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PubMed2003

Factors associated with progression of carcinoid heart disease.

BACKGROUND: By releasing vasoactive substances into the circulation, carcinoid tumors can cause right-sided valvular heart disease. Factors associated with the progression of carcinoid heart disease are poorly understood. We conducted a retrospective study to identify such factors. METHODS: Our sample included 71 patients with the carcinoid syndrome who underwent serial echocardiographic studies performed more than one year apart and 32 patients referred directly for surgical intervention after an initial echocardiographic evaluation. A score for carcinoid heart disease was determined on the basis of an assessment of valvular anatomy and function and the function of the right ventricle. An increase of more than 25 percent in the score between studies was considered suggestive of disease progression. Tumor progression was assessed on the basis of abdominal computed tomographic scans and changes in the level of urinary 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin. RESULTS: Of the patients with serial echocardiographic studies, 25 (35 percent) had an increase of more than 25 percent in the cardiac score. As compared with patients whose score changed by 25 percent or less, these patients had higher urinary peak 5-HIAA levels (median, 265 mg per 24 hours [interquartile range, 209 to 593] vs. 189 mg per 24 hours [interquartile range, 75 to 286]; P=0.004) and were more likely to have biochemical progression (10 of 25 patients vs. 9 of 46, P=0.05) and to have received chemotherapy (13 of 25 vs. 10 of 46, P=0.009). Logistic-regression analysis showed that a higher peak urinary 5-HIAA level and previous chemotherapy were predictors of an increase in the cardiac score that exceeded 25 percent (odds ratio for each increase in 5-HIAA of 25 mg per 24 hours, 1.08 [95 percent confidence interval, 1.03 to 1.13]; P=0.009); odds ratio associated with chemotherapy, 3.65 [95 percent confidence interval, 1.74 to 7.48]; P=0.001). CONCLUSIONS: Serotonin is related to the progression of carcinoid heart disease, and the risk of progressive heart disease is higher in patients who receive chemotherapy than in those who do not.

Aged↗
PubMed2004

A randomized trial of multivitamin supplements and HIV disease progression and mortality.

BACKGROUND: Results from observational studies suggest that micronutrient status is a determinant of the progression of human immunodeficiency virus (HIV) disease. METHODS: We enrolled 1078 pregnant women infected with HIV in a double-blind, placebo-controlled trial in Dar es Salaam, Tanzania, to examine the effects of daily supplements of vitamin A (preformed vitamin A and beta carotene), multivitamins (vitamins B, C, and E), or both on progression of HIV disease, using survival models. The median follow-up with respect to survival was 71 months (interquartile range, 46 to 80). RESULTS: Of 271 women who received multivitamins, 67 had progression to World Health Organization (WHO) stage 4 disease or died--the primary outcome--as compared with 83 of 267 women who received placebo (24.7 percent vs. 31.1 percent; relative risk, 0.71; 95 percent confidence interval, 0.51 to 0.98; P=0.04). This regimen was also associated with reductions in the relative risk of death related to the acquired immunodeficiency syndrome (0.73; 95 percent confidence interval, 0.51 to 1.04; P=0.09), progression to WHO stage 4 (0.50; 95 percent confidence interval, 0.28 to 0.90; P=0.02), or progression to stage 3 or higher (0.72; 95 percent confidence interval, 0.58 to 0.90; P=0.003). Multivitamins also resulted in significantly higher CD4+ and CD8+ cell counts and significantly lower viral loads. The effects of receiving vitamin A alone were smaller and for the most part not significantly different from those produced by placebo. Adding vitamin A to the multivitamin regimen reduced the benefit with regard to some of the end points examined. CONCLUSIONS: Multivitamin supplements delay the progression of HIV disease and provide an effective, low-cost means of delaying the initiation of antiretroviral therapy in HIV-infected women.

AIDS-Related Opportunistic Infections↗
PubMed2004

Radiological progression of joint damage in a longitudinal cohort of early DMARD-treated rheumatoid arthritis patients followed for 10 years.

