Growth recovery lines: a specific indicator of child abuse and neglect?

BACKGROUND: Growth recovery lines are radiodense lines in long bones reported to be indicators of stress. OBJECTIVE: The purpose of this study was to understand the distribution, quantity and associations of growth recovery lines in children ages 0-24 months with high and low risk for child maltreatment. MATERIALS AND METHODS: We conducted a retrospective cohort study of children ages 0-24 months who had skeletal surveys and an assessment for maltreatment. Growth recovery lines, fractures and osteopenia were assessed independently by two pediatric radiologists blinded to the abuse likelihood. RESULTS: Of the 135 children in this study, 58 were in the low-risk group, 26 were in the neglect group, and 51 were in the physical abuse group. Children in the neglected and physically abused groups had 1.73 times (95% confidence interval [CI] of 1.16, 2.59), P=0.007) and 1.84 times (95% CI 1.28, 2.63, P<0.001) more growth recovery lines than the low-risk group, respectively. Growth recovery lines occurred at an earlier age in the neglect group (age interaction P=0.03) and abuse group (age interaction P=0.01) compared to the low-risk group. The specificity for maltreatment in children with at least 10 growth recovery lines in the long bones was greater than 84%, while sensitivity was less than 35%. The most common locations for growth recovery lines were distal radius, proximal tibia and distal tibia. CONCLUSION: In the absence of a known major stressor, physical abuse and neglect should be considered in children younger than 24 months with at least 10 growth recovery lines.

Dynamic macrophage polarization-specific miRNA patterns reveal increased soluble VEGF receptor 1 by miR-125a-5p inhibition.

Dynamic, epigenetic mechanisms can regulate macrophage phenotypes following exposure to different stimulating conditions and environments. However, temporal patterns of microRNAs (miRNAs or miRs) across multiple macrophage polarization phenotypes have not been defined. We determined miRNA expression in bone marrow-derived murine macrophages over multiple time points (0.5, 1, 3, 24 h) following exposure to cytokines and/or LPS. We hypothesized that dynamic changes in miRNAs regulate macrophage phenotypes. Changes in macrophage polarization markers were detected as early as 0.5 and as late as 24 h; however, robust responses for most markers occurred within 3 h. In parallel, many polarization-specific miRNAs were also changed by 3 h and expressed divergent patterns between M1 and M2a conditions, with increased expression in M1 (miR-155, 199a-3p, 214-3p, 455-3p, and 125a) or M2a (miR-511 and 449a). Specifically, miR-125a-5p exhibited divergent patterns: increased at 12-24 h in M1 macrophages and decreasing trend in M2a. VEGF in the culture media of macrophages was dependent upon the polarization state, with greatly diminished VEGF in M2a compared with M1 macrophage culture media despite similar VEGF in cell lysates. Inhibition of miR-125a-5p in media-only controls (MO) and M1 macrophages greatly increased expression and secretion of soluble VEGF receptor-1 (sVEGFR1) leading to diminished VEGF in the culture media, partially converting MO and M1 into an M2a phenotype. Thus, the divergent expression patterns of polarization-specific miRNAs led to the identification and demonstrated the regulation of a specific macrophage polarization phenotype, sVEGFR1 by inhibition of miR-125a-5p.

Pharmacokinetic interaction of rifapentine and raltegravir in healthy volunteers.

OBJECTIVES: Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated the effect of rifapentine on the pharmacokinetic properties of raltegravir. METHODS: In this open-label, fixed-sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1-4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12-15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4-8 and 11-14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11-14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718. RESULTS: In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0-12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0-12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated. CONCLUSIONS: The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV.

Facilitators of and barriers to gastric cancer and precursor diagnosis among South Texas residents: Social determinants of health.

