Liver-specific overexpression of SIRT3 enhances oxidative metabolism, but does not impact metabolic defects induced by high fat feeding in mice.

The mitochondrial enzyme SIRT3 is an NAD+-dependent deacetylase important in cell metabolism, and a decline in its protein expression or activity has been linked with insulin resistance in obesity, ageing and type 2 diabetes. While studies in SIRT3 knockout mice have dramatically improved our understanding of the function of SIRT3, the impact of increasing SIRT3 levels remains under-examined. In this study we investigated the effects of liver-specific SIRT3 overexpression in mice on mitochondrial function and metabolic profile in both isolated hepatocytes and in vivo. Primary hepatocytes overexpressing SIRT3 displayed increased oxygen consumption and a reduction in triglyceride accumulation. In mice with hepatic SIRT3 overexpression, increased fasting ß-hydroxybutyrate levels were observed, coupled with an increase in oxygen consumption in isolated mitochondria and increased substrate utilization in liver homogenates. However, metabolic profiling of mice exposed to either chow or high-fat diet revealed no effect of hepatic SIRT3 overexpression on glucose tolerance, body composition or tissue triglyceride accumulation. These findings suggest limited whole-body benefit of increasing hepatic SIRT3 during the development of diet-induced insulin resistance.

Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock.

Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in gene expression and metabolite fluctuations.

Perspectives of pregnant and breastfeeding women on longitudinal clinical studies that require non-invasive biospecimen collection - a qualitative study.

BACKGROUND: Investigation of the microbiome during early life has stimulated an increasing number of cohort studies in pregnant and breastfeeding women that require non-invasive biospecimen collection. The objective of this study was to explore pregnant and breastfeeding women's perspectives on longitudinal clinical studies that require non-invasive biospecimen collection and how they relate to study logistics and research participation. METHODS: We completed in-depth semi-structured interviews with 40 women who were either pregnant (n = 20) or breastfeeding (n = 20) to identify their understanding of longitudinal clinical research, the motivations and barriers to their participation in such research, and their preferences for providing non-invasive biospecimen samples. RESULTS: Perspectives on research participation were focused on breastfeeding and perinatal education. Participants cited direct benefits of research participation that included flexible childcare, lactation support, and incentives and compensation. Healthcare providers, physician offices, and social media were cited as credible sources and channels for recruitment. Participants viewed lengthy study visits and child protection as the primary barriers to research participation. The barriers to biospecimen collection were centered on stool sampling, inadequate instructions, and drop-off convenience. CONCLUSION: Women in this study were interested in participating in clinical studies that require non-invasive biospecimen collection, and motivations to participate center on breastfeeding and the potential to make a scientific contribution that helps others. Effectively recruiting pregnant or breastfeeding participants for longitudinal microbiome studies requires protocols that account for participant interests and consideration for their time.

Adult weight change and premenopausal breast cancer risk: A prospective pooled analysis of data from 628,463 women.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors.

Educational, supportive and behavioural interventions to improve usage of continuous positive airway pressure machines in adults with obstructive sleep apnoea.

BACKGROUND: Although highly effective in the treatment of obstructive sleep apnoea (OSA), continuous positive airway pressure (CPAP) is not universally accepted by users. Educational, supportive and behavioural interventions may help people with OSA initiate and maintain regular and continued use of CPAP. OBJECTIVES: To assess the effectiveness of educational, supportive, behavioural, or mixed (combination of two or more intervention types) strategies that aim to encourage adults who have been prescribed CPAP to use their devices. SEARCH METHODS: Searches were conducted on the Cochrane Airways Group Specialised Register of trials. Searches are current to 29 April 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed intervention(s) designed to inform participants about CPAP/OSA, to support them in using CPAP, or to modify their behaviour to increase use of CPAP devices. DATA COLLECTION AND ANALYSIS: We assessed studies to determine their suitability for inclusion in the review. Data were extracted independently and were entered into RevMan for analysis. 'Risk of bias' assessments were performed, using the updated 'Risk of bias 2' tool, for the primary outcome, CPAP usage. Study-level 'Risk of bias' assessments were performed using the original 'Risk of bias' tool. GRADE assessment was performed using GRADEpro. MAIN RESULTS: Forty-one studies (9005 participants) are included in this review; 16 of these studies are newly identified with updated searches. Baseline Epworth Sleepiness Scale (ESS) scores indicate that most participants suffered from excessive daytime sleepiness. The majority of recruited participants had not used CPAP previously. When examining risk of bias for the primary outcome of hourly machine usage/night, 58.3% studies have high overall risk (24/41 studies), 39.0% have some concerns (16/41 studies), and 2.4% have low overall risk (1/41 studies). We are uncertain whether educational interventions improve device usage, as the certainty of evidence was assessed as very low. We were unable to perform meta-analyses for number of withdrawals and symptom scores due to high study heterogeneity. Supportive interventions probably increase device usage by 0.70 hours/night (95% confidence interval (CI) