Muscle Torque-Velocity Relationships and Fatigue With Reduced Knee Joint Range of Motion in Young and Older Adults.

The purpose of this study was to evaluate the influence of knee joint range of motion (RoM) on the torque-velocity relationship and fatigue in the knee extensor muscles of 7 young (median = 26 y) and 7 older (68 y) adults. Each leg was assigned a RoM (35° or 75°) over which to perform a torque-velocity protocol (maximal isokinetic contractions, 60-300°·s-1) and a fatigue protocol (120 maximal contractions at 120°·s-1, 0.5 Hz). Six older participants were unable to reach 300°·s-1 over 35°. Therefore, the velocity eliciting 75% of peak torque at 60°·s-1 (V75, °·s-1) was calculated for each RoM from a fit of individual torque-velocity curves (60-240°·s-1), and ΔV75 (35°-75°) was determined. Fatigue (final torque/initial torque) was used to calculate Δfatigue (35°-75°). ΔV75 was not different from 0 in young (-28.3°·s-1 [-158.6 to 55.7], median [range], P = .091) or older (-18.5°·s-1 [-95.0 to 23.9], P = .128), with no difference by age (P = .710). In contrast, fatigue was greater for 75° in young (Δfatigue = 25.9% [17.5-30.3], P = .018) and older (17.2% [11.9-52.9], P = .018), with no effect of age (P = .710). These data indicate that, regardless of age, RoM did not alter the torque-velocity relationship between 60 and 240°·s-1, and fatigue was greater with a larger RoM.

Inter-Individual Variation in Response to Estrogen in Human Breast Explants.

Exposure to estrogen is strongly associated with increased breast cancer risk. While all women are exposed to estrogen, only 12% are expected to develop breast cancer during their lifetime. These women may be more sensitive to estrogen, as rodent models have demonstrated variability in estrogen sensitivity. Our objective was to determine individual variation in expression of estrogen receptor (ER) and estrogen-induced responses in the normal human breast. Human breast tissue from female donors undergoing reduction mammoplasty surgery were collected for microarray analysis of ER expression. To examine estrogen-induced responses, breast tissue from 23 female donors were cultured ex- vivo in basal or 10 nM 17ß-estradiol (E2) media for 4 days. Expression of ER genes (ESR1 and ESR2) increased significantly with age. E2 induced consistent increases in global gene transcription, but expression of target genes AREG, PGR, and TGFß2 increased significantly only in explants from nulliparous women. E2-treatment did not induce consistent changes in proliferation or radiation induced apoptosis. Responses to estrogen are highly variable among women and not associated with levels of ER expression, suggesting differences in intracellular signaling among individuals. The differences in sensitivity to E2-stimulated responses may contribute to variation in risk of breast cancer.

High-resolution analysis of differential gene expression during skeletal muscle atrophy and programmed cell death.

Skeletal muscles can undergo atrophy and/or programmed cell death (PCD) during development or in response to a wide range of insults, including immobility, cachexia, and spinal cord injury. However, the protracted nature of atrophy and the presence of multiple cell types within the tissue complicate molecular analyses. One model that does not suffer from these limitations is the intersegmental muscle (ISM) of the tobacco hawkmoth Manduca sexta. Three days before the adult eclosion (emergence) at the end of metamorphosis, the ISMs initiate a nonpathological program of atrophy that results in a 40% loss of mass. The ISMs then generate the eclosion behavior and initiate a nonapoptotic PCD during the next 30 h. We have performed a comprehensive transcriptomics analysis of all mRNAs and microRNAs throughout ISM development to better understand the molecular mechanisms that mediate atrophy and death. Atrophy involves enhanced protein catabolism and reduced expression of the genes involved in respiration, adhesion, and the contractile apparatus. In contrast, PCD involves the induction of numerous proteases, DNA methylases, membrane transporters, ribosomes, and anaerobic metabolism. These changes in gene expression are largely repressed when insects are injected with the insect steroid hormone 20-hydroxyecdysone, which delays death. The expression of the death-associated proteins may be greatly enhanced by reductions in specific microRNAs that function to repress translation. This study not only provides fundamental new insights into basic developmental processes, it may also represent a powerful resource for identifying potential diagnostic markers and molecular targets for therapeutic intervention.

Predictors of urinary phthalate biomarker concentrations in postmenopausal women.