BACKGROUND: Latinos/Hispanics are at higher risk for developing gastric cancer (GC) compared with non-Hispanic whites, and social determinants of health (SDoH) are thought to contribute. AIMS/MATERIALS AND METHODS: This study addressed SDoH and their interactions contributing to disparities in the testing and treatment of Helicobacter pylori (HP) infection and diagnosis of GC and its known precursors, among Latinos/Hispanics relative to non-Latinos at two affiliated but independent health systems in San Antonio, Texas, using a mixed methods approach. RESULTS: Secondary data abstraction and analysis showed that GCs represented 2.6% (n = 600) of our population. Men and older individuals were at higher GC risk. Individuals with military insurance were 2.7 times as likely to be diagnosed as private insurance. Latinos/Hispanics had significantly (24%) higher GC risk than Whites. Poverty and lack of insurance contributed to GC risk among the minorities classified as other (Asians, Native Americans, Multiracial; all p < 0.01). All SDoH were associated with H. pylori infection (p < 0.001). Qualitative analysis of patient and provider interviews showed providers reporting insurance as a major care barrier; patients reported appointment delays, and lack of clinic staff. Providers universally agreed treatment of H. pylori was necessary, but disagreed on its prevalence. Patients did not report discussing H. pylori or its cancer risk with providers. DISCUSSION/CONCLUSION: These data indicate the importance of considering SDoH in diagnosis and treatment of GC and its precursors, and educating providers and patients on H. pylori risks for GC.

Mood disorders in individuals with distal 18q deletions.

We examined 36 participants at least 4 years old with hemizygous distal deletions of the long arm of Chromosome 18 (18q-) for histories of mood disorders and to characterize these disorders clinically. Since each participant had a different region of 18q hemizygosity, our goal was also to identify their common region of hemizygosity associated with mood disorders; thereby identifying candidate causal genes in that region. Lifetime mood and other psychiatric disorders were determined by semi-structured interviews of patients and parents, supplemented by reviews of medical and psychiatric records, and norm-referenced psychological assessment instruments, for psychiatric symptoms, cognitive problems, and adaptive functioning. Sixteen participants were identified with lifetime mood disorders (ages 12-42 years, 71% female, 14 having had unipolar depression and 2 with bipolar disorders). From the group of 20 who did not meet criteria for a mood disorder; a comparison group of 6 participants were identified who were matched for age range and deletion size. Mood-disordered patients had high rates of anxiety (75%) and externalizing behavior disorders (44%), and significant mean differences from comparison patients (P < 0.05), including higher overall and verbal IQs and lower autistic symptoms. A critical region was defined in the mood-disordered group that included a hypothetical gene, C18orf62, and two known genes, ZADH2 and TSHZ1. We conclude that patients having terminal deletions of this critical region of the long arm of Chromosome 18 are highly likely to have mood disorders, which are often comorbid with anxiety and to a lesser extent with externalizing disorders.

MiR-351 transiently increases during muscle regeneration and promotes progenitor cell proliferation and survival upon differentiation.

MicroRNAs (miRNAs) regulate many biological processes including muscle development. However, little is known regarding miRNA regulation of muscle regeneration. Murine tibialis anterior muscle was evaluated after cardiotoxin-induced injury and used for global miRNA expression analysis. From day 1 through day 21 following injury, 298 miRNAs were significantly changed at least at one time point, including 86 miRNAs that were altered >10-fold compared with uninjured skeletal muscle. Temporal miRNA expression patterns included inflammation-related miRNAs (miR-223 and -147) that increased immediately after injury; this pattern contrasted to that of mature muscle-specific miRNAs (miR-1, -133a, and -499) that abruptly decreased following injury followed by upregulation in later regenerative events. Another cluster of miRNAs were transiently increased in the early days of muscle regeneration including miR-351, a miRNA that was also transiently expressed during myogenic progenitor cell (MPC) differentiation in vitro. Based on computational predictions, further studies demonstrated that E2f3 was a target of miR-351 in myoblasts. Moreover, knockdown of miR-351 expression inhibited MPC proliferation and promoted apoptosis during MPC differentiation, whereas miR-351 overexpression protected MPC from apoptosis during differentiation. Collectively, these observations suggest that miR-351 is involved in both the maintenance of MPC proliferation and the transition into differentiated myotubes. Thus, a novel, time-dependent sequence of molecular events during muscle regeneration has been identified; miR-351 inhibits E2f3 expression, a key regulator of cell cycle progression and proliferation, and promotes MPC proliferation and protects early differentiating MPC from apoptosis, important events in the hostile tissue environment after acute muscle injury.

