceral fat area (VFA) measured by magnetic resonance imaging linking to risk of the metabolic syndrome (MetS) and the corresponding waist circumference in Chinese. METHODS AND RESULTS: Totally 1140 individuals (men 525, women 615) aged from 35 to 75 years were included. The components of the MetS were defined by International Diabetes Federation (IDF) and Chinese Diabetes Society (CDS) definition, respectively. Receive operating characteristic curve analyses were used to determine the appropriate cutoffs of VFA and corresponding waist circumference in the prediction of the MetS. The optimal VFA cutoff was near 80cm(2) in identifying the MetS with two or more components but not including overweight/obesity by either of the two definitions in all subjects. There was no difference in men by ages while women aged <50 years tended to have lower VFA cutoff than those aged >/=50 years by the two definitions. The appropriate waist circumference cutoffs were 90cm in men and 85cm in women for the MetS. CONCLUSION: The optimal cutoff of waist circumference for abdominal obesity is 90cm for men and 85cm for women in Chinese.

Insulin Reduces Plasma Arginase Activity in Type 2 Diabetic Patients

Sangeeta Kashyap — 2008-06-06T01:45:24-00:00

Diabetes Care, Vol. 31, No. 1. (1 January 2008), pp. 134-139.

OBJECTIVE--We sought to determine whether dysregulation of arginine metabolism is related to insulin resistance and underlies impaired nitric oxide (NO) generation in type 2 diabetic patients. RESEARCH DESIGN AND METHODS--We measured plasma arginase activity, arginine metabolites, and skeletal muscle NO synthase (NOS) activity in 12 type 2 diabetic and 10 age-/BMI-matched nondiabetic subjects before and following a 4-h euglycemic-hyperinsulinemic clamp with muscle biopsies. Arginine metabolites were determined by tandem mass spectroscopy. Arginase activity was determined by conversion of [14C] guanidoinoarginine to [14C] urea. RESULTS--Glucose disposal (Rd) was reduced by 50% in diabetic versus control subjects. NOS activity was fourfold reduced in the diabetic group (107 +/- 45 vs. 459 +/- 100 pmol middle dot min-1 middle dot mg protein-1; P < 0.05) and failed to increase with insulin. Plasma arginase activity was increased by 50% in the diabetic versus control group (0.48 +/- 0.11 vs. 0.32 +/- 0.12 micromol middle dot ml-1 middle dot h-1; P < 0.05) and markedly declined in diabetic subjects with 4-h insulin infusion (to 0.13 +/- 0.04 micromol middle dot ml-1 middle dot h-1 vs. basal; P < 0.05). In both groups collectively, plasma arginase activity correlated positively with fasting plasma glucose (R = 0.46, P < 0.05) and A1C levels (R = 0.51, P < 0.02) but not with Rd. CONCLUSIONS--Plasma arginase activity is increased in type 2 diabetic subjects with impaired NOS activity, correlates with the degree of hyperglycemia, and is reduced by physiologic hyperinsulinemia. Elevated arginase activity may contribute to impaired NO generation in type 2 diabetes, and insulin may ameliorate this defect via reducing arginase activity. 10.2337/dc07-1198

A PCR based method to construct small interference RNA expression vectors.

Zhiyong Zhang — 2008-06-04T16:05:20-00:00

Molecular biology reports (12 April 2008)

Small interference RNAs (siRNA) have been shown to be useful in the field of gene therapy and gene function studies. As a siRNA expression vector, pSilencer employ RNA polymerase III promoters and could stably produce siRNA for weeks. But once one siRNA sequence was inserted into the pSilencer vector, the other siRNA sequence will hardly be reconstructed, because the site of siRNA production has been occupied and difficult to be changed, so it is not suitable for screen of effective siRNA sequence. To solve this problem, we constructed the subclone pSilcencer329, which generated from pSilencer3.1, then developed a PCR based method of constructing siRNA expression vectors, and generated pSilencerBCL2L2 recombinants efficiently. This method was proven to be effective, reliable, and less expensive, and thus will be of great help in regular gene silencing studies, and will be especially suitable for large scale gene function analysis.

Genetics of gene expression and its effect on disease

Valur Emilsson — 2008-03-18T04:25:40-00:00

Nature (16 March 2008)

The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study

Guangwei Li — 2008-05-25T21:29:37-00:00

The Lancet, Vol. 371, No. 9626., pp. 1783-1789.

