Citations

AbstractPurpose: Colorectal carcinoma (CRC) can be divided into two nonoverlapping groups: those that are chromosomally unstable but microsatellite stable (MSS CIN+) and those that are chromosomally stable but microsatellite unstable (MSI CIN−). However, a third group with neither chromosome nor microsatellite instability (MSS CIN−) makes a substantial contribution to the total CRC burden. The clinicopathologic features of MSS CIN− CRC are not well delineated. We assessed the relationship between age and chromosomal instability (CIN) status as measured by ploidy and allelic imbalance in a series of MSS tumors.Experimental Design: We studied a prospectively collected series of CRC patients at Mayo Clinic Rochester. A total of 84 samples of MSS CRC in patients ≤50 years old were identified between 1994 and 1997. A consecutive series of 90 MSS CRC in patients ≥65 years old served as a comparison group. CIN status was assessed using two techniques: ploidy analysis by flow cytometry and small chromosome changes as measured by genomewide fractional allelic imbalance.Results: CRC in the young-onset group was more likely to involve the rectum and to be high stage. MSS tumors in the young-onset group were more often diploid (46%) than those in older patients (26%; P = 0.006). This difference was maintained in the subset of MSS CRC that were high stage (42% versus 18%; P = 0.02) and in rectal cancers (50% versus 23%; P = 0.04).Conclusion: A greater proportion of young patients with MSS CRC has diploid tumors than patients who develop MSS CRC over age 65.

Abstract Two variants (rs1447295/DG8S737) of chromosome 8q24 were recently reported to be associated with increased risk of prostate cancer (PC). To confirm this finding, we genotyped and compared the frequencies of these polymorphisms among 1,121 Caucasian men with PC (435 men with familial PC, 491 men with sporadic PC, and 195 men with aggressive PC) to 545 population-based controls. For the single nucleotide polymorphism marker rs1447295, frequencies of the minor allele (A) were 10.3% in controls, 11.9% in sporadic cases, 16.7% in familial cases, and 17.2% in aggressive cases. Compared with controls, the A allele was significantly more common in both familial PC [odds ratios (OR), 1.93; 95% confidence intervals (95% CI), 1.37–2.72; P = 0.0004] and aggressive PC (OR, 1.87; 95% CI, 1.28–2.74; P = 0.0005) but not for sporadic PC (OR, 1.16; 95% CI, 0.85–1.58; P = 0.25). Although the A allele was more frequent in aggressive PC cases when compared with controls, the allele frequencies were similar among cases with high- and low-grade PC (Gleason grades <7 and ≥7, respectively). For the microsatellite marker DG8S737, the −8 allele was significantly more frequent in familial PC (OR, 1.68; 95% CI, 1.09–2.60; P = 0.031), whereas the −10 allele was more frequent in aggressive PC (OR, 2.85; 95% CI, 1.52–5.36; P = 0.0004). Haplotype analysis showed significant differences in haplotype frequencies between the familial PC (P = 0.006) and aggressive PC (P = 0.005) cases versus controls. The −8/A haplotype showed the strongest association with familial PC (P = 0.008), whereas the −10/A haplotype was most strongly associated with aggressive PC (P = 0.00005). These results further confirm the importance of these two polymorphic variants (rs1447295 and DG8S737) as risk factors for PC. However, the mechanism explaining this increased risk has not yet been established. [Cancer Res 2007;67(7):2944–50]

Cerebral white matter hyperintensities on brain MRI (leukoaraiosis) are associated with increased risk of stroke and dementia. To assess the relationships of blood pressure level and circadian pattern with leukoaraiosis, we obtained 24-hour ambulatory blood pressure recordings and brain magnetic resonance images in 343 white and 267 black adults who were members of sibships that had ≥2 siblings with essential hypertension. In multiple linear regression models, factors associated with greater leukoaraiosis in both racial groups included age ( P ≤0.002), homocysteine levels ( P ≤0.006), and brain volume ( P ≤0.008). In blacks, ambulatory blood pressure measures associated with greater leukoaraiosis were higher awake, asleep, and 24-hour systolic and diastolic levels ( P ≤0.009 for each). In addition, there was a trend for smaller nocturnal declines in systolic and diastolic levels (ie, nondipping patterns) to be associated with greater leukoaraiosis, and all of these associations, except nondipping of diastolic level, remained or became significant after controlling for office blood pressure ( P <0.05 for each). In whites, among ambulatory blood pressure measures, only higher asleep diastolic levels trended toward association with greater leukoaraiosis. However, similar to findings in blacks, nondipping of systolic and diastolic ambulatory blood pressure levels were each associated with greater leukoaraiosis ( P ≤0.008), and all of these associations remained or became significant after controlling for office blood pressure ( P ≤0.009 for each). Higher ambulatory blood pressure levels and a nondipping circadian pattern contribute to greater leukoaraiosis volume after controlling for office blood pressure.