Immunoenrichment microwave and magnetic proteomics for quantifying CD47 in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

We hypothesized that quantitative MS/MS-based proteomics at multiple time points, incorporating immunoenrichment prior to rapid microwave and magnetic (IM(2) ) sample preparation, might enable correlation of the relative expression of CD47 and other low abundance proteins to disease progression in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis. To test our hypothesis, anti-CD47 antibodies were used to enrich for low abundance CD47 prior to microwave and magnetic proteomics in EAE. Decoding protein expression at each time point, with CD47-immunoenriched samples and targeted proteomic analysis, enabled peptides from the low abundance proteins to be precisely quantified throughout disease progression, including: CD47: 86-99, corresponding to the "marker of self" overexpressed by myelin that prevents phagocytosis, or "cellular devouring," by microglia and macrophages; myelin basic protein: 223-228, corresponding to myelin basic protein; and migration inhibitory factor: 79-87, corresponding to a proinflammatory cytokine that inhibits macrophage migration. While validation in a larger cohort is underway, we conclude that IM(2) proteomics is a rapid method to precisely quantify peptides from CD47 and other low abundance proteins throughout disease progression in EAE. This is likely due to improvements in selectivity and sensitivity, necessary to partially overcome masking of low abundance proteins by high abundance proteins and improve dynamic range.

Microwave and magnetic (M(2) ) proteomics of the experimental autoimmune encephalomyelitis animal model of multiple sclerosis.

We hypothesized that quantitative MS/MS-based proteomics at multiple time points, incorporating rapid microwave and magnetic (M(2) ) sample preparation, could enable relative protein expression to be correlated to disease progression in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis. To test our hypothesis, microwave-assisted reduction/alkylation/digestion of proteins from brain tissue lysates bound to C8 magnetic beads and microwave-assisted isobaric chemical labeling were performed of released peptides, in 90 s prior to unbiased proteomic analysis. Disease progression in EAE was assessed by scoring clinical EAE disease severity and confirmed by histopathologic evaluation for central nervous system inflammation. Decoding the expression of 283 top-ranked proteins (p <0.05) at each time point relative to their expression at the peak of disease, from a total of 1191 proteins observed in four technical replicates, revealed a strong statistical correlation to EAE disease score, particularly for the following four proteins that closely mirror disease progression: 14-3-3ε (p = 3.4E-6); GPI (p = 2.1E-5); PLP1 (p = 8.0E-4); PRX1 (p = 1.7E-4). These results were confirmed by Western blotting, signaling pathway analysis, and hierarchical clustering of EAE risk groups. While validation in a larger cohort is underway, we conclude that M(2) proteomics is a rapid method to quantify putative prognostic/predictive protein biomarkers and therapeutic targets of disease progression in the EAE animal model of multiple sclerosis.

Outcome of pulpotomy in permanent teeth with irreversible pulpitis: a systematic review and meta-analysis.

Treatment planning is key to clinical success. Permanent teeth diagnosed with "irreversible pulpitis" have long been implied to have an irreversibly damaged dental pulp that is beyond repair and warranting root canal treatment. However, newer clinical approaches such as pulpotomy, a minimally invasive and biologically based procedure have re-emerged to manage teeth with pulpitis. The primary aim of the study was to conduct a meta-analysis to comprehensively estimate the overall success rate of pulpotomy in permanent teeth with irreversible pulpitis as a result of carious pulp exposure. The secondary aim of the study was to investigate the effect of predictors such as symptoms, root apex development (closed versus open), and type of pulp capping material on the success rate of pulpotomy. Articles were searched using PubMed, Scopus, CENTRAL, and Web of Science databases, until January 2021. Outcomes were calculated by pooling the success rates with a random effect model. Comparison between the different subgroups was conducted using the z statistic test for proportion with significance set at alpha = 0.05. A total of 1,116 records were retrieved and 11 studies were included in the quantitative analysis. The pooled success rate for pulpotomy in teeth with irreversible pulpitis was 86% [95% CI: 0.76-0.92; I2 = 81.9%]. Additionally, prognostic indicators of success were evaluated. Stratification of teeth based on (1) symptoms demonstrated that teeth with symptomatic and asymptomatic irreversible pulpitis demonstrated success rate of 84% and 91% respectively, with no significant difference (p = 0.18) using z-score analysis; (2) open apex teeth demonstrated a significantly greater success rate (96%) compared to teeth with closed apex (83%) (p = 0.02), and (3) pulp capping materials demonstrated that Biodentine yielded significantly better success rates compared to Mineral Trioxide Aggregate (MTA), calcium hydroxide, and Calcium Enriched Mixture (CEM.) Collectively, this is the first meta-analytical study to determine the clinical outcome of pulpotomy for carious teeth with irreversible pulpitis and it's predictors for success. Moreover, we identify the stage of root development and type of biomaterial as predictors for success of pulpotomy.