BACKGROUND: Phthalates are ubiquitous endocrine disrupting chemicals present in a wide variety of consumer products. However, the personal characteristics associated with phthalate exposure are unclear. OBJECTIVES: We sought to describe personal, behavioral, and reproductive characteristics associated with phthalate metabolite concentrations in an ongoing study nested within the Women's Health Initiative (WHI). MATERIALS AND METHODS: We measured thirteen phthalate metabolites in two or three archived urine samples collected in 1993-2001 from each of 1257 WHI participants (2991 observations). We fit multivariable generalized estimating equation models to predict urinary biomarker concentrations from personal, behavioral, and reproductive characteristics. RESULTS: Older age was predictive of lower concentrations of monobenzyl phthalate (MBzP), mono-carboxyoctyl phthalate (MCOP), mono-3-carboxypropyl phthalate (MCPP), and the sum of di-n-butyl phthalate metabolites (ΣDBP). Phthalate metabolite concentrations varied by race/region, with generally higher concentrations observed among non-Whites and women from the West region. Higher neighborhood socioeconomic status predicted lower MBzP concentrations, and higher education predicted lower monoethyl phthalate (MEP) and higher concentrations of the sum of metabolites of di-isobutyl phthalate (ΣDiBP). Overweight/obesity predicted higher MBzP, MCOP, monocarboxynonyl phthalate (MCNP), MCPP, and the sum of metabolites of di(2-ethylhexyl) phthalate (ΣDEHP) and lower MEP concentrations. Alcohol consumption predicted higher concentrations of MEP and ΣDBP, while current smokers had higher ΣDBP concentrations. Better diet quality as assessed by Healthy Eating Index 2005 scores predicted lower concentrations of MBzP, ΣDiBP, and ΣDEHP. CONCLUSION: Factors predictive of lower biomarker concentrations included increased age and healthy behaviors (e.g. lower alcohol intake, lower body mass index, not smoking, higher quality diet, and moderate physical activity). Racial group (generally higher among non-Whites) and geographic regions (generally higher in Northeast and West compared to South regions) also were predictive of phthalate biomarker concentrations.

Urinary concentrations of phthalate biomarkers and weight change among postmenopausal women: a prospective cohort study.

BACKGROUND: Some phthalates are endocrine disrupting chemicals used as plasticizers in consumer products, and have been associated with obesity in cross-sectional studies, yet prospective evaluations of weight change are lacking. Our objective was to evaluate associations between phthalate biomarker concentrations and weight and weight change among postmenopausal women. METHODS: We performed cross-sectional (N = 997) and longitudinal analyses (N = 660) among postmenopausal Women's Health Initiative participants. We measured 13 phthalate metabolites and creatinine in spot urine samples provided at baseline. Participants' weight and height measured at in-person clinic visits at baseline, year 3, and year 6 were used to calculate body mass index (BMI). We fit multivariable multinomial logistic regression models to explore cross-sectional associations between each phthalate biomarker and baseline BMI category. We evaluated longitudinal associations between each biomarker and weight change using mixed effects linear regression models. RESULTS: In cross-sectional analyses, urinary concentrations of some biomarkers were positively associated with obesity prevalence (e.g. sum of di (2-ethylhexyl) phthalate metabolites [ΣDEHP] 4th vs 1st quartile OR = 3.29, 95% CI 1.80-6.03 [p trend< 0.001] vs normal). In longitudinal analyses, positive trends with weight gain between baseline and year 3 were observed for mono-(2-ethyl-5-oxohexyl) phthalate, monoethyl phthalate (MEP), mono-hydroxybutyl phthalate, and mono-hydroxyisobutyl phthalate (e.g. + 2.32 kg [95% CI 0.93-3.72] for 4th vs 1st quartile of MEP; p trend < 0.001). No statistically significant associations were observed between biomarkers and weight gain over 6 years. CONCLUSIONS: Certain phthalates may contribute to short-term weight gain among postmenopausal women.

Protein intake and the risk of premenstrual syndrome.