OBJECTIVE: The efficacy of DMARD therapy in rheumatoid arthritis (RA) can be judged by radiological analysis. This study aimed to determine the time-dependent progression of joint damage, acute-phase response, and rates of radiologic progression in early DMARD-treated RA patients over 10 years. PATIENTS AND METHODS: We evaluated outpatient records, and radiographs of hands and feet of 54 early RA patients on DMARDs for 10 years. Radiographs were quantified by the Larsen method using recently developed quantification software. RESULTS: Radiological damage attenuated, with disease progression from baseline to Year 10 [correlation coefficient (r)=0.95, probability (p)<0.001]. Radiographic scores progressed more rapidly during the first 5 years than thereafter. Cumulative erythrocyte sedimentation rate (ESR) was strongly correlated with radiological progression (p<0.001, r=0.88). CONCLUSION: Our findings reveal a higher amount of radiographic RA progression during the first years of DMARD treatment. Thus, our data provide strong evidence for the importance of both early DMARD therapy and continuous radiographic assessments in RA.

Adult↗
PubMed2004

Primary progressive aphasia: a review.

This review summarizes clinical and imaging features associated with primary progressive aphasia (PPA). We investigate the hypothesis that these patients can be divided into subgroups of progressive non-fluent aphasia (PNFA) and semantic dementia (SD), based on their linguistic profiles and related imaging studies, and examine whether each of these major subgroups can be further subdivided. We focus on several critical features within each progressive aphasic subgroup. In PNFA, we examine agrammatism, phonologic disorder, and impaired verb processing to determine whether this syndrome is related to a modality-specific impairment in word formation and articulation, or a conceptual deficit that interferes with grammatical processing. In SD, we examine impaired semantic memory, limited remote memory, and anomia to assess whether this syndrome is due to a modality-neutral interruption of semantic memory, or the degradation of various material-specific representations of object features and words. We conclude that there is sufficiently consistent and converging evidence from clinical and imaging studies to support the claim that PNFA and SD are distinct subgroups of PPA. However, there does not appear to be sufficient evidence at this point to support further discrimination within these progressive aphasic subgroups. Testing hypotheses about finer-grained syndromes such as progressive dysarthria or progressive anomia has important consequences for improving our understanding of language organization and the neural basis for language.

Aphasia, Primary Progressive↗
PubMed2003

Genetic influence of CCR5, CCR2, and SDF1 variants on human immunodeficiency virus 1 (HIV-1)-related disease progression and neurological impairment, in children with symptomatic HIV-1 infection.

The role that host genetics plays in the modification of the rate of human immunodeficiency virus 1 (HIV-1)-related disease progression was evaluated in a seroprevalent cohort of 1049 children with symptomatic HIV-1 infection who participated in 2 clinical trials in the United States. Variants including CCR2-V64I, CCR5-wt/Delta32, CCR5-59029-G/A, CCR5-59353-T/C, CCR5-59356-C/T, and SDF1-3'-G/A were identified by polymerase chain-reaction genotyping. Children with the CCR5-wt/Delta32 genotype experienced significantly delayed disease progression, including less neurocognitive impairment. In the CCR5-wt/wt group, the most rapid disease progression was in those with the CCR5-59029-A/A genotype, which was present in 23% of the children. Although the SDF1-3'-A/A variant was associated with more-rapid disease progression, it occurred in <2% of the children studied. Modest or little impact was associated with the CCR5-59353, CCR5-59356, or CCR2 genotypes. Thus, in children with the CCR5-wt/wt genotype, variants at CCR5-59029 have the broadest impact on disease progression. These data suggest that, in children, host genetics plays an important role in HIV-1-related disease progression and neurological impairment.

AIDS Dementia Complex↗
PubMed2005

Hepatitis C virus coinfection and HIV load, CD4+ cell percentage, and clinical progression to AIDS or death among HIV-infected women: Women and Infants Transmission Study.

BACKGROUND: Despite previous study, it remains unclear whether hepatitis C virus (HCV) coinfection affects the progression of human immunodeficiency virus (HIV) type 1 infection. The Women and Infants Transmission Study provided an opportunity to assess this issue. METHODS: Longitudinal data on 652 HIV-1-infected women enrolled in the study before the availability of highly active antiretroviral therapy (HAART; 1989-1995) were analyzed. Random effects models were used to determine whether HCV coinfection was associated with different CD4+ cell percentages and HIV-1 RNA levels over time, and Cox proportional hazards models were used to compare the rates of clinical progression to acquired immunodeficiency syndrome (AIDS) or death. RESULTS: Of 652 women, 190 (29%) were HCV infected. During follow-up, 19% of women were exposed to HAART. After controlling for indicators of disease progression (CD4+ cell percentages and HIV-1 RNA levels determined closest to the time of delivery in pregnant women), ongoing drug use, receipt of antiretroviral therapy, and other important covariates, no differences were detected in the HIV-1 RNA levels, but the CD4+ cell percentages were slightly higher in HCV-infected women than in HCV-uninfected women. During follow-up, 48 women had progression to a first clinical AIDS-defining illness (ADI), and 26 died with no documented antecedent ADI. In multivariable analyses, HCV-infected participants did not have faster progression to a first class C AIDS-defining event or death (relative hazard, 0.75; 95% confidence interval, 0.37-1.53). CONCLUSIONS: In this cohort, the rate of clinical progression of HIV-1 infection was not greater for HCV-infected women.

