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Fourteen hundred and forty-seven 12–16-yr-old subjects in selected fluoridated and non-fluoridated areas were assessed for caries experience (DMFS index) and enamel fluoride (biopsy technique). Fluoride was measured as log e mass F corrected to a standardized depth. A square root transformation of decayed, missing and filled surfaces (DMFS) was carried out in order to achieve homogeneity of variance for this variable across all levels of fluoride. A simple, linear relationship was found between log e mass F and √(DMFS). Taking age into account, the Pearsonian correlation was R = 0.40, corresponding to 16 per cent of the variance explained. Within communities the fluoride-caries relationship was consistent with the overall model but could not be demonstrated as securely because of the smaller sample sizes and the limited range of fluoride values at this level of disaggregation.

Risk factors for the development of severe forms of diabetic retinopathy were examined prospectively in a group of 153 patients with long-standing insulin-dependent diabetes mellitus. During a 4-yr follow-up study, 34 individuals progressed to preproliferative and proliferative retinopathy. The risk of progression to severe forms of diabetic retinopathy was determined by the degree of background diabetic retinopathy and several systemic factors. It increased steeply with hemoglobin A1c, declined proportionally with increasing age, and was dramatically different in patients with diastolic blood pressure below versus above 70 mmHg. Although the mechanisms of action of these systemic factors are unclear, the findings emphasize the multifactorial nature of the pathogenesis of severe forms of eye lesions.

The risk of end-stage renal disease (ESRD) remains high in patients with type 1 diabetes and proteinuria; however, little is known about the rate of decline in their renal function. To help determine this, we enrolled patients with type 1 diabetes and proteinuria whose estimated glomerular filtration rate (eGFR) was normal (equal to or above 60 ml/min per 1.73 m(2)). Using a minimum of five serial measurements of serum creatinine for 161 patients, we determined individual trajectories of eGFR change and the occurrence of ESRD during 5-18 years of follow-up. The rates were linear for 110 patients, for 24 the nonlinear rate was mild enough to satisfy a linear model, and the rates were clearly nonlinear for only 27 patients. Overall, in more than one-third of patients, the eGFR decline was less than 3.5 ml/min per 1.73 m(2) per year and the lifetime risk of ESRD could be considered negligible. In the remainder of patients, eGFR declined with widely different slopes and ESRD developed within 2 to 18 years. Based on up to 5 years observation, when renal function was within the normal range, the estimates of early eGFR slope predicted the risk of ESRD during subsequent follow-up better than the baseline clinical characteristics of glycated hemoglobin, blood pressure, or the albumin to creatinine ratio. Thus, the early slope of eGFR decline in patients with type 1 diabetes and proteinuria can be used to predict the risk of ESRD.

Urinary albumin excretion in families with type 2 diabetes is heritable and genetically correlated to blood pressure.BackgroundLevels of urinary albumin excretion (UAE) are used to define both the diagnosis of diabetic nephropathy and its progression. Predisposition to high blood pressure is also a risk factor for susceptibility to nephropathy, but its relationship with UAE in type 2 diabetes remains unclear. In this study, we have estimated heritabilities of UAE and blood pressure and their correlation attributable to genetic effects using 96 large families ascertained for type 2 diabetes.MethodsIn these families, 630 individuals with type 2 diabetes and 639 individuals with normoglycemia were examined. All of them had a determination of UAE as the urinary albumin creatinine ratio (ACR), a convenient index of UAE, together with blood pressure and other variables, such as age, sex, and body mass index. A variance components approach was used to estimate heritability and genetic correlations for ACR and systolic and diastolic blood pressures (SBP and DBP) after adjustment for relevant covariates.ResultsIn the 96 pedigrees, 6481 usable pairs of relatives were identified. In the total collection of pairs, heritability for ACR (h2 = 0.27, P β; 0.001) was similar to that for blood pressure. When only pairs of diabetic relatives were analyzed (N = 1732), the estimates of heritability increased slightly for ACR (h2 = 0.31), SBP (h2 = 0.33), and DBP (h2 = 0.23). A significant genetic correlation was found between ACR and SBP (rg 0.27) and DBP (rg 0.26) in all pairs of relatives (P β; 0.001). In pairs of diabetic relatives, these values were higher for SBP and DBP, 0.38 and 0.52, respectively.ConclusionIn families with type 2 diabetes, UAE is a heritable trait, with a heritability similar to that for blood pressure. A significant genetic correlation between UAE and blood pressure, particularly in the presence of diabetes, indicates that these traits share common genetic determinants.