SummaryBackground Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance, but how long these benefits extend beyond the period of active intervention, and whether such interventions reduce the risk of cardiovascular disease (CVD) and mortality, is unclear. We aimed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes, diabetes-related macrovascular and microvascular complications, and mortality.Methods In 1986, 577 adults with impaired glucose tolerance from 33 clinics in China were randomly assigned to either the control group or to one of three lifestyle intervention groups (diet, exercise, or diet plus exercise). Active intervention took place over 6 years until 1992. In 2006, study participants were followed-up to assess the long-term effect of the interventions. The primary outcomes were diabetes incidence, CVD incidence and mortality, and all-cause mortality.Findings Compared with control participants, those in the combined lifestyle intervention groups had a 51% lower incidence of diabetes (hazard rate ratio [HRR] 0·49; 95% CI 0·33-0·73) during the active intervention period and a 43% lower incidence (0·57; 0·41-0·81) over the 20 year period, controlled for age and clustering by clinic. The average annual incidence of diabetes was 7% for intervention participants versus 11% in control participants, with 20-year cumulative incidence of 80% in the intervention groups and 93% in the control group. Participants in the intervention group spent an average of 3·6 fewer years with diabetes than those in the control group. There was no significant difference between the intervention and control groups in the rate of first CVD events (HRR 0·98; 95% CI 0·71-1·37), CVD mortality (0·83; 0·48-1·40), and all-cause mortality (0·96; 0·65-1·41), but our study had limited statistical power to detect differences for these outcomes.Interpretation Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention. However, whether lifestyle intervention also leads to reduced CVD and mortality remains unclear.Funding Centers for Disease Control and Prevention, WHO, the China-Japan Friendship Hospital, and Da Qing First Hospital.

Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells.

X Ye — 2007-11-09T22:25:08-00:00

Mol Cell, Vol. 27, No. 2. (20 July 2007), pp. 183-196.

Cellular senescence is an irreversible proliferation arrest of primary cells and an important tumor suppression process. Senescence is often characterized by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which repress expression of proliferation-promoting genes. Formation of SAHF is driven by a complex of histone chaperones, HIRA and ASF1a, and depends upon prior localization of HIRA to PML nuclear bodies. However, how the SAHF assembly pathway is activated in senescent cells is not known. Here we show that expression of the canonical Wnt2 ligand and downstream canonical Wnt signals are repressed in senescent human cells. Repression of Wnt2 occurs early in senescence and independently of the pRB and p53 tumor suppressor proteins and drives relocalization of HIRA to PML bodies, formation of SAHF and senescence, likely through GSK3beta-mediated phosphorylation of HIRA. These results have major implications for our understanding of both Wnt signaling and senescence in tissue homeostasis and cancer progression.

Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury.

R Vittal — 2008-05-30T03:26:40-00:00

The American journal of pathology, Vol. 166, No. 2. (February 2005), pp. 367-375.

Progressive fibrotic diseases involving diverse organ systems are associated with the persistence of fibroblasts/myofibroblasts in injured tissues. Activation of focal adhesion kinase (FAK) and protein kinase B (PKB/Akt) by transforming growth factor-beta1 mediate stable induction of myofibroblast differentiation and survival. In this report, we demonstrate that transforming growth factor-beta1-induced activation of both PKB/Akt and FAK are dose dependently inhibited by the protein kinase inhibitor, AG1879, in cultured human lung fibroblasts. In a murine model of intratracheal bleomycin-induced lung fibrosis, regions of active fibrogenesis demonstrate elevated expression of PKB/Akt and FAK phosphorylation in vivo, effects that are attenuated in mice receiving daily intraperitoneal injections of AG1879 (bleomycin-AG1879) versus a chemically inactive analog (bleomycin-control). PKB/Akt and FAK phosphorylation are elevated in fibroblasts isolated from lungs of bleomycin-injured mice, effects that are inhibited in bleomycin-AG1879 mice. Accumulation of alpha-smooth muscle actin-expressing myofibroblasts is markedly reduced in lungs of bleomycin-AG1879 mice. The numbers of recruited inflammatory cells were not significantly different between these groups. Bleomycin-AG1879 mice are protected from lung fibrosis as evidenced by histopathology, trichrome staining, and biochemical analysis for collagen. Thus, targeting of prosurvival signaling pathways in fibroblasts/myofibroblasts may provide a novel and effective strategy for anti-fibrotic therapy of treatment-unresponsive fibrotic disorders.