Adult↗
PubMed2005

Genetic polymorphisms in CX3CR1 predict HIV-1 disease progression in children independently of CD4+ lymphocyte count and HIV-1 RNA load.

BACKGROUND: The impact of CX3CR1 polymorphisms on human immunodeficiency virus type 1 (HIV-1) pathogenesis is controversial, with conflicting reports of their role in disease progression in HIV-1-infected adults. METHODS: A cohort of 1055 HIV-1-infected children were genotyped for 2 CX3CR1 polymorphisms, V/I249 and T/M280, and their impact on HIV-1-related disease progression, including central nervous system (CNS) impairment, was evaluated. RESULTS: Children with the CX3CR1 I/I249 genotype experienced more-rapid disease progression (I/I249 vs. V/V249: relative hazard [RH], 2.19 [95% confidence interval {CI}, 1.30-3.68], P=.003; I/I249 vs. V/I249: RH, 1.77 [95% CI, 1.00-3.14], P=.05) and a trend toward more CNS impairment (I/I249 vs. V/V249: RH, 2.19 [95% CI, 1.00-4.78], P=.049; I/I249 vs. V/I249: RH, 2.02 [95% CI, 0.85-4.83], P=.11). Children with the V249-T280 haplotype experienced significantly less disease progression (RH, 0.42 [95% CI, 0.24-0.73]; P=.002) and CNS impairment (RH, 0.39 [95% CI, 0.39-0.22]; P=.001). Of note, these effects remained significant after CD4+ lymphocyte count and plasma HIV-1 RNA load at baseline were adjusted for and in a longitudinal, multivariate analysis. CONCLUSIONS: CX3CR1 genotypes and haplotypes impact HIV-1 disease progression independently of CD4+ lymphocyte count and plasma HIV-1 RNA load, suggesting that the fundamental role of CX3CR1 in the alteration of disease progression might be the recruitment of immunomodulatory cells responsible for the control of HIV-1.

CD4 Lymphocyte Count↗
PubMed2006

Different rates of disease progression of HIV type 1 infection in Tanzania based on infecting subtype.

BACKGROUND: Many different subtypes of human immunodeficiency virus (HIV) type 1 have been identified, particularly in sub-Saharan Africa. However, much remains unknown regarding the relative pathogenicity of these subtypes and their influence on the clinical progression of HIV infection. We examined prospectively the associations between HIV-1 subtypes A, C, and D and recombinant viruses, as well as the rates of disease progression in a cohort of seropositive women from Dar es Salaam, Tanzania. METHODS: A total of 428 pregnant mothers participating in a larger controlled trial of the effect of vitamin supplements were selected for DNA sequencing of their HIV-1 subtype. Plasma viral load was measured at baseline, and CD4+ cell counts was assessed at baseline and at regular intervals throughout the follow-up period. Proportional hazards regression (hazards ratio [HR]) analysis was used to measure the association between viral subtype and the rate of disease progression. RESULTS: Relative to patients with subtype A, patients with subtype D experienced the most rapid progression to death (HR, 2.27; 95% confidence interval [CI], 1.46-3.52) or to the World Health Organization stage 4 of illness (HR, 1.94; 95% CI, 1.20-3.14) and to a CD4+ cell count of <200 cells/mm3 (HR, 2.12; 95% CI, 1.42-3.17). After adjustment for viral load, CD4+ cell count, and other baseline covariates, the associations remained similar. CONCLUSIONS: We observed heterogeneity in the rates of disease progression of HIV-1 disease in infected persons, on the basis of the infecting subtype. Subtype D was associated with the most rapid progression of the disease, relative to the other 3 categories of viruses in our cohort.

Adult↗
PubMed2001

Analysis of transition from long-term nonprogressive to progressive infection identifies sequences that may attenuate HIV type 1.

