Lead, Diabetes, Hypertension, and Renal Function: The Normative Aging Study

In this prospective study, we examined changes in renal function during 6 years of follow-up in relation to baseline lead levels, diabetes, and hypertension among 448 middle-age and elderly men, a subsample of the Normative Aging Study. Lead levels were generally low at baseline, with mean blood lead, patella lead, and tibia lead values of 6.5 μg/dL, 32.4 μg/g, and 21.5 μg/g, respectively. Six percent and 26% of subjects had diabetes and hypertension at baseline, respectively. In multivariate-adjusted regression analyses, longitudinal increases in serum creatinine (SCr) were associated with higher baseline lead levels but these associations were not statistically significant. However, we observed significant interactions of blood lead and tibia lead with diabetes in predicting annual change in SCr. For example, increasing the tibia lead level from the midpoints of the lowest to the highest quartiles (9–34 μg/g) was associated with an increase in the rate of rise in SCr that was 17.6-fold greater in diabetics than in nondiabetics (1.08 mg/dL/10 years vs. 0.062 mg/dL/10 years; p < 0.01). We also observed significant interactions of blood lead and tibia lead with diabetes in relation to baseline SCr levels (tibia lead only) and follow-up SCr levels. A significant interaction of tibia lead with hypertensive status in predicting annual change in SCr was also observed. We conclude that longitudinal decline of renal function among middle-age and elderly individuals appears to depend on both long-term lead stores and circulating lead, with an effect that is most pronounced among diabetics and hypertensives, subjects who likely represent particularly susceptible groups

Determinants of Bone and Blood Lead Levels among Minorities Living in the Boston Area

We measured blood and bone lead levels among minority individuals who live in some of Boston’s neighborhoods with high minority representation. Compared with samples of predominantly white subjects we had studied before, the 84 volunteers in this study (33:67 male:female ratio; 31–72 years of age) had similar educational, occupational, and smoking profiles and mean blood, tibia, and patella lead levels (3 μg/dL, 11.9 μg/g, and 14.2 μg/g, respectively) that were also similar. The slopes of the univariate regressions of blood, tibia, and patella lead versus age were 0.10 μg/dL/year (p < 0.001), 0.45 μg/g/year (p < 0.001), and 0.73 μg/g/year (p < 0.001), respectively. Analyses of smoothing curves and regression lines for tibia and patella lead suggested an inflection point at 55 years of age, with slopes for subjects ≥ 55 years of age that were not only steeper than those of younger subjects but also substantially steeper than those observed for individuals > 55 years of age in studies of predominantly white participants. This apparent racial disparity at older ages may be related to differences in historic occupational and/or environmental exposures, or possibly the lower rates of bone turnover that are known to occur in postmenopausal black women. The higher levels of lead accumulation seen in this age group are of concern because such levels have been shown in other studies to predict elevated risks of chronic disease such as hypertension and cognitive dysfunction. Additional research on bone lead levels in minorities and their socioeconomic and racial determinants is needed

Identification of a Novel Gene for Diabetic Traits in Rats, Mice, and Humans

The genetic basis of type 2 diabetes remains incompletely defined despite the use of multiple genetic strategies. Multiparental populations such as heterogeneous stocks (HS) facilitate gene discovery by allowing fine mapping to only a few megabases, significantly decreasing the number of potential candidate genes compared to traditional mapping strategies. In the present work, we employed expression and sequence analysis in HS rats (Rattus norvegicus) to identify Tpcn2 as a likely causal gene underlying a 3.1-Mb locus for glucose and insulin levels. Global gene expression analysis on liver identified Tpcn2 as the only gene in the region that is differentially expressed between HS rats with glucose intolerance and those with normal glucose regulation. Tpcn2 also maps as a cis-regulating expression QTL and is negatively correlated with fasting glucose levels. We used founder sequence to identify variants within this region and assessed association between 18 variants and diabetic traits by conducting a mixed-model analysis, accounting for the complex family structure of the HS. We found that two variants were significantly associated with fasting glucose levels, including a nonsynonymous coding variant within Tpcn2. Studies in Tpcn2 knockout mice demonstrated a significant decrease in fasting glucose levels and insulin response to a glucose challenge relative to those in wild-type mice. Finally, we identified variants within Tpcn2 that are associated with fasting insulin in humans. These studies indicate that Tpcn2 is a likely causal gene that may play a role in human diabetes and demonstrate the utility of multiparental populations for positionally cloning genes within complex loci