Berberine inhibits aldose reductase and oxidative stress in rat mesangial cells cultured under high glucose.

Weihua Liu — 2008-05-30T02:47:53-00:00

Archives of biochemistry and biophysics (29 April 2008)

Diabetic nephropathy (DN), one of the most serious microvascular complications of diabetes mellitus, is a major cause of end-stage renal disease. Berberine is one of the main constituents of Coptidis rhizoma and Cortex phellodendri. In the present study, we examined effects of berberine (BBR) on renal injury in streptozotocin-induced diabetic rats, and on the changes of aldose reductase (AR) and oxidative stress in cultured rat mesangial cells exposed to high glucose. Fasting blood glucose, blood urea nitrogen, creatinine, and urine protein over 24h were detected by using the commercially available kits. Cell proliferation, collagen synthesis, aldose reductase (AR), superoxide anion, superoxide dismutase (SOD), and malondialdehyde (MDA) were detected, respectively, by different methods. In streptozotocin-induced diabetic rats, fasting blood glucose, blood urea nitrogen, creatinine, and urine protein over 24h were significantly decreased in rats treated with 200mg/kg berberine for 12 weeks compared with diabetic control rats (P<0.05). This was accompanied by a reduced AR activity and gene expression at both mRNA and protein levels. In cultured rat mesangial cells exposed to high glucose, incubation of BBR significantly decreased cell proliferation, collagen synthesis and AR activity as well as its mRNA and protein levels compared with control cells (P<0.05). In vitro, BBR also significantly increased SOD activity and decreased superoxide anion and MDA compared with control cells (P<0.05). These results suggested that BBR could ameliorate renal dysfunction in DN rats, which may be ascribed to inhibition of AR in mesangium, reduction of oxidative stress, and amelioration of extracellular matrix synthesis and cell proliferation. Further studies are warranted to explore the role of AR in DN and the therapeutic implications by AR inhibitors such as BBR.

RhoA/Rho-Kinase Contribute to the Pathogenesis of Diabetic Renal Disease

Fangfang Peng — 2008-05-30T02:29:46-00:00

Diabetes, Vol. 57, No. 6. (1 June 2008), pp. 1683-1692.

OBJECTIVE--Accumulation of glomerular matrix proteins is central to the pathogenesis of diabetic nephropathy, with resident mesangial cells (MCs) known to upregulate matrix protein synthesis in response to high glucose. Because activation of the GTPase RhoA has been implicated in matrix upregulation, we studied its role in induction of the matrix protein fibronectin in diabetic MCs and in vivo in diabetic nephropathy. RESEARCH DESIGN AND METHODS--Glucose (30 mmol/l)-induced RhoA/Rho-kinase, AP-1 activation, and fibronectin upregulation were assessed by immunoblotting, luciferase, electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, real-time PCR, Northern blots, and immunofluorescence. Streptozotocin-induced diabetic rats were treated with the rho-kinase inhibitor fasudil, which was compared with enalapril, and functional and pathologic parameters were assessed. RESULTS--Glucose led to RhoA and downstream Rho-kinase activation. Mannitol was without effect. Activity of the transcription factor AP-1, increased in diabetic MCs and kidneys, is important in the profibrotic effects of glucose, and this was dependent on Rho-kinase signaling. Upregulation of fibronectin by glucose, shown to be mediated by activator protein-1 (AP-1), was prevented by Rho-kinase inhibition. RhoA siRNA and dominant-negative RhoA also markedly attenuated fibronectin upregulation by high glucose. Applicability of these findings were tested in vivo. Fasudil prevented glomerular fibronectin upregulation, glomerular sclerosis, and proteinuria in diabetic rats, with effectiveness similar to enalapril. CONCLUSIONS--High glucose activates RhoA/Rho-kinase in MCs, leading to downstream AP-1 activation and fibronectin induction. Inhibition of this pathway in vivo prevents the pathologic changes of diabetic nephropathy, supporting a potential role for inhibitors of RhoA/Rho in the treatment of diabetic renal disease. 10.2337/db07-1149

Tissue inhibitor of metalloproteinase-1 exacerbated renal interstitial fibrosis through enhancing inflammation

Guangyan Cai — 2008-05-22T05:59:45-00:00

Nephrol. Dial. Transplant., Vol. 23, No. 6. (1 June 2008), pp. 1861-1875.