Long-term nonprogressive human immunodeficiency virus type 1 (HIV-1) infection and its transition to progressive infection presents an opportunity to identify the molecular determinants of HIV-1 attenuation and pathogenesis. We studied an individual who underwent a transition from long-term nonprogressive to rapidly progressive infection. Because HIV-1 RNA genomes in plasma represent replicating virus, we developed a technique to clone full-length HIV-1 RNA genomes from plasma and used this technique to obtain clones from this individual before and during the transition. Most clones assayed were infectious, demonstrating that the RNA genomes encoded viable virus. Analysis of 20 complete HIV-1 RNA genomic sequences revealed one major difference between sequences found during the two phases of infection. During the nonprogressive phase, the predominant sequences had a large deletion in an Sp1-binding site and adjacent promoter in the U3 part of the long terminal repeat (LTR); when the infection became progressive, all viruses had intact Sp1 and promoter sequences and were derived from a minor species present earlier. Analysis of 184 clones of the LTR region obtained at five time points spanning a 7-year period confirmed this switch. In an in vitro assay, the deletion downregulated LTR-driven transcription of a reporter gene. In addition, analysis of cytotoxic T lymphocyte (CTL) epitopes predicted from the complete viral RNA genomes revealed multiple potential escape mutants that accumulated by the time of progression. These studies suggest that during the nonprogressive phase, the Sp1 enhancer-promoter deletion is likely to have played a role in decreasing replication, thereby attenuating HIV-1. The accumulation of CTL escape mutants suggests that a breakdown in immunologic surveillance may have allowed proliferation of intact virus, thus leading to rapid disease progression. These data reveal the viral and immune interactions characterizing a transition from long-term nonprogressive to rapidly progressive infection.

Base Sequence↗
PubMed1998

Tumor necrosis factor beta and soluble APO-1/Fas independently predict progression to AIDS in HIV-seropositive patients.

The relationship between serum concentration of different components of the nerve growth factor/tumor necrosis factor (TNF) receptor family, including soluble APO-1/Fas (sAPO-1/Fas) and progression of HIV infection, was analyzed in a case-control study of individuals selected from a cohort of HIV-seropositive patients who were progressing or not progressing to AIDS while being treated with nucleoside analogs. HIV-seronegative healthy controls were also analyzed. The results showed that, despite close matching for immunologic (CD4 cell count, beta2-microglobulin concentration) and virologic (p24 antigen, detection of HIV syncytium-inducing phenotype, plasma HIV viremia) parameters, the baseline serum concentrations of TNF-beta and sAPO-1/Fas were statistically different between progressing and nonprogressing patients. In addition, serum concentrations of TNF-beta and sAPO-1/Fas showed the strongest independent predictive power for progression to AIDS in a multivariate conditional logistic regression model. Because TNF-beta and Fas were suggested to be mediators of antigen-induced cell death (AICD) in HIV infection and sAPO-1/Fas was hypothesized to protect lymphocyte against AICD, these data suggest an important pathogenetic role for AICD in the progression of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed2026

From genes to trajectories: mapping genetic influences on Huntington's disease progression.

MOTIVATION: There are many diseases with established genetic factors, such as Huntington's disease (HD), that are characterized by variable rates of progression. However, beyond the contribution of the known genetic factors - in this case the Huntingtin (HTT) gene - the impact of the full human genome on the natural progression of such diseases throughout a patient's life remains largely unknown. The increased availability of genome wide association (GWA) data in HD gene expansion carriers (HDGECs), combined with the clinical assessment scores on the same set of patients, has provided a perfect opportunity to assess the potentially broader genetic impact on the natural progression of HD. RESULTS: We present a genetics-driven, probabilistic disease progression model designed to identify and investigate the ways in which a range of genetic factors affect the natural progression of HD. When applied to a clinico-genomic HD dataset, our model identified several single nucleotide polymorphisms (SNPs) with previously unreported effects on disease progression that act at distinct stages and with varying magnitudes. This discovery may shed light on the potential mechanistic impact of previously unidentified genes on HD that may have implications for clinical management. As increasing amounts of GWA data become available more generally, we anticipate that this modeling framework will be broadly applicable to other diseases with strong genetic components. AVAILABILITY AND IMPLEMENTATION: The source code for IHDPM is available at https://github.com/BiomedSciAI/IHDPM.