Aging in the kidney can cause albuminuria, and discovering molecular mechanisms responsible for this might offer a new perspective on the etiology of this abnormality. Haplotype association mapping in the mouse is a novel approach which uses the haplotypes of the relatively closely related mouse inbred strains and the phenotypic variation among these strains to find associations between haplotypes and phenotype. The albumin-to-creatinine ratios, a measure of urinary albumin excretion, were determined in 30 inbred mouse strains at 12, 18, and 24 months of age. Mapping was performed for males and females separately at all three time points using a high density set of 63,222 single-nucleotide polymorphisms to determine genetic loci involved in albuminuria. One significant and eight suggestive loci were found, some of which map to previously identified loci for traits associated with kidney damage in the mouse, but with a much higher resolution thus narrowing their chromosomal location. These nine loci were then compared with genome-wide association scans for diabetic nephropathy (DN) in human type I diabetes. Our study found that two of the nine mouse loci for age-related albuminuria were significantly associated with DN and consistent across male and female strata. This suggests common underlying genes predispose to kidney disease in mice and humans.

Only one third of patients with juvenile-onset insulin-dependent diabetes seem to be susceptible to diabetic nephropathy. To test whether this susceptibility is related to a predisposition to hypertension, we investigated the association of nephropathy with markers of risk for hypertension. We randomly selected 89 patients with insulin-dependent diabetes from a roster of children and adolescents who were seen between 1968 and 1972 at about the time the diagnosis was made. These 89 patients were recalled for examination, as young adults, in 1986 and 1987. Patients with nephropathy (cases, n = 33) were compared with controls without nephropathy (n = 56). Having a parent with hypertension tripled the risk of nephropathy (odds ratio, 3.7; 95 percent confidence interval, 1.4 to 10.1). Moreover, cases had significantly higher values for maximal velocity of lithium-sodium countertransport in red cells than controls (mean maximal velocity +/- SE, 0.51 +/- 0.04 vs. 0.38 +/- 0.02 mmol per liter of cells per hour; P less than 0.05). The excess risk associated with both these indicators of a predisposition to hypertension was evident principally in patients with poor glycemic control during their first decade of diabetes; the odds ratios were 4.5 (95 percent confidence interval, 1.1 to 18.7) for patients with a parental history of hypertension and 7.7 (95 percent confidence interval, 1.8 to 33.8) for patients with a maximal velocity of lithium-sodium countertransport greater than or equal to 0.35 mmol per liter of cells per hour. We conclude that the risk of renal disease in patients with juvenile-onset insulin-dependent diabetes is associated with a genetic predisposition to hypertension. Predisposition to hypertension appears to increase susceptibility for renal disease principally in patients with poor glycemic control.

The prevalence of hypertension in various age groups of diabetics and its role as a risk factor in juvenileonset insulin-dependent diabetics followed for 40 yr after diagnosis was evaluated. The results show clearly that hypertension is more prevalent in diabetics of any age after age 24 yr than in the general population. In this type of diabetes, although death due to renal disease occurs earlier than that due to coronary heart disease, both causes of death are significantly related to hypertension. Those patients with an onset of diabetes 13 yr of age or younger can expect to live longer following the diagnosis of diabetes mellitus than those with an onset after 13 yr of age, perhaps because hypertension appears at about the same age in both groups. Case/control analysis of the data shows that survivors have significantly less hypertension than those dying of renal or cardiac disease. Furthermore, the close temporal relationship between the onset of hypertension and the onset of proteinuria in patients with either renal or coronary deaths suggests that the hypertension in these patients is renal in origin. Two other risk factors, smoking and serum lipids, were evaluated in this population. From the data thus far accumulated, neither smoking nor lipids appear to influence mortality significantly. We conclude that hypertension is the major additive risk factor for mortality in juvenile-onset insulin-dependent diabetics.

Oral glucose tolerance tests with plasma glucose and insulin determinations were performed on 195 patients with impaired glucose tolerance. Patients were divided into three groups according to blood pressure levels: normal, below 140/90 mm Hg; diastolic hypertension, diastolic pressure above 90 mm Hg; and systolic hypertension, systolic pressure above 140 and diastolic pressure below 90 mm Hg. Sex, age, and glucose levels were similar among the groups. By contrast, serum insulin levels were significantly elevated for the patients with diastolic hypertension (p less than 0.01). This difference persisted after correction for body weight. These results suggest a causal relationship between the level of circulating insulin and diastolic blood pressure, and support the concept that hyperinsulinemia may be the common link in the clustering of hypertension, diabetes, and obesity.

Diabetic nephropathy is manifested by albuminuria, hypertension and progressive loss of renal function. Only one-third of patients with insulin-dependent diabetes mellitus of juvenile onset develop nephropathy and the risk of nephropathy does not increase with increasing duration of diabetes. Hypertension occurs almost exclusively in patients with nephropathy. Therefore, there is a subset of patients at risk for both nephropathy and hypertension. It is important to identify the patients destined to develop nephropathy, to define the pathophysiology responsible for the nephropathy in this subset of patients and to develop programs to interrupt the pathophysiology early in its course and hopefully prevent the progression to end-stage renal failure. Potential markers to identify patients who will develop nephropathy include a family history of hypertension, increased glomerular filtration rate and renal mass and presence of significant microalbuminuria. Studies are needed to evaluate various classes of drugs for their efficacy in altering the pathophysiologic hemodynamic changes leading to nephropathy.