Children's Afterschool Culinary Education Improves Eating Behaviors.

Objectives: Culinary education may be one way to improve children's eating behaviors. We formatively evaluated the effect of a hands-on afterschool 12-module, registered dietitian-led culinary education program on healthy eating behaviors in a predominately Hispanic/Latino, low-socioeconomic community. Methods: Of 234 children participating in the program, 77% completed both pre- and post-assessment surveys (n = 180; mean age 9.8 years; 63.3% female; 74.3% Hispanic/Latino, 88.4% receiving free/reduced lunch). In addition to program satisfaction, we assessed changes in children's self-reported fruit, vegetable, and whole-grain consumption, knowledge, and culinary skills using binary and continuous mixed effects models. We report false discovery rate adjusted p-values and effect sizes. Results: 95.5% of participants reported liking the program. Improved whole grain consumption had a medium effect size, while effect sizes for whole grain servings and vegetable consumption were small, but significant (all p < 0.05). Culinary skills increased between 15.1 to 43.4 percent points (all p < 0.01), with medium to large effect sizes. Conclusions: The program was well-received by participants. Participants reported improved eating behaviors and culinary skills after program completion. Therefore, this hands-on afterschool culinary education program can help improve healthy eating in a predominantly Hispanic/Latino, low-socioeconomic community.

Candidate gene association analysis of acute lymphoblastic leukemia identifies new susceptibility locus at 11p15 (LMO1).

To determine the contribution of susceptibility loci in explaining the genetic basis of acute lymphoblastic leukemia (ALL), we genotyped 29 high-potential candidate genes with 672 tagged single-nucleotide polymorphisms (SNPs) in a sample (163 cases and 251 healthy controls) of Caucasian children. Fifty SNPs in 15 genes were significantly associated with ALL risk at the P < 0.05 level. After correction for multiple testing, rs442264 within the LIM domain only 1 (LMO1) gene at 11p15 remained significant [odds ratio (OR) = 1.90, P = 3 × 10(-5)]. In addition, a major haplotype within LMO1 comprising 14 SNPs with individual risk associations was found to significantly increase ALL risk (OR = 1.79, P = 0.0006). A stratified analysis on subtype indicated that risk associations of LMO1 variants are significant in children with precursor B-cell leukemia. These data show that genetic variants within LMO1 are associated with ALL and identify this gene as a strong candidate for precursor B-cell leukemogenesis.

Principles for the ethical analysis of clinical and translational research.

Statistical analysis is a cornerstone of the scientific method and evidence-based medicine, and statisticians serve an increasingly important role in clinical and translational research by providing objective evidence concerning the risks and benefits of novel therapeutics. Researchers rely on statistics and informatics as never before to generate and test hypotheses and to discover patterns of disease hidden within overwhelming amounts of data. Too often, clinicians and biomedical scientists are not adequately proficient in statistics to analyze data or interpret results, and statistical expertise may not be properly incorporated within the research process. We argue for the ethical imperative of statistical standards, and we present ten nontechnical principles that form a conceptual framework for the ethical application of statistics in clinical and translational research. These principles are drawn from the literature on the ethics of data analysis and the American Statistical Association Ethical Guidelines for Statistical Practice.

San Antonio Nathan Shock Center: your one-stop shop for aging research.

With evolving cores, enrichment and training programs, and supported research projects, the San Antonio (SA) Nathan Shock Center has for 26 years provided critical support to investigators locally, nationally, and abroad. With its existing and growing intellectual capital, the SA Nathan Shock Center provides to local and external investigators an enhanced platform to conduct horizontally integrated (lifespan, healthspan, pathology, pharmacology) transformative research in the biology of aging, and serves as a springboard for advanced educational and training activities in aging research. The SA Nathan Shock Center consists of six cores: Administrative/Program Enrichment Core, Research Development Core, Aging Animal Models and Longevity Assessment Core, Pathology Core, Analytical Pharmacology and Drug Evaluation Core, and Integrated Physiology of Aging Core. The overarching goal of the SA Nathan Shock Center is to advance knowledge in the basic biology of aging and to identify molecular and cellular mechanisms that will facilitate the development of pharmacologic interventions and other strategies to extend healthy lifespan. In pursuit of this goal, we provide an innovative "one-stop shop" venue to accelerate transformative research in the biology of aging through our integrated research cores. Moreover, we aim to foster and promote career development of early-stage investigators in aging biology through our research development programs, to serve as a resource and partner to investigators from other Shock Centers, and to disseminate scientific knowledge and enhanced awareness about aging research. Overall, the SA Nathan Shock Center aims to be a leader in research that advances our understanding of the biology of aging and development of approaches to improve longevity and healthy aging.