Huntington Disease↗
PubMed1997

Proton magnetic resonance spectroscopic imaging in progressive supranuclear palsy, Parkinson's disease and corticobasal degeneration.

We used proton magnetic resonance spectroscopic imaging (1H-MRSI) to assess the in vivo cortical and subcortical neuronal involvement in progressive supranuclear palsy, Parkinson's disease and corticobasal degeneration. This technique permitted the simultaneous measurement of compounds containing N-acetylaspartate (NA), choline (Cho), creatine-phosphocreatine (Cre) and lactate, from four 15-mm slices divided into 0.84-ml single-volume elements. The study included 12 patients with progressive supranuclear palsy, 10 with Parkinson's disease, nine with corticobasal degeneration and 11 age-matched normal control subjects. Regions of interest were selected from the brainstem, caudate, thalamus, lentiform nucleus, centrum semiovale, and from frontal, parietal, precentral, temporal and occipital cortices. Progressive supranuclear palsy patients, compared with control subjects, had significantly reduced NA/Cre in the brainstem, centrum semiovale, frontal and precentral cortex, and significantly reduced NA/Cho in the lentiform nucleus. Corticobasal degeneration patients, compared with control subjects, had significantly reduced NA/Cre in the centrum semiovale, and significantly reduced NA/Cho in the lentiform nucleus and parietal cortex. There were no significant differences between Parkinson's disease patients and control subjects, or between patients groups in any individual region of interest. In the parietal cortex of corticobasal degeneration patients, NA/Cho was significantly reduced contralateral to the most affected side. There were statistically significant group differences in the regional pattern of NA/Cre and NA/Cho reduction, comparing normal control subjects with all patient groups, Parkinson's disease with corticobasal degeneration, and Parkinson's disease with progressive supranuclear palsy. Although the occurrence of significant groups differences does not imply that it is possible to differentiate between individual patients using 1H-MRSI in progressive supranuclear palsy and corticobasal degeneration, detection of specific cortical and subcortical patterns of neuronal involvement is possible with this technique. We suggest that this regional pattern of neuronal involvement found in progressive supranuclear palsy and corticobasal degeneration may help in the diagnostic evaluation of affected individuals.

Aged↗
PubMed1995

Incidence and progression of diabetic retinopathy among non-insulin-dependent diabetic subjects: a 4-year follow-up.

BACKGROUND: To assess the incidence and progression of diabetic retinopathy and explore risk factors associated with them among non-insulin-dependent diabetes mellitus (NIDDM) patients. METHODS: A total of 471 NIDDM subjects aged > or 40 were recruited from four primary health care centres of northern Taiwan in 1986 and followed up for 4 years. Their ocular fundi were clearly visible by ophthalmoscopy and the status of diabetic retinopathy could be graded. A structured questionnaire interview was conducted to collect basic data. Overnight fasting venous blood was collected every year to measure the levels of glucose, glycosylated haemoglobin (HbA1c), cholesterol and high density lipoprotein cholesterol. RESULTS: Among the 344 subjects who had no retinopathy initially, 66 subjects developed retinopathy 4 years later giving a 4-year cumulative incidence of 19.2%. Of the 120 subjects initially with background or preproliferative retinopathy, evidence of deterioration developed in 36 subjects. The cumulative incidence of progression was 30%. Seven subjects developed proliferative retinopathy giving a cumulative incidence of progression to proliferative retinopathy of 5.8%. The univariate analysis disclosed that the development of retinopathy was correlated with mean fasting blood glucose (MFBG) and HbA1c, diabetic duration, diabetic treatment and residential area. The progression of retinopathy correlated with MFBG and proteinuria, and the progression to proliferative retinopathy correlated with MFBG. Stepwise logistic regression analysis revealed that MFBG and HbA1c were the significant risk factors related to the development of retinopathy. CONCLUSIONS: Diabetic control assessed by MFBG or HbA1c was the significant risk factor correlated with the incidence and progression of retinopathy.

Adult↗
PubMed2006

Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate.