Needle Biopsy Accelerates Pro-metastatic Changes and Systemic Dissemination in Breast Cancer: Implications for Mortality by Surgery Delay

ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE2/EP2 feedforward loop, which favors M2 polarization and its associated pro-metastatic changes but are abrogated by oral treatment with COX-2 or EP2 inhibitors in estrogen-receptor-positive (ER+) syngeneic mouse tumor models. Therefore, we conclude that needle biopsy of ER+ BC provokes progressive pro-metastatic changes, which may explain the mortality risk posed by surgery delay after diagnosis

Mirc11 Disrupts Inflammatory but Not Cytotoxic Responses of NK Cells

Natural killer (NK) cells generate proinflammatory cytokines that are required to contain infections and tumor growth. However, the posttranscriptional mechanisms that regulate NK cell functions are not fully understood. Here, we define the role of the microRNA cluster known as Mirc11 (which includes miRNA-23a, miRNA-24a, and miRNA-27a) in NK cell–mediated proinflammatory responses. Absence of Mirc11 did not alter the development or the antitumor cytotoxicity of NK cells. However, loss of Mirc11 reduced generation of proinflammatory factors in vitro and interferon-γ–dependent clearance of Listeria monocytogenes or B16F10 melanoma in vivo by NK cells. These functional changes resulted from Mirc11 silencing ubiquitin modifiers A20, Cbl-b, and Itch, allowing TRAF6-dependent activation of NF-κB and AP-1. Lack of Mirc11 caused increased translation of A20, Cbl-b, and Itch proteins, resulting in deubiquitylation of scaffolding K63 and addition of degradative K48 moieties on TRAF6. Collectively, our results describe a function of Mirc11 that regulates generation of proinflammatory cytokines from effector lymphocytes

Racial and Ethnic Disparities in Maternal and Neonatal Outcomes among Women with Chronic Hypertension

Objective The objective of this study was to compare maternal and neonatal outcomes in women with chronic hypertension by maternal race and ethnicity. Methods A retrospective cohort study of women with chronic hypertension was performed from the Consortium on Safe Labor (2002–2008). Maternal self-reported race and ethnicity were analyzed as non-Hispanic White, non-Hispanic Black, and Hispanic. Maternal outcomes included cesarean birth, postpartum hemorrhage, blood transfusion, placental abruption, eclampsia, maternal intensive care unit admission, and death. Neonatal outcomes included preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), 5-minute Apgar &lt;7, respiratory distress syndrome, hypoxic-ischemic encephalopathy, intraventricular hemorrhage, neonatal intensive care unit admission, sepsis, and death. Univariable and multivariable analyses were performed to examine the association between maternal race and ethnicity and perinatal outcomes. Results A total of 2,729 women were included. In unadjusted analysis, non-Hispanic White women had higher rates of placental abruption and Hispanic women had higher rates of placental abruption and eclampsia. In multivariable analysis, non-Hispanic Black continued to have higher odds of placental abruption (adjusted odds ratio 4.16, 95% confidence interval 1.29–18.70), but the rest of the maternal outcomes did not differ between the groups. When comparing neonatal outcomes, PTB, SGA, and LBW were more frequent in, 5-minute Apgar &lt;7 non-Hispanic Black and Hispanic women compared with non-Hispanic White women. In addition, 5-minute Apgar &lt;7 and neonatal sepsis were more frequent in non-Hispanic Black neonates and neonatal death was more frequent in Hispanic neonates compared with non-Hispanic White women. In multivariable regression, neonates of non-Hispanic Black women had higher odds of PTB, SGA, LBW, 5-minute Apgar &lt; 7, and sepsis compared with non-Hispanic White women. Similarly, neonates of Hispanic women had higher odds of SGA, LBW, and death. Conclusion Significant racial and ethnic disparities were identified mainly in neonatal outcomes of women with chronic hypertension. Key Points </jats:p