Mobilization-based transplantation of young-donor hematopoietic stem cells extends lifespan in mice.

Mammalian aging is associated with reduced tissue regeneration and loss of physiological integrity. With age, stem cells diminish in their ability to regenerate adult tissues, likely contributing to age-related morbidity. Thus, we replaced aged hematopoietic stem cells (HSCs) with young-donor HSCs using a novel mobilization-enabled hematopoietic stem cell transplantation (HSCT) technology as an alternative to the highly toxic conditioning regimens used in conventional HSCT. Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (HR: 0.42, CI: 0.273-0.638) in aged mice following transplantation of young-donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young-donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti-aging/life-extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.

Association of chromosome 8q variants with prostate cancer risk in Caucasian and Hispanic men.

Genotyping of a 615 kb region within 8q24 with 49 haplotype-tagged single-nucleotide polymorphisms (SNPs) in 2109 samples (797 cases and 1312 controls) of two ethnic/racial groups found SNPs that are significantly associated with the risk for prostate cancer (PCa). The highest significance in Caucasian men was found for rs6983267; the AA genotype reduced the risk for PCa [odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.35-0.65, P = 2.74 x 10(-6)]. This SNP also had a significant independent effect from other SNPs in the region in this group. In Hispanic men, rs7837328 and rs921146 showed independent effects (OR = 2.55, 95% CI = 1.51-4.31, P = 4.33 x 10(-4), OR = 2.09, 95% CI = 1.40-3.12, P = 3.13 x 10(-4), respectively). Significant synergist effects for increasing numbers of high-risk alleles were found in both ethnicities. Haplotype analysis revealed major haplotypes, containing the non-risk alleles, conferred protection against PCa. We found high linkage disequilibrium between significant SNPs within the region and SNPs within the CUB and Sushi Multiple Domains 1 gene (CSMD1), on the short arm of chromosome 8 in both ethnicities. These data suggest that multiple interacting SNPs within 8q24, as well as different regions on chromosome 8 far beyond this 8q24 candidate region, may confer increased risk of PCa. This is the first report to investigate the involvement of 8q24 variants in the susceptibility for PCa in Hispanic men.

Reproducibility of quantitative RT-PCR array in miRNA expression profiling and comparison with microarray analysis.

BACKGROUND: MicroRNAs (miRNAs) have critical functions in various biological processes. MiRNA profiling is an important tool for the identification of differentially expressed miRNAs in normal cellular and disease processes. A technical challenge remains for high-throughput miRNA expression analysis as the number of miRNAs continues to increase with in silico prediction and experimental verification. Our study critically evaluated the performance of a novel miRNA expression profiling approach, quantitative RT-PCR array (qPCR-array), compared to miRNA detection with oligonucleotide microchip (microarray). RESULTS: High reproducibility with qPCR-array was demonstrated by comparing replicate results from the same RNA sample. Pre-amplification of the miRNA cDNA improved sensitivity of the qPCR-array and increased the number of detectable miRNAs. Furthermore, the relative expression levels of miRNAs were maintained after pre-amplification. When the performance of qPCR-array and microarrays were compared using different aliquots of the same RNA, a low correlation between the two methods (r=-0.443) indicated considerable variability between the two assay platforms. Higher variation between replicates was observed in miRNAs with low expression in both assays. Finally, a higher false positive rate of differential miRNA expression was observed using the microarray compared to the qPCR-array. CONCLUSION: Our studies demonstrated high reproducibility of TaqMan qPCR-array. Comparison between different reverse transcription reactions and qPCR-arrays performed on different days indicated that reverse transcription reactions did not introduce significant variation in the results. The use of cDNA pre-amplification increased the sensitivity of miRNA detection. Although there was variability associated with pre-amplification in low abundance miRNAs, the latter did not involve any systemic bias in the estimation of miRNA expression. Comparison between microarray and qPCR-array indicated superior sensitivity and specificity of qPCR-array.