BACKGROUND: Although most patients with gastrointestinal stromal tumor (GIST) treated with imatinib mesylate achieve remission or disease stabilization, a significant proportion show progressive disease (PD) with or without initial favorable responses. We evaluated and categorized the patterns of progression of metastatic or unresectable GIST treated with imatinib to identify the prognostic significance and contribution to further treatment decision-making. METHODS: We prospectively gathered clinical data from 62 GIST patients treated with imatinib mesylate (400 mg/day) over a median period of 26 months. Twenty-one of these patients showed evidence of PD based on Response Evaluation Criteria in Solid Tumor criteria. RESULTS: Four patterns of PD were defined: focal progression (FP, N = 4), general progression (GP, N = 6), new cystic lesion (NCL, N = 6) and new solid lesion (NSL, N = 5). The groups were found to differ in terms of time to progression and prior response to imatinib. The proportion of patients who responded to escalated doses of imatinib (600-800 mg/day) was significantly higher in NCL patients (P = 0.04). Overall survival and survival from the confirmation of PD were significantly better in NCL or FP patients compared with NSL or GP patients (P = 0.0157, P = 0.0013). CONCLUSIONS: We identified four patterns of disease progression based on radiographic criteria with different clinical characteristics and impact on survival. Knowledge of these patterns was relevant for early detection and may be helpful in further treatment decision-making.

Adult↗
PubMed1997

Low serum vitamin B-12 concentrations are associated with faster human immunodeficiency virus type 1 (HIV-1) disease progression.

We conducted a nonconcurrent prospective cohort study to examine associations between serum concentrations of vitamin B-6, vitamin B-12 and folate and the risk of progression to first acquired immunodeficiency syndrome (AIDS) diagnosis and CD4+ cell decline to < 2 x 10(8) cells/L. The study population was drawn from a cohort of homosexual and bisexual men in the Baltimore-Washington, DC, area. Eligible subjects were human immunodeficiency virus type 1 (HIV-1)-seropositive at study entry and had serum available in the serum repository from their 1984 baseline study visit. Serum micronutrient levels were assessed in 310 subjects. The follow-up period (April 1984 through December 1993) was approximately 9 y. In Kaplan-Meier analyses, participants with low serum vitamin B-12 concentrations (< 120 pmol/L) had significantly shorter AIDS-free time than those with adequate vitamin B-12 concentrations (median AIDS-free time = 4 vs. 8 y, respectively, P = 0.004). This effect persisted in Cox proportional hazards models after adjusting for HIV-1-related symptoms, CD4+ cell count, age, serum albumin, use of antiretroviral therapy before AIDS, frequency of alcohol consumption and serum folate concentration [relative hazard (RH) = 1.89, 95% confidence interval (CI) = 1.15-3.10). To further explore the temporal relation between low serum vitamin B-12 concentrations and disease progression, additional analyses were performed excluding subjects with more advanced disease at baseline. In these analyses, the increase in risk of progression to AIDS for those with low serum vitamin B-12 concentrations remained significant (RH = 2.21, 95% CI = 1.13-4.34), providing further evidence that low vitamin B-12 concentrations preceded disease progression. In contrast, low serum concentrations of vitamin B-6 and folate were not associated with either progression to AIDS or decline in CD4+ lymphocyte count. Intervention studies are needed to determine whether correction of low serum vitamin B-12 concentrations in early HIV-1 infection will influence the natural history of disease progression.

Adult↗
PubMed2002

Osteopontin identified as lead marker of colon cancer progression, using pooled sample expression profiling.

BACKGROUND: New tumor markers and markers of tumor progression are needed for improved staging and for better assessment of treatment of many cancers. Gene expression profiling techniques offer the opportunity to discover such markers. We investigated the feasibility of sample pooling strategy in combination with a novel analysis algorithm to identify markers. METHODS: Total RNA from human colon tumors (n = 60) of multiple stages (adenomas; cancers with modified Astler Collier stages B, C, and D; and liver metastases) were pooled within stages and compared with pooled normal mucosal specimens (n = 10) by using oligonucleotide expression arrays. Genes that showed consistent increases or decreases in their expression through tumor progression were identified. Northern blot analysis was used to validate the findings. All statistical tests were two-sided. RESULTS: More than 300 candidate tumor markers and more than 100 markers of tumor progression were identified. Northern analysis of 11 candidate tumor markers confirmed the gene expression changes. The gene for the secreted integrin-binding protein osteopontin was most consistently differentially expressed in conjunction with tumor progression. Its potential as a progression marker was validated (Spearman's rho = 0.903; P<.001) with northern blot analysis using RNA from an independent set of 10 normal and 43 tumor samples representing all stages. Moreover, a statistically significant correlation between osteopontin protein expression and advancing tumor stage was identified with the use of 303 additional specimens (human cancer = 185, adenomas = 67, and normal mucosal specimens = 51) (Spearman's rho = 0.667; P<.001). CONCLUSIONS: Sample pooling can be a powerful, cost-effective, and rapid means of identifying the most common changes in a gene expression profile. We identified osteopontin as a clinically useful marker of tumor progression by use of gene expression profiling on pooled samples.