OBJECTIVE: To examine the relationship between protein intake and the risk of incident premenstrual syndrome (PMS). DESIGN: Nested case-control study. FFQ were completed every 4 years during follow-up. Our main analysis assessed protein intake 2-4 years before PMS diagnosis (for cases) or reference year (for controls). Baseline (1991) protein intake was also assessed. SETTING: Nurses' Health Study II (NHS2), a large prospective cohort study of registered female nurses in the USA.ParticipantsParticipants were premenopausal women between the ages of 27 and 44 years (mean: 34 years), without diagnosis of PMS at baseline, without a history of cancer, endometriosis, infertility, irregular menstrual cycles or hysterectomy. Incident cases of PMS (n 1234) were identified by self-reported diagnosis during 14 years of follow-up and validated by questionnaire. Controls (n 2426) were women who did not report a diagnosis of PMS during follow-up and confirmed experiencing minimal premenstrual symptoms. RESULTS: In logistic regression models adjusting for smoking, BMI, B-vitamins and other factors, total protein intake was not associated with PMS development. For example, the OR for women with the highest intake of total protein 2-4 years before their reference year (median: 103·6 g/d) v. those with the lowest (median: 66·6 g/d) was 0·94 (95 % CI 0·70, 1·27). Additionally, intakes of specific protein sources and amino acids were not associated with PMS. Furthermore, results substituting carbohydrates and fats for protein were also null. CONCLUSIONS: Overall, protein consumption was not associated with risk of developing PMS.

Intake of dietary fat and fat subtypes and risk of premenstrual syndrome in the Nurses' Health Study II.

Approximately 8-20 % of reproductive-aged women experience premenstrual syndrome (PMS), substantially impacting quality of life. Women with PMS are encouraged to reduce fat intake to alleviate symptoms; however, its role in PMS development is unclear. We evaluated the association between dietary fat intake and PMS development among a subset of the prospective Nurses' Health Study II cohort. We compared 1257 women reporting clinician-diagnosed PMS, confirmed by premenstrual symptom questionnaire and 2463 matched controls with no or minimal premenstrual symptoms. Intakes of total fat, subtypes and fatty acids were assessed via FFQ. After adjustment for age, BMI, smoking, Ca and other factors, intakes of total fat, MUFA, PUFA and trans-fat measured 2-4 years before were not associated with PMS. High SFA intake was associated with lower PMS risk (relative risk (RR) quintile 5 (median=28·1 g/d) v. quintile 1 (median=15·1 g/d)=0·75; 95 % CI 0·58, 0·98; P trend=0·07). This association was largely attributable to stearic acid intake, with women in the highest quintile (median=7·4 g/d) having a RR of 0·75 v. those with the lowest intake (median=3·7 g/d) (95 % CI 0·57, 0·97; P trend=0·03). Individual PUFA and MUFA, including n-3 fatty acids, were not associated with risk. Overall, fat intake was not associated with higher PMS risk. High intake of stearic acid may be associated with a lower risk of developing PMS. Additional prospective research is needed to confirm this finding.

The myonuclear domain is not maintained in skeletal muscle during either atrophy or programmed cell death.

Skeletal muscle mass can increase during hypertrophy or decline dramatically in response to normal or pathological signals that trigger atrophy. Many reports have documented that the number of nuclei within these cells is also plastic. It has been proposed that a yet-to-be-defined regulatory mechanism functions to maintain a relatively stable relationship between the cytoplasmic volume and nuclear number within the cell, a phenomenon known as the "myonuclear domain" hypothesis. While it is accepted that hypertrophy is typically associated with the addition of new nuclei to the muscle fiber from stem cells such as satellite cells, the loss of myonuclei during atrophy has been controversial. The intersegmental muscles from the tobacco hawkmoth Manduca sexta are composed of giant syncytial cells that undergo sequential developmental programs of atrophy and programmed cell death at the end of metamorphosis. Since the intersegmental muscles lack satellite cells or regenerative capacity, the tissue is not "contaminated" by these nonmuscle nuclei. Consequently, we monitored muscle mass, cross-sectional area, nuclear number, and cellular DNA content during atrophy and the early phases of cell death. Despite a ∼75-80% decline in muscle mass and cross-sectional area during the period under investigation, there were no reductions in nuclear number or DNA content, and the myonuclear domain was reduced by ∼85%. These data suggest that the myonuclear domain is not an intrinsic property of skeletal muscle and that nuclei persist through atrophy and programmed cell death.

Intake of selected minerals and risk of premenstrual syndrome.