Modeling Anemia of Aging in Inbred Mouse Strains

Abstract Anemia of aging is now recognized as a significant medical problem. The National Health and Nutrition Examination Survey (NHANES III) revealed a steady increase in anemia in both males and females after the age of 50. Based upon the WHO definition of anemia (&lt;13 g/dL hemoglobin (Hgb) in men; &lt;12 g/dL in women), ~10% of the community dwelling population ≥ 65 years of age are anemic. Underlying causes fall into three broad groups, each representing ~1/3 of cases: nutritional deficits/blood loss; inflammation, kidney disease and myelodysplasia; and unexplained anemia. Although anemia of aging is usually mild, it is no longer considered a normal part of aging. It is associated with poor health and increased vulnerability to adverse outcomes in a multitude of circumstances, placing an enormous burden on the healthcare system that will only grow as the population continues to age. As part of The Jackson Laboratory Aging Center (http://agingmice.jax.org/), we are performing an extensive phenotypic analysis of multiple traits related to aging in 32 inbred mouse strains. All data are, or will be upon completion, publicly available via the Mouse Phenome Database (MPD, www.jax.org/phenome). Complete blood counts were obtained at 6, 12, 18, and 24 months of age in 30 strains. Two-way ANOVA reveals that both strain and age significantly impact Hgb in mice. A highly significant strain-by-age interaction is also seen. Substantial inter-strain and within strain sex variability in the decline in Hgb levels with age is seen among the strains analyzed, suggesting genetic influences. Significant declines in Hgb levels in females at 18 and/or 24 months vs. 6 months occurred in 21 of the 30 strains and, in males, 17 strains. Haplotype association mapping (HAM) using a dense SNP panel identified multiple distinct, age-related loci influencing Hgb levels. For example, a locus on chromosome (Chr) 13 significantly associated with Hgb levels at 12 months of age in males was not detected even at the suggestive level at 18 months of age where two new highly significant loci emerged (Chrs 14, 17). Only two strains show a statistically significant increase in percent circulating reticulocytes with age, indicative of a proliferative anemia. Failure of a significant reticulocyte response in all other strains suggests that an age-related compromise in bone marrow function (hematopoiesis-restricted anemia) predominates in aged, anemic mice. The ratio of urinary albumin to creatinine (ACR) is commonly used as an indicator of kidney damage in mice. In females, the ACR is stable and does not rise significantly with age in the majority of strains, suggesting that declining kidney function is not a major cause of anemia of aging in female inbred mice. Significant increases in IL-6 and TNFα are seen in strains 129SvImJ, C3H/HeJ, and DBA/2J, suggesting a pro-inflammatory state. From this preliminary analysis of a large ongoing project, we can conclude: Hgb levels in mice vary significantly by strain and sex, and decline significantly with age in many strains. Other baseline hematological traits (e.g., red blood cell counts, platelet counts) likewise vary by strain, age and sex. These data are available via the Mouse Phenome Database (project Peters4). The anemia of aging seen in most strains correlates most closely with restricted hematopoiesis, as indicated by the failure of the reticulocyte count to increase in response to declining Hgb levels. There is growing evidence that decrements in hematopoietic stem cell number and function play a role in the aging process in humans. Notably, hematopoietic stem cell numbers and bone marrow cellularity data will be available on the MPD as these analyses are completed. HAM analysis suggests that distinct age-related loci influence Hgb levels in mice. In a small subset of strains, anemia of aging may reflect declining kidney function, as occurs in humans. Preliminary data suggests an increase in cytokine levels in some strains, again mimicking the aging human population. Increased IL-6 levels as a cause of anemia of aging is of particular interest due to its inhibition of hepcidin and thus iron availability. Overall, the data indicate that anemia of aging occurs in mice and models that seen in elderly human populations. Additional data including iron levels, T4, BUN, and more on aging inbred mouse strains will be posted to the MPD in the near future.</jats:p