In the present study, we investigated whether measures of brachial artery reactivity were associated with the presence and extent of subclinical coronary atherosclerosis in asymptomatic adults. Electron beam computed tomography was employed to assess the presence and quantity of CAC (coronary artery calcium) in 441 participants (mean age, 61 years; 49% men) without prior history of CHD (coronary heart disease) or stroke, and CAC score was calculated using the method described by Agatston and co-workers [(1990) J. Am. Coll. Cardiol. 15, 827–832] High-resolution ultrasound was employed to measure BAD (brachial artery diameter), FMD (flow-mediated dilatation) and NMD (nitroglycerine-mediated dilatation). CAC score and FMD were log-transformed after adding 1 to reduce skewness. Multivariable logistic and linear regression models based on generalized estimating equations were used to assess whether BAD, FMD and NMD were each independently associated with the presence and quantity of CAC after adjustment for CHD risk factors and use of statin and hypertension medication. CAC was detectable in 64% of participants. After adjustment for age and sex, FMD was not correlated (r=−0.06; P=0.27), BAD was positively correlated (r=0.16; P=0.004) and NMD was inversely correlated in a borderline significant manner (r=−0.10; P=0.084) with log(CAC+1). In multivariable logistic regression analyses, FMD was not associated, whereas higher BAD (P=0.021) and lower NMD (P=0.030) were independently associated with the presence of CAC. In multivariable linear regression analyses, higher BAD (P=0.004) and lower NMD (P=0.016), but not FMD, were independently associated with log(CAC+1). We conclude that greater diameter of the brachial artery and lower vasodilator response to nitroglycerine, but not FMD, are associated with subclinical coronary atherosclerosis.

Little is known about the fate of the lipolytic products produced by the action of lipoprotein lipase (LPL) on circulating triglyceride-rich lipoproteins in humans. We studied eight lean, healthy male subjects after an overnight fast. Subjects received infusions of lipid emulsions containing triolein labeled with 3H on both the glycerol backbone and the fatty acid portion of the molecule; 14C glycerol and 14C oleate were coinfused to quantify the systemic and forearm release of 3H glycerol and 3H oleate resulting from LPL action. There was significant forearm uptake of both whole plasma triglyceride (presumed to represent primarily VLDL; extraction fraction 2.6 ± 0.6%, P &lt; 0.005 vs. zero) and radiolabeled triglyceride derived from the lipid emulsion (a surrogate for chylomicrons; extraction fraction 31 ± 4%, P &lt; 0.005 vs zero). Systemic clearance and forearm fractional extraction of glycerol was greater than that of oleate (P &lt; 0.001 and P &lt; 0.02, respectively). The systemic and forearm fractional release of LPL-generated glycerol were similar at 51 ± 4 and 59 ± 1%, respectively (NS). In contrast, the forearm fractional release of LPL-generated oleate was less than systemic fractional release (14 ± 2 vs. 36 ± 4%, P &lt; 0.0001). These results indicate that there is escape, or spillover, of the lipolytic products of LPL action on triglyceride-rich lipoproteins in humans. They further suggest that LPL-mediated fatty acid uptake is an inefficient process, but may be more efficient in muscle than in adipose tissue.

OBJECTIVE—Growing evidence supports that nonenzymatic glycation products may cause hyperglycemia-induced diabetes complications. Amadori-modified proteins are the intermediate products of nonenzymatic glycation and constitute the forms of glycated proteins in diabetes. The objective of the current study was to utilize two-dimensional gel electrophoresis, Western blot, and mass spectrometry to identify Amadori-modified plasma proteins in type 2 diabetic patients with poor glycemic control and assess the impact of short-term insulin treatment on the glycation of these proteins. RESEARCH DESIGN AND METHODS—We compared eight type 2 diabetic subjects (aged 56 ± 3 years and BMI 29.7 ± 0.9 kg/m2) with an average diabetes duration of 8.5 years (range 3–19) with equal numbers of weight-matched (aged 56 ± 2 years and BMI 30.1 ± 10.0 kg/m2) and lean (aged 58 ± 2 years and BMI 25 ± 00.5 kg/m2) nondiabetic subjects who have no first-degree relatives with diabetes. Two separate blood samples were collected from the type 2 diabetic subjects, one following 2 weeks of withdrawal of all antidiabetic medications (T2D−; plasma glucose 12.6 ± 1.0 mmol/l) and another following 10 days of intensive insulin treatment (T2D+; plasma glucose 5.5 ± 0.2 mmol/l). Plasma proteins were separated using single and two-dimensional gel electrophoresis. Western blot analysis was performed, and several proteins, which reacted with the Amadori-antibody (1-deoxyfructosyl lysine), were identified by tandem mass spectrometry. RESULTS—No significant differences in the glycation of proteins between the obese and lean groups were noted, but type 2 diabetic patients had several proteins with higher glycation than the control groups. We identified 12 plasma proteins with reduced reaction to the anti-Amadori antibody upon intensive insulin treatment. A significant (P &lt; 0.03) difference in Amadori modification was observed between the T2D− and control subjects for all these proteins except the Ig light chain. Insulin treatment reduced Amadori modification of albumin (23.2%, P &lt; 0.02), fibrin (34.6%, P &lt; 0.001), Ig heavy chain constant region (20.7%, P &lt; 0.05), transferrin (25.4%, P &lt; 0.04), and Ig light chain (13%, P &lt; 0.02). In addition, Western blot analysis of two-dimensional gel electrophoresis identified α-fibrinogen precursor, β-fibrinogen precursor, fibrinogen γ-B chain precursor, hemopexin, vitamin D binding protein, and serine protease inhibitor as proteins with a reduced reaction to anti-Amadori antibody upon intensive insulin treatment. CONCLUSIONS—The current approach offers the opportunity to identify Amadori modification of many proteins that may cause functional alterations and offers the potential for monitoring short-term glycemic control in diabetic patients.