Iron, potassium, zinc, and other minerals might impact the development of premenstrual syndrome (PMS) through multiple mechanisms, but few studies have evaluated these relations. We conducted a case-control study nested within the prospective Nurses' Health Study II (1991-2001). Participants were free from PMS at baseline. After 10 years, 1,057 women were confirmed as PMS cases and 1,968 as controls. Mineral intake was assessed using food frequency questionnaires completed in 1991, 1995, and 1999. After adjustment for calcium intake and other factors, women in the highest quintile of nonheme iron intake had a relative risk of PMS of 0.64 (95% confidence interval (CI): 0.44, 0.92; P for trend = 0.04) compared with women in the lowest quintile. Women in the highest quintile of potassium intake had a relative risk of 1.46 (95% CI: 0.99, 2.15; P for trend = 0.04) compared with women in the lowest quintile. High intake of zinc from supplements was marginally associated with PMS (for intake of ≥25 mg/day vs. none, relative risk = 0.69, 95% CI: 0.46, 1.02; P for trend = 0.05). Intakes of sodium, magnesium, and manganese were unrelated to PMS risk. These findings suggest that dietary minerals may be useful in preventing PMS. Additional studies are needed to confirm these relations.

Association of comorbidities with home care service utilization of patients with heart failure while receiving telehealth.

BACKGROUND: Comorbidities adversely impact heart failure (HF) outcomes. Telehealth can assist healthcare providers, especially nurses, in guiding their patients to follow the HF regimen. However, factors, including comorbidity patterns, that act in combination with telehealth to reduce home care nursing utilization are still unclear. PURPOSE: The purpose of this article was to examine the association of the comorbidity characteristics of HF patients with nursing utilization along with withdrawal from telehealth service during an episode of tele-home care. METHODOLOGY: A descriptive, correlational study design using retrospective chart review was used. The sample comprised Medicare patients admitted to a New England home care agency who had HF as a diagnosis and had used telehealth from 2008 to 2010. The electronic documentation at the home care agency served as the data source, which included Outcome and Assessment Information Set data of patients with HF. Logistic and multiple regression analyses were used to analyze data. RESULTS: The sample consisted of 403 participants, of whom 70% were older than 75 years, 55% were female, and 94% were white. Comorbidities averaged 5.19 (SD, 1.92), ranging from 1 to 11, and nearly 40% of the participants had 5 or more comorbidities. The mean (SD) nursing contacts in the sample was 9.9 (4.7), ranging from 1 to 26, and 52 (12.7%) patients withdrew from telehealth service. For patients with HF on telehealth, comorbidity characteristics of anemia, anxiety, musculoskeletal, and depression were significantly associated with nursing utilization patterns, and renal failure, cancer, and depression comorbidities were significantly associated with withdrawal from telehealth service. CLINICAL IMPLICATIONS: Knowledge of the association of comorbidity characteristics with the home care service utilization patterns of patients with HF on telehealth can assist the home health nurse to develop a tailored care plan that attains optimal patient outcomes. Knowledge of such associations would also focus home care resources, avoiding redundancy of resource utilization in this era of strained healthcare resources.

Defining soldier equipment trade space: load effects on combat marksmanship and perception-action coupling.

Soldier equipment compromises task performance as temporal constraints during critical situations and load increase inertial and interactive forces during movement. Methods are necessary to optimise equipment that relate task performance to underlying coordination and perception-action coupling. Employing ecological task analysis and methods from dynamical systems theory, equipment load and coordination was examined during two sub-tasks embedded in combat performance, threat discrimination and dynamic marksmanship. Perception-action coupling was degraded with load during threat discrimination, leading to delays in functional reaction time. Reduced speed and accuracy during dynamic marksmanship under load was related to disrupted segmental coordination and adaptability during postural transitions between targets. These results show how reduced performance under load relates to coordination changes and perception-action coupling. These changes in functional capability are directly related to soldier survivability in combat. The methods employed may aid equipment design towards more optimised performance by modifying equipment or its distribution on humans.

The novel lupus antigen related protein acheron enhances the development of human breast cancer.