A Bayesian hidden Markov model for motif discovery through joint modeling of genomic sequence and ChIP-chip data.

We propose a unified framework for the analysis of chromatin (Ch) immunoprecipitation (IP) microarray (ChIP-chip) data for detecting transcription factor binding sites (TFBSs) or motifs. ChIP-chip assays are used to focus the genome-wide search for TFBSs by isolating a sample of DNA fragments with TFBSs and applying this sample to a microarray with probes corresponding to tiled segments across the genome. Present analytical methods use a two-step approach: (i) analyze array data to estimate IP-enrichment peaks then (ii) analyze the corresponding sequences independently of intensity information. The proposed model integrates peak finding and motif discovery through a unified Bayesian hidden Markov model (HMM) framework that accommodates the inherent uncertainty in both measurements. A Markov chain Monte Carlo algorithm is formulated for parameter estimation, adapting recursive techniques used for HMMs. In simulations and applications to a yeast RAP1 dataset, the proposed method has favorable TFBS discovery performance compared to currently available two-stage procedures in terms of both sensitivity and specificity.

Genetically heterogeneous mice exhibit a female survival advantage that is age- and site-specific: Results from a large multi-site study.

The female survival advantage is a robust characteristic of human longevity. However, underlying mechanisms are not understood, and rodent models exhibiting a female advantage are lacking. Here, we report that the genetically heterogeneous (UM-HET3) mice used by the National Institute on Aging Interventions Testing Program (ITP) are such a model. Analysis of age-specific survival of 3,690 control ITP mice revealed a female survival advantage paralleling that of humans. As in humans, the female advantage in mice was greatest in early adulthood, peaking around 350 days of age and diminishing progressively thereafter. This persistent finding was observed at three geographically distinct sites and in six separate cohorts over a 10-year period. Because males weigh more than females and bodyweight is often inversely related to lifespan, we examined sex differences in the relationship between bodyweight and survival. Although present in both sexes, the inverse relationship between bodyweight and longevity was much stronger in males, indicating that male mortality is more influenced by bodyweight than is female mortality. In addition, male survival varied more across site and cohort than female survival, suggesting greater resistance of females to environmental modulators of survival. Notably, at 24 months the relationship between bodyweight and longevity shifted from negative to positive in both sexes, similar to the human condition in advanced age. These results indicate that the UM-HET3 mouse models the human female survival advantage and provide evidence for greater resilience of females to modulators of survival.

Acarbose improves health and lifespan in aging HET3 mice.

To follow-up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log-rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%-11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2-(2-hydroxyphenyl) benzothiazole (HBX), and INT-767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose-control drugs in humans.

CYP1B1 variants are associated with prostate cancer in non-Hispanic and Hispanic Caucasians.

Cytochrome P450 1B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones. We compared allele, genotype and haplotype frequencies of six single-nucleotide polymorphisms (SNPs) within CYP1B1 among non-Hispanic Caucasians (496 cases and 498 controls) and Hispanic Caucasians (153 cases and 240 controls). In the Hispanic Caucasians, the GG genotype for rs1056836 decreased the risk for prostate cancer (PCa) when compared with the CC genotype [odds ratio (OR) = 0.31, P = 0.04, 95% confidence interval (CI) = 0.10-0.96]. Among non-Hispanic Caucasian men with more aggressive PCa, the prevalence of several SNPs (rs2567206, rs2551188, rs2617266, rs10012 and rs1056836) was significantly associated with the disease status. A common C-G-C-C-G-A haplotype for rs2567206-rs2551188-rs2617266-rs10012-rs1056836-rs1800440 showed an inverse association with PCa risk in Hispanic Caucasians (OR = 0.19, P = 0.04, 95% CI = 0.04-0.95) and with aggressive disease status (i.e. Gleason score >or=7) in non-Hispanic Caucasian cases (OR = 0.64, P = 0.008, 95% CI = 0.47-0.89). In the non-Hispanic Caucasian cases, a second major haplotype T-A-T-G-C-A was positively associated with the high-grade disease status (OR = 1.77, P = 0.002, 95% CI = 1.24-2.53). Our findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for PCa and support the role of CYP1B1 as a candidate gene for PCa.