OBJECTIVE—The prevalence of autonomic symptoms and deficits in certain systems is known, but a comprehensive autonomic symptom profile in diabetes is not available. We aimed to estimate this using a laboratory evaluation of autonomic function and a validated self-report measure of autonomic symptoms in patients and matched control subjects from the population-based Rochester Diabetic Neuropathy Study. RESEARCH DESIGN AND METHODS—Participants included 231 patients with diabetes (type 1, n = 83; type 2, n = 148) and 245 healthy age-matched control subjects. We assessed symptoms using a validated self-report instrument (Autonomic Symptom Profile) and evaluated the severity and distribution of autonomic deficits (cardiovagal, sudomotor, adrenergic) with the objective, laboratory-based Composite Autonomic Severity Score (CASS). RESULTS—Autonomic symptoms were present more commonly in type 1 than in type 2 diabetes, with symptoms of orthostatic intolerance, secretomotor, urinary control, diarrhea, and sleep disturbance and pupillomotor, vasomotor, and erectile dysfunction significantly increased over healthy control subjects in type 2 diabetic patients. The prevalence of autonomic impairment was 54% in type 1 and 73% in type 2 diabetic patients. Severity of autonomic failure was mild overall (mean CASS 2.3; maximum 10), with orthostatic hypotension occurring in 8.4 and 7.4% of type 1 and 2 diabetic patients, respectively. Fourteen percent of patients had a CASS ≥5, indicating moderate to severe generalized autonomic failure. The correlation of symptoms with autonomic deficits (CASS) was better in type 1 than type 2 diabetic subjects and was weak overall. CONCLUSIONS—These findings indicate that autonomic symptoms and deficits are common in diabetes, but mild in severity, and that the correlation between symptom scores and deficits is overall weak in mild diabetic neuropathy, emphasizing the need to separately evaluate autonomic symptoms.

Background and Purpose— Genetic factors influence risk for ischemic stroke and likely do so at multiple steps in the pathogenic process. Variants in genes related to inflammation contribute to risk of stroke. The purpose of this study was to confirm our earlier finding of an association between allele 2 of a variable number tandem repeat of the IL-1 receptor antagonist gene ( IL1RN ) and cerebrovascular disease. Methods— An association study of the variable number tandem repeat genotype with ischemic stroke and stroke subtypes was performed on samples from a North American study of affected sibling pairs concordant for ischemic stroke and 2 North American cohorts of prospectively ascertained ischemic stroke cases and unrelated controls. DNA analysis was performed on cases and controls, stratified by race. Results— After adjustment for age, sex, and stroke risk factors, the odds ratio for association of allele 2 and ischemic stroke was 2.80 (95% confidence interval, 1.29 to 6.11; P =0.03) for the white participants. The effect of allele 2 of IL1RN on stroke risk most closely fits a recessive genetic model ( P =0.009). For the smaller sample of nonwhite participants, the results were not significant. Conclusions— Allele 2 of IL1RN , present in nearly one-quarter of stroke patients, may contribute to genetic risk for ischemic stroke and confirm the previously identified association with cerebrovascular disease. These results are driven by the association in the white participants. Further exploration in a larger nonwhite sample is warranted.

AbstractRecent gene-expression data have suggested that host immune genetic signatures may predict outcomes in patients with follicular lymphoma. We evaluated the hypothesis that germ line common variation in candidate immune genes is associated with survival. Cox models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals for individual SNPs after accounting for age, clinical, and other demographic factors. The median age at diagnosis of the 278 patients was 57 years, and 59 (21%) of the patients died during follow-up, with a median follow-up of 59 months (range, 27-78 months) for surviving patients. SNPs in IL8 (rs4073; HRTT = 2.14, 1.26-3.63), IL2 (rs2069762; HRGT/TT = 1.80, 1.06-3.05), IL12B (rs3212227; HRAC/CC = 1.83, 1.06-3.06), and IL1RN (rs454078; HRAA = 1.93, 1.11-3.34) were the most robust predictors of survival. A summary score of the number of deleterious genotypes from these genes was strongly associated with survival (P = .001). A risk score that combined the 4 SNPs with the clinical and demographic factors was even more strongly associated with survival (P < .001); the 5-year Kaplan-Meier survival estimates were 96% (93%-100%), 72% (62%-83%), and 58% (48%-72%) for groups at low, intermediate, and high risk, respectively. Common variation in host immune genes warrants further evaluation as a promising class of prognostic factors in follicular lymphoma.