Acheron (Achn) is a new member of the Lupus antigen family of RNA binding proteins. Previous studies have shown that Achn controls developmental decisions in neurons and muscle. In the human mammary gland, Achn expression is restricted to ductal myoepithelial cells. Microarray analysis and immunohistochemistry have shown that Achn expression is elevated in some basal-like ductal carcinomas. To study the possible role of Achn in breast cancer, we engineered human MDA-MB-231 cells to stably express enhanced green fluorescent protein-tagged wild-type Achn (AchnWT), as well as Achn lacking either its nuclear localization signal (AchnNLS) or its nuclear export signal (AchnNES). In in vitro assays, AchnWT and AchnNES, but not AchnNLS, enhanced cell proliferation, lamellipodia formation, and invasive activity and drove expression of the elevated expression of the metastasis-associated proteins MMP-9 and VEGF. To determine if Achn could alter the behavior of human breast cancer cells in vivo, Achn-engineered MDA-MB-231 cells were injected into athymic SCID/Beige mice. AchnWT and AchnNES-expressing tumors displayed enhanced angiogenesis and an approximately 5-fold increase in tumor size relative to either control cells or those expressing AchnNLS. These data suggest that Achn enhances human breast tumor growth and vascularization and that this activity is dependent on nuclear localization.

Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression.

Activation of inflammatory pathways is one plausible mechanism underlying the association between obesity and increased breast cancer risk. However, macrophage infiltration and local biomarkers of inflammation in breast adipose tissue have seldom been studied in association with obesity. Gene expression profiles of normal breast tissue from reduction mammoplasty patients were evaluated by whole genome microarrays to identify patterns associated with obesity status (normal-weight, body mass index (BMI) <25; overweight, BMI 25-29.9; obese, BMI ≥30). The presence of macrophage-enriched inflammatory loci with immunopositivity for CD68 protein was evaluated by immunohistochemistry (IHC). After adjusting for confounding by age, 760 genes were differentially expressed (203 up and 557 down; FDR = 0.026) between normal-weight and obese women. Gene ontology analysis suggested significant enrichment for pathways involving IL-6, IL-8, CCR5 signaling in macrophages and RXRα and PPARα activation, consistent with a pro-inflammatory state and suggestive of macrophage infiltration. Gene set enrichment analysis also demonstrated that the genomic signatures of monocytes and macrophages were over-represented in the obese group with FDR of 0.08 and 0.13, respectively. Increased macrophage infiltration was confirmed by IHC, which showed that the breast adipose tissue of obese women had higher average macrophage counts (mean = 8.96 vs. 3.56 in normal-weight women) and inflammatory foci counts (mean = 4.91 vs. 2.67 in normal-weight women). Obesity is associated with local inflammation and macrophage infiltration in normal human breast adipose tissues. Given the role of macrophages in carcinogenesis, these findings have important implications for breast cancer etiology and progression.

Repression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity.

Breast cancer is the most common tumor among women with inherited mutations in the p53 gene (Li-Fraumeni syndrome). The tumors represent the basal-like subtype, which has been suggested to originate from mammary stem/progenitor cells. In mouse mammary epithelium, mammosphere-forming potential was increased with decreased dosage of the gene encoding the p53 tumor suppressor protein (Trp53). Limiting dilution transplantation also showed a 3.3-fold increase in the frequency of long-term regenerative mammary stem cells in Trp53-/- mice. The repression of mammospheres by p53 was apparent despite the absence of apoptotic responses to radiation indicating a dissociation of these two activities of p53. The effects of p53 on progenitor cells were also observed in TM40A cells using both mammosphere-forming assays and the DsRed-let7c-sensor. The frequency of long-term label-retaining epithelial cells was decreased in Trp53-/- mammary glands indicating that asymmetric segregation of DNA is diminished and contributes to the expansion of the mammary stem cells. Treatment with an inhibitor of γ-secretase (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) reduced the number of Trp53-/- mammospheres to the level found in Trp53+/+ cells. These results demonstrate that basal levels of p53 restrict mammary stem/progenitor cells through Notch and that the Notch pathway is a therapeutic target to prevent expansion of this vulnerable pool of cells.

Association between statins given in hospital and mortality in pneumonia patients.

