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1.  Intellectual Impairment in Children with Blood Lead Concentrations below 10 µg per Deciliter 
The New England journal of medicine  2003;348(16):1517-1526.
Despite dramatic declines in children’s blood lead concentrations and a lowering of the Centers for Disease Control and Prevention’s level of concern to 10 µg per deciliter (0.483 µmol per liter), little is known about children’s neurobehavioral functioning at lead concentrations below this level.
We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and administered the Stanford–Binet Intelligence Scale at the ages of 3 and 5 years. The relation between IQ and blood lead concentration was estimated with the use of linear and nonlinear mixed models, with adjustment for maternal IQ, quality of the home environment, and other potential confounders.
The blood lead concentration was inversely and significantly associated with IQ. In the linear model, each increase of 10 µg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the subsample of 101 children whose maximal lead concentrations remained below 10 µg per deciliter, the change in IQ associated with a given change in lead concentration was greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 µg per deciliter.
Blood lead concentrations, even those below 10 µg per deciliter, are inversely associated with children’s IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated.
PMCID: PMC4046839  PMID: 12700371
2.  Hypercholesterolemic Aortic-Valve Disease 
The New England journal of medicine  2003;349(7):717-718.
PMCID: PMC3951872  PMID: 12917318
3.  Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer 
The New England journal of medicine  2003;349(3):247-257.
Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer.
Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers.
Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004). Among patients who received adjuvant chemotherapy, high-frequency microsatellite instability was not correlated with increased overall survival (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80). The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 [95 percent confidence interval, 0.53 to 0.99]; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability.
Fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability but not those with tumors exhibiting high-frequency microsatellite instability.
PMCID: PMC3584639  PMID: 12867608
4.  Mammographic Screening for Breast Cancer 
The New England journal of medicine  2003;348(17):1672-1680.
A 44-year-old woman who is a new patient has no known current health problems and no family history of breast or ovarian cancer. Eighteen months ago, she had a normal screening mammogram. She recently read that mammograms may not help to prevent death from breast cancer and that “the patient should decide.” But she does not think she knows enough. She worries that there is a breast-cancer epidemic. What should her physician advise?
PMCID: PMC3157308  PMID: 12711743
5.  Intensive Diabetes Therapy and Carotid Intima–Media Thickness in Type 1 Diabetes Mellitus 
The New England journal of medicine  2003;348(23):2294-2303.
Cardiovascular disease causes severe morbidity and mortality in type 1 diabetes, although the specific risk factors and whether chronic hyperglycemia has a role are unknown. We examined the progression of carotid intima–media thickness, a measure of atherosclerosis, in a population with type 1 diabetes.
As part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term follow-up of the Diabetes Control and Complications Trial (DCCT), 1229 patients with type 1 diabetes underwent B-mode ultrasonography of the internal and common carotid arteries in 1994–1996 and again in 1998–2000. We assessed the intima–media thickness in 611 subjects who had been randomly assigned to receive conventional diabetes treatment during the DCCT and in 618 who had been assigned to receive intensive diabetes treatment.
At year 1 of the EDIC study, the carotid intima–media thickness was similar to that in an age- and sex-matched nondiabetic population. After six years, the intima–media thickness was significantly greater in the diabetic patients than in the controls. The mean progression of the intima–media thickness was significantly less in the group that had received intensive therapy during the DCCT than in the group that had received conventional therapy (progression of the intima–media thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima–media thickness of the common and internal carotid arteries, −0.155 vs. 0.007; P=0.02) after adjustment for other risk factors. Progression of carotid intima–media thickness was associated with age, and the EDIC base-line systolic blood pressure, smoking, the ratio of low-density lipoprotein to high-density lipoprotein cholesterol, and urinary albumin excretion rate and with the mean glycosylated hemoglobin value during the mean duration (6.5 years) of the DCCT.
Intensive therapy during the DCCT resulted in decreased progression of intima–media thickness six years after the end of the trial.
PMCID: PMC2701300  PMID: 12788993
6.  A Randomized Trial of Bevacizumab, an Anti–Vascular Endothelial Growth Factor Antibody, for Metastatic Renal Cancer 
The New England journal of medicine  2003;349(5):427-434.
Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma.
A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point.
Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose–antibody group as compared with the placebo group (hazard ratio, 2.55; P<0.001). There was a small difference, of borderline significance, between the time to progression of disease in the low-dose–antibody group and that in the placebo group (hazard ratio, 1.26; P=0.053). The probability of being progression-free for patients given high-dose antibody, low-dose–antibody, and placebo was 64 percent, 39 percent, and 20 percent, respectively, at four months and 30 percent, 14 percent, and 5 percent at eight months. At the last analysis, there were no significant differences in overall survival between groups (P>0.20 for all comparisons).
Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer.
PMCID: PMC2275324  PMID: 12890841

Results 1-6 (6)