Background. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is associated with renal fibrosis. Furthermore, it is a multi-functional protein, and whether it has other roles in renal fibrosis is unknown. As several inflammatory mediators are substrates of matrix metalloproteinases (MMPs), TIMP-1 might affect renal fibrosis via inflamatory pathways. Methods. Plasmids containing the sense and antisense human TIMP-1 sequence were stably transfected into the human kidney proximal tubular epithelial cell line (HKC), MMP-2 and MMP-9 siRNA were transiently transfected into HKC and the transfected cells were stimulated with phorbol 12-myristate 13-acetate (PMA). In vivo, we established unilateral ureteral obstruction (UUO) models by using homozygote human TIMP-1 transgenic mice. The expression of intercellular adhesion molecule-1 (ICAM-1) in transfected cells and F4/80-positive cells in the renal interstitium were examined by indirect immunofluorescence. Protein levels in the cells and UUO models were examined by western blot, and the activities of the gelatinases and TIMP-1 were examined by gelatin zymography and reverse zymography, respectively. Results. After stimulation with PMA, the activities of the gelatinases were decreased, ICAM-1 was upregulated, and soluble ICAM-1 in the supernatant was decreased, in HKC transfected with sense TIMP-1, and ICAM-1 was increased in HKC transfected with MMP-9 siRNA. At 14 days after UUO, it was found that compared with wild-type mice, in transgenic mice, with upregulation of TIMP-1, activities of gelatinases were downregulated, ICAM-1, transforming growth factor-1 (TGF-1), collagens I and III were upregulated, and the extent of renal fibrosis and infiltration of macrophages was more severe. Conclusion. Overexpression of TIMP-1 could promote renal interstitial fibrosis through the inflammatory pathway, which might be partly induced by upregulating ICAM-1. 10.1093/ndt/gfm666

Mechanisms of epigenetic inheritance.

C Martin — 2008-05-22T03:32:16-00:00

Current opinion in cell biology, Vol. 19, No. 3. (June 2007), pp. 266-272.

The mechanisms by which stable gene expression patterns are inherited during cell division are not well understood. Chromatin is subject to a number of covalent modifications and it is generally believed that the transfer of these modifications between cell generations plays a critical role in inheritance, though how this occurs is a matter of debate. In one proposed model, replication of chromatin in a semi-conservative fashion would allow 'template reading' and 'writing' mechanisms to copy modifications from old histones to new histones. Conversely, if chromatin is replicated in a conservative fashion, then other mechanisms, such as the replacement and/or modification of histones during transcription, may mediate the replication of these modifications. Finally, several recent studies suggest that the faithful replication of DNA methylation patterns may be used to propagate histone modifications associated with gene silencing.

Bioluminescence imaging of hollow fibers in living animals: its application in monitoring molecular pathways

Guo-Jun Zhang — 2008-05-20T03:52:12-00:00

Nat. Protocols, Vol. 3, No. 5. (May 2008), pp. 891-899.

Variations in DNA elucidate molecular networks that cause disease

Yanqing Chen — 2008-03-18T04:25:40-00:00

Nature (16 March 2008)

Using Generalized Procrustes Analysis (GPA) for normalization of cDNA microarray data

Huiling Xiong — 2008-01-18T03:49:31-00:00

BMC Bioinformatics, Vol. 9 (16 January 2008), 25.

The t-mixture model approach for detecting differentially expressed genes in microarrays.

Shuo Jiao — 2008-04-28T14:47:28-00:00

Functional & integrative genomics (22 January 2008)

The finite mixture model approach has attracted much attention in analyzing microarray data due to its robustness to the excessive variability which is common in the microarray data. Pan (2003) proposed to use the normal mixture model method (MMM) to estimate the distribution of a test statistic and its null distribution. However, considering the fact that the test statistic is often of t-type, our studies find that the rejection region from MMM is often significantly larger than the correct rejection region, resulting an inflated type I error. This motivates us to propose the t-mixture model (TMM) approach. In this paper, we demonstrate that TMM provides significantly more accurate control of the probability of making type I errors (hence of the familywise error rate) than MMM. Finally, TMM is applied to the well-known leukemia data of Golub et al. (1999). The results are compared with those obtained from MMM.