BACKGROUND: Statins are prescribed to lower cholesterol, but also have anti-inflammatory properties. Some observational studies suggest that statins may reduce mortality from sepsis. METHODS: Using a highly detailed administrative database, we conducted an observational cohort study of all patients aged ≥18 years who received a discharge diagnosis of pneumonia from 2003-2005 at 376 hospitals. Patients with contraindications to statins, and those unable to take oral medications or discharged within 2 days were excluded. We used multivariable logistic regression and propensity matching to compare mortality among patients who did and did not receive statins on hospital day 1 or 2. RESULTS: Of the 121,254 patients who met the inclusion criteria, median age was 74; 56% were female and 70% were white; 19% received a statin on day 1 or 2. Compared to patients who did not receive statins, statin-treated patients were less likely to be admitted to intensive care (15.7% vs 18.1%, p < 0.001), require mechanical ventilation (6.9% vs. 9.3%, p < 0.001), or die in hospital (3.9% vs 5.7%, p < 0.001). After multivariable adjustment, including the propensity for statin treatment and severity at presentation, mortality was lower in statin-treated patients [OR for propensity-adjusted 0.86 (95% CI 0.79 to 0.93) OR for propensity-matched 0.90, (0.82 to 0.99)]. For patients admitted to intensive care the adjusted odds ratio for mortality with statins was 0.93 (95% CI 0.81 to 1.06), whereas outside intensive care it was 0.79 (95% CI 0.71 to 0.87). CONCLUSIONS: Inpatient treatment with statins is associated with a modest reduction in pneumonia mortality outside of intensive care.

Dietary intervention of flaxseed: effect on serum levels of IGF-1, IGF-BP3, and C-peptide.

Higher levels of insulin and insulin-like growth factor 1 (IGF-1) increase cancer risk by stimulating cell proliferation and increasing survival of DNA-damaged cells through antiapoptotic mechanisms. Laboratory studies suggest that flaxseed added to the diet may lower circulating levels of insulin and IGF-1, but there is limited information on the effects of dietary flaxseed on these biomarkers of cancer risk in humans. The aim of this study was to determine the effect of flaxseed supplementation in postmenopausal women on serum levels of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGF-BP3), and C-peptide, a marker of insulin production. Forty-eight postmenopausal women participated in this 12-wk baseline to postintervention study. Participants were asked to consume 7.5 g per day of ground flaxseed for 6 wk and 15 g per day for an additional 6 wk. No significant changes were observed in blood levels of IGF-1, IGF-BP3, or C-peptide over the study intervention. Flaxseed supplementation did not impact circulating levels of IGF-1, IGF-BP3, or C-peptide. Longer duration of intake may be necessary to observe changes in these biomarkers of cancer risk.

Biomarkers of phthalates and inflammation: Findings from a subgroup of Women's Health Initiative participants.

BACKGROUND: Recent experimental work has shown that phthalates may increase inflammation. Prior research has not examined the role of exposure to phthalates in relation to inflammatory status among postmenopausal women who are at higher risk of developing inflammation-related chronic disorders. OBJECTIVES: We aimed to examine the associations of urinary phthalate biomarker concentrations with circulating levels of c-reactive protein [CRP] and interleukin-6 [IL-6] among 443 postmenopausal women selected into a breast cancer case-control study nested within the Women's Health Initiative (WHI). METHODS: A total of 13 phthalate metabolites were measured in urine samples provided at WHI enrollment from 1993 to 1998. We also measured baseline levels of CRP and IL-6 in these women's serum or plasma samples. Multivariable linear models were used to investigate the role of each phthalate biomarker in relation to CRP and IL-6, adjusting for potential confounding factors and specifically evaluating the role of BMI. RESULTS: In adjusted models we observed positive associations of monocarboxynonyl phthalate (MCNP) with CRP (ß = 0.092; 95% CI 0.026, 0.158) and IL-6 (ß = 0.108; 95% CI 0.013, 0.204). These positive associations were attenuated and non-significant, however, after further adjustment for body mass index (BMI). In contrast, we observed inverse associations of monoethyl phthalate (MEP) (ß = -0.019; 95% CI -0.036, -0.001) and monobenzyl phthalate (MBzP) (ß = -0.034; 95% CI -0.058, -0.010) with CRP levels only after adjustment for BMI. Other phthalate biomarkers examined were not significantly associated with either CRP or IL-6 levels. CONCLUSIONS: Overall, these results do not suggest an important role for phthalates in promoting an inflammatory response. Future prospective studies are warranted to improve understanding of these associations, particularly in clarifying the role of BMI.

Urinary Phthalate Biomarkers and Bone Mineral Density in Postmenopausal Women.