A technique is described for the estimation of fluoride (F) in enamel samples of varying weight. The data are used to derive a generalized relationship of F to sample weight that permits the adjustment of any observed F value to the "expected" value at a standaidized weight.

We studied 10 vegetarian and 10 nonvegetarian premenopausal women on four occasions approximately four months apart. During each study period, the participants kept three-day dietary records, and estrogens were measured in plasma, urinary, and fecal samples. Vegetarians consumed less total fat than omnivores did (30 per cent of total calories, as compared with 40 per cent) and more dietary fiber (28 g per day, as compared with 12 g). There was a positive correlation between fecal weight and fecal excretion of estrogens in both groups (P less than 0.001), with vegetarians having higher fecal weight and increased fecal excretion of estrogens. Urinary excretion of estriol was lower in vegetarians (P less than 0.05), and their plasma levels of estrone and estradiol were negatively correlated with fecal excretion of estrogen (P = 0.005). Among the vegetarians the beta-glucuronidase activity of fecal bacteria was significantly reduced (P = 0.05). We conclude that vegetarian women have an increased fecal output, which leads to increased fecal excretion of estrogen and a decreased plasma concentration of estrogen.

Women who consume a diet low in fat are at lower risk for breast cancer than women whose diet is relatively high in fat. To investigate the effects of a low fat diet on estrogen metabolism, six normal young women were studied while eating a Western-style high fat diet and again after 2 months of consuming a defined low fat diet. Both studies involved the simultaneous administration of [3H]estradiol [( 3H]E2) orally and [14C]E2 iv and the subsequent collection of multiple blood samples and urine for 96 h. The blood samples were analyzed for radioactivity as estrone (E1), E2, their glucuronides, and E1 sulfate. An aliquot of the pooled 96-h urine was analyzed for radioactivity as the glucuronides and sulfates of E1, E2, estriol, 16 alpha-hydroxyestrone (16 alpha-OHE1), and the catechol estrogens, i.e. 2-hydroxy and 2-methoxy metabolites of E1 and E2. The low fat diet resulted in a consistent and significant (P less than 0.05) decrease in urinary excretion of both 16-hydroxylated metabolites, estriol and 16 alpha-OHE1, expressed as a percentage of administered dose of [3H]E2 and [14C]E2, and an increase in the excretion of the catechol estrogens. These changes in metabolite excretion were not, however, mirrored by changes in the MCRs or conversion ratios of either [3H]E2 or [14C]E2. Thus, while neither the clearance of E2 from the blood nor its absorption from the intestinal tract was altered by a relatively short term decrease in dietary fat, there was a shift in the pattern of urinary metabolites away from the purported carcinogenic estrogen (16 alpha-OHE1) and toward the less active catechol estrogens. This may represent an important mechanism whereby low fat diets decrease the risk of breast cancer.

Is non-insulin-dependent diabetes (NIDDM) a disease of insulin deficiency, a disease of insulin resistance, or both? This problem has confronted diabetologists and researchers for years.

Variation in survival of breast cancer patients has been examined for relationship to three demographic variables known to affect incidence rates—geography, socioeconomic status and age at birth of first child. Three-year relative survival ratios in two areas with high incidence rates (Boston, USA and Glamorgan, Wales) were 75.3% and 66.4%, respectively. In an area with a low incidence rate (Tokyo, Japan) the ratio was 85.6%. The overall survival ratios differed significantly between areas, but the pattern is not such as to suggest a consistent correlation — either positive or negative — with incidence rates. The differences in survival ratios between areas were not explained by differences in the extent of disease at diagnosis. Survival ratios did not vary consistently with socioeconomic status, as measured by duration of schooling. Neither childbearing nor age at which porous patients first became pregnant was related to probability of survival.

The effectiveness of prophylactic ingestion of a commercial preparation of lactobacilli (Lactinex) for the prevention or modification of traveler's diarrhea was tested in a randomized double blind clinical trial in 50 volunteer travelers to Mexico from the United States. Twenty-six subjects received the lactobacilli preparation and 24 received placebo. The incidence of diarrhea and its duration during the 4 weeks of observation were quite similar for the two preparations: 35% for lactobacilli-treated subjects and 29% for placebo subjects. Typically, the diarrhea was mild, lasting 2 days. From the observations during this study we conclude that prophylactic ingestion of lactobacilli for 1 week does not reduce the incidence or duration of traveler's diarrhea either during the period of ingestion or during the following 3 weeks.