GORouter: an RDF model for providing semantic query and inference services for Gene Ontology and its associations

Qingwei Xu — 2008-03-25T19:23:05-00:00

BMC Bioinformatics, Vol. 9, No. Suppl 1. (2008)

BACKGROUND:The most renowned biological ontology, Gene Ontology (GO) is widely used for annotations of genes and gene products of different organisms. However, there are shortcomings in the Resource Description Framework (RDF) data file provided by the GO consortium: 1) Lack of sufficient semantic relationships between pairs of terms coming from the three independent GO sub-ontologies, that limit the power to provide complex semantic queries and inference services based on it. 2) The term-centric view of GO annotation data and the fact that all information is stored in a single file. This makes attempts to retrieve GO annotations based on big volume datasets unmanageable. 3) No support of GOSlim.RESULTS:We propose a RDF model, GORouter, which encodes heterogeneous original data in a uniform RDF format, creates additional ontology mappings between GO terms, and introduces a set of inference rulebases. Furthermore, we use the Oracle Network Data Model (NDM) as the native RDF data repository and the table function RDF_MATCH to seamlessly combine the result of RDF queries with traditional relational data. As a result, the scale of GORouter is minimized; information not directly involved in semantic inference is put into relational tables.CONCLUSION:Our work demonstrates how to use multiple semantic web tools and techniques to provide a mixture of semantic query and inference solutions of GO and its associations. GORouter is licensed under Apache License Version 2.0, and is accessible via the website: http://www.scbit.org/gorouter/.

Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Zongzhong Tong — 2008-05-13T23:41:12-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 19. (13 May 2008), pp. 6998-7003.

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 x 10-3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 x 10-8; and Boston: P = 2.1 x 10-2]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. 10.1073/pnas.0800454105

Epigenetic inhibition of nuclear receptor small heterodimer partner is associated with and regulates hepatocellular carcinoma growth.

N He — 2008-05-14T15:55:57-00:00

Gastroenterology, Vol. 134, No. 3. (March 2008), pp. 793-802.

BACKGROUND & AIMS: Aberrant hypermethylation of promoter regions in cytosine-guanine dinucleotides (CpG) islands has been shown to be associated with transcriptional silencing of tumor-suppressor genes in many cancers. This study evaluated the methylation profile and the tumor-suppressive function of the small heterodimer partner (SHP, NR0B2) in the development of human hepatocellular carcinoma (HCC). METHODS: Human HCC pathologic specimens and cell lines were used as model systems in this study. RESULTS: The expression of SHP is diminished in HCC pathologic specimens and cell lines by epigenetic silencing owing to SHP promoter hypermethylation. In vitro methylation decreased SHP promoter transactivation and nuclear receptor LRH-1 binding, an event that was reversed by demethylation. Overexpression of SHP inhibited HCC foci formation, arrested HCC tumor growth in xenografted nude mice, and increased the sensitivity of HCC cells to apoptotic stimuli. Further analysis of a total of 19 normal liver and 57 HCC specimens showed that down-regulation of SHP gene expression may be a common denominator of HCC. CONCLUSIONS: We propose that SHP functions as a novel tumor suppressor in the development of HCC. These findings provide new insight into the molecular mechanisms leading to this common cancer and may have both diagnostic and therapeutic applications.

Analysis of siRNA specificity on targets with double-nucleotide mismatches.

Cecilia Dahlgren — 2008-05-13T08:15:01-00:00

Nucleic acids research (17 April 2008)

Although RNA interference as a tool for gene knockdown is a great promise for future applications, the specificity of small interfering RNA (siRNA)-mediated gene silencing needs to be thoroughly investigated. Most research regarding siRNA specificity has involved analysis of affected off-target genes instead of exploring the specificity of the siRNA itself. In this study we have developed an efficient method for generating a siRNA target library by combining a siRNA target validation vector with a nucleotide oligomix. We have used this library to perform an analysis of the silencing effects of a functional siRNA towards its target site with double-nucleotide mismatches. The results indicated that not only the positions of the mismatched base pair have an impact on silencing efficiency but also the identity of the mismatched nucleotide. Our data strengthen earlier observations of widespread siRNA off-target effects and shows that approximately 35% of the double-mutated target sites still causes knockdown efficiency of >50%. We also provide evidence that there may be substantial differences in knockdown efficiency depending on whether the mutations are positioned within the siRNA itself or in the corresponding target site.