CONTEXT: Phthalates are endocrine-disrupting chemicals that could disrupt normal physiologic function, triggering detrimental impacts on bone. OBJECTIVE: We evaluated associations between urinary phthalate biomarkers and BMD in postmenopausal women participating in the prospective Women's Health Initiative (WHI). METHODS: We included WHI participants enrolled in the BMD substudy and selected for a nested case-control study of phthalates and breast cancer (N = 1255). We measured 13 phthalate biomarkers and creatinine in 2 to 3 urine samples per participant collected over 3 years, when all participants were cancer free. Total hip and femoral neck BMD were measured at baseline and year 3, concurrent with urine collection, via dual-energy x-ray absorptiometry. We fit multivariable generalized estimating equation models and linear mixed-effects models to estimate cross-sectional and longitudinal associations, respectively, with stratification on postmenopausal hormone therapy (HT) use. RESULTS: In cross-sectional analyses, mono-3-carboxypropyl phthalate and the sum of di-isobutyl phthalate metabolites were inversely associated with total hip BMD among HT nonusers, but not among HT users. Longitudinal analyses showed greater declines in total hip BMD among HT nonusers and with highest concentrations of mono-3-carboxyoctyl phthalate (-1.80%; 95% CI, -2.81% to -0.78%) or monocarboxynonyl phthalate (-1.84%; 95% CI, -2.80% to -0.89%); similar associations were observed with femoral neck BMD. Among HT users, phthalate biomarkers were not associated with total hip or femoral neck BMD change. CONCLUSION: Certain phthalate biomarkers are associated with greater percentage decreases in total hip and femoral neck BMD. These findings suggest that phthalate exposure may have clinically important effects on BMD, and potentially fracture risk.

Effect of flaxseed consumption on urinary levels of estrogen metabolites in postmenopausal women.

Flaxseed is a rich source of dietary lignans. It has been hypothesized that lignans may decrease breast cancer risk through modulation of endogenous hormone levels. The aim of this study was to determine the effect of flaxseed supplementation on urinary levels of estrogen metabolites that may be involved in the development of breast cancer. Forty-three postmenopausal women participated in this 12-wk preintervention-postintervention study. Participants consumed 7.5 g/day of ground flaxseed for 6 wk, followed by 15 g/day for an additional 6 wk. The mean urinary level of 16alpha -hydroxyestrone (16alpha -OHE1) was higher at the end of 12 wk compared to baseline (change of 1.32 ug/day, P = 0.02). There was no significant change in 2-OHE1 excretion. The mean urinary level of the 2-OHE1/16alpha -OHE1 ratio was lower at the end of 12 wk compared to baseline (change of -1.1, P = 0.02). Mean urinary excretion of 2-methoxyestradiol was also lower at 12 wk than at baseline (P = 0.03). Based on the current paradigm of the effects of estrogen metabolism on breast cancer risk, the regimen of dietary flaxseed intake used in this study did not appear to favorably alter breast cancer risk through shifts in estrogen metabolism pathways in postmenopausal women.

Acheron/Larp6 Is a Survival Protein That Protects Skeletal Muscle From Programmed Cell Death During Development.

The term programmed cell death (PCD) was coined in 1965 to describe the loss of the intersegmental muscles (ISMs) of moths at the end of metamorphosis. While it was subsequently demonstrated that this hormonally controlled death requires de novo gene expression, the signal transduction pathway that couples hormone action to cell death is largely unknown. Using the ISMs from the tobacco hawkmoth Manduca sexta, we have found that Acheron/LARP6 mRNA is induced ∼1,000-fold on the day the muscles become committed to die. Acheron functions as a survival protein that protects cells until cell death is initiated at eclosion (emergence), at which point it becomes phosphorylated and degraded in response to the peptide Eclosion Hormone (EH). Acheron binds to a novel BH3-only protein that we have named BBH1 (BAD/BNIP3 homology 1). BBH1 accumulates on the day the ISMs become committed to die and is presumably liberated when Acheron is degraded. This is correlated with the release and rapid degradation of cytochrome c and the subsequent demise of the cell. RNAi experiments in the fruit fly Drosophila confirmed that loss of Acheron results in precocious ecdysial muscle death while targeting BBH1 prevents death altogether. Acheron is highly expressed in neurons and muscles in humans and drives metastatic processes in some cancers, suggesting that it may represent a novel survival protein that protects terminally differentiated cells and some cancers from death.