Adenoma↗
PubMed1999

Dyslipidaemia and the progression of renal disease in chronic renal failure patients.

BACKGROUND: Dyslipidaemia is common in patients with chronic renal failure (CRF), and there is increasing evidence to support the role of dyslipidaemia as a contributing factor in the progression of chronic renal disease. However, few prospective studies have been carried out which address the possible relationship between dyslipidaemia and the rate of progression of renal disease in patients with renal failure. METHODS: Between January 1985 and December 1997, we prospectively assessed the risk of CRF progression to dialysis in a cohort of 138 patients. Forty CRF patients reached end-stage renal disease (ESRD) and had to start supportive therapy during the follow-up period [group ESRD(+)]. The remaining 98 CRF patients served as controls [group ESRD(-)]. Potential clinical and laboratory risk factors for more rapid CRF decline to dialysis, including lipid abnormalities and baseline creatinine clearance were determined at the start of the follow-up period. RESULTS: Several significant differences were found in univariate analysis between the two groups of CRF, ESRD(+) and ESRD(-), namely a shorter follow-up period, a lower level of baseline creatinine clearance, a faster rate of creatinine clearance decline, a higher level of serum triglycerides, fibrinogen, total homocyst(e)ine and proteinuria, and a lower level of serum high-density lipoprotein in the ESRD(+) group than in the ESRD(-) group. However, by multivariate Cox analysis proteinuria [relative risk (95% confidence interval) 1.32 (1.16-1.50) for each g/day P = 0.001], baseline creatinine clearance [0.53 (0.40-0.70) for each 10 ml/min, P = 0.001] and chronic interstitial nephritis and hypertensive nephrosclerosis [0.38 (0.17-0.84) for presence, P = 0.005] were the only significant risk factors for CRF progression to dialysis. Hypertriglyceridaemia and male gender were selected in the final model, but were of borderline significance. CONCLUSIONS: These results suggest a limited role for dyslipidaemia in the progression of chronic renal disease to dialysis in CRF patients, in contrast with the powerful influence of proteinuria, baseline creatinine clearance and nephropathy type in predicting this progression.

Aged↗
PubMed2001

Angiographic progression of coronary artery disease in patients with end-stage renal disease.

BACKGROUND: Patients with end-stage renal disease have an increased risk of developing coronary artery disease (CAD). The cardiovascular mortality of dialysis patients is 10-15 times higher compared with the general population. The aim of our study was to evaluate the morphological progression of coronary arteriosclerosis in this cardiovascular high-risk group by visual assessment and quantitative coronary angiography. Methods and results. In 26 patients with chronic renal failure (age, 47+/-11 years; 15 male; duration of dialysis, 23+/-25 months) the severity of CAD and degree of coronary stenoses were assessed in two coronary angiograms after a mean follow-up interval of 30+/-15 months (12-60). Baseline angiography revealed CAD in 13/22 patients (59%). The second angiography was performed as screening procedure prior to renal transplantation (n=20) and/or as follow-up angiography after coronary angioplasty (n=10). Visual assessment showed a progression defined by the development of haemodynamically relevant stenosis of >50% luminal diameter in 13 patients. Quantitative angiographic evaluation was performed in a total of 45 segments showing >25% narrowing at the second angiogram. A progression (>15% luminal reduction) was found in 17 of 45 segments, a new lesion (initial luminal diameter <20%) was detected in nine segments, resulting in progression or new lesion in 16 patients (62%). Patients with or without progression did not differ in age, duration of dialysis treatment, number of cardiovascular risk factors, or serum total cholesterol and fibrinogen levels. After percutaneous transluminal coronary angioplasty (PTCA) a restenosis was seen in seven of 16 primarily successfully dilated segments. After the second angiography, myocardial revascularization was performed in eight patients (1 PTCA, 7 coronary artery bypass graft). CONCLUSIONS: Patients with end-stage renal disease have a high prevalence of CAD. In line with the clinical course, CAD patients on maintenance dialysis undergo rapid angiographic progression of CAD, which results in a high rate of subsequent myocardial revascularizations.

Adult↗