HIP2: An Online Database of Human Plasma Proteins from Healthy Individuals.

Sudipto Saha — 2008-05-13T04:53:39-00:00

BMC medical genomics, Vol. 1, No. 1. (25 April 2008)

ABSTRACT: BACKGROUND: With the introduction of increasingly powerful mass spectrometry (MS) techniques for clinical research, several recent large-scale MS proteomics studies have sought to characterize the entire human plasma proteome with a general objective for identifying thousands of proteins leaked from tissues in the circulating blood. Understanding the basic constituents, diversity, and variability of the human plasma proteome is essential to the development of sensitive molecular diagnosis and treatment monitoring solutions for future biomedical applications. Biomedical researchers today, however, do not have an integrated online resource in which they can search for plasma proteins collected from different mass spectrometry platforms, experimental protocols, and search software for healthy individuals. The lack of such a resource for comparisons has made it difficult to interpret proteomics profile changes in patients' plasma and to design protein biomarker discovery experiments. Description: To aid future protein biomarker studies of disease and health from human plasma, we developed an online database, HIP2 (Healthy Human Individual's Integrated Plasma Proteome). The current version contains 12,787 protein entries linked to 86,831 peptide entries identified using different MS platforms. CONCLUSIONS: This web-based database will be useful to biomedical researchers involved in biomarker discovery research. This database has been developed to be the comprehensive collection of healthy human plasma proteins, and has protein data captured in a relational database schema built to contain mappings of supporting peptide evidence from several high-quality and high-throughput mass-spectrometry (MS) experimental data sets. Users can search for plasma protein/peptide annotations, peptide/protein alignments, and experimental/sample conditions with options for filter-based retrieval to achieve greater analytical power for discovery and validation.

Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study

JB Richards — 2008-05-12T04:50:23-00:00

The Lancet, Vol. 371, No. 9623., pp. 1505-1512.

SummaryBackground Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density.Methods In this genome-wide association study, we identified the most promising of 314[punctuation space]075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies.Findings We identified genome-wide evidence for an association between bone mineral density and two SNPs (p<5×10-8). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10-12 for lumbar spine and p=1·9×10-4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09-1·52, p=0·002) and osteoporosis (OR 1·3, 1·08-1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10-10 for lumbar spine and p=3·3×10-8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01-1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10-6). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10-17). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08-1·63, p=0·006) and this effect was independent of bone mineral density.Interpretation Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening.Funding Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebéc, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.

WGAViewer: Software for genomic annotation of whole genome association studies

Dongliang Ge — 2008-05-05T18:41:31-00:00

Genome Res., Vol. 18, No. 4. (1 April 2008), pp. 640-643.

To meet the immediate need for a framework of post-whole genome association (WGA) annotation, we have developed WGAViewer, a suite of JAVA software tools that provides a user-friendly interface to automatically annotate, visualize, and interpret the set of P-values emerging from a WGA study. Most valuably, it can be used to highlight possible functional mechanisms in an automatic manner, for example, by directly or indirectly implicating a polymorphism with an apparent link to gene expression, and help to generate hypotheses concerning the possible biological bases of observed associations. The easily interpretable diagrams can then be used to identify the associations that seem most likely to be biologically relevant, and to select genomic regions that may need to be resequenced in a search for candidate causal variants. In this report, we used our recently completed study on host control of HIV-1 viral load during the asymptomatic set point period as an illustration for the heuristic annotation of this software and its contributive role in a successful WGA project. 10.1101/gr.071571.107

Computational analyses of eukaryotic promoters.

MQ Zhang — 2007-10-03T06:56:45-00:00

BMC Bioinformatics, Vol. 8 Suppl 6 (2007)

ABSTRACT : Computational analysis of eukaryotic promoters is one of the most difficult problems in computational genomics and is essential for understanding gene expression profiles and reverse-engineering gene regulation network circuits. Here I give a basic introduction of the problem and recent update on both experimental and computational approaches. More details may be found in the extended references. This review is based on a summer lecture given at Max Planck Institute at Berlin in 2005.

Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial.

Craig S Anderson — 2008-05-09T09:49:13-00:00

Lancet neurology, Vol. 7, No. 5. (May 2008), pp. 391-399.

BACKGROUND: There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. METHODS: Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. FINDINGS: Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >/=33% or >/=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days. INTERPRETATION: Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. FUNDING: National Health and Medical Research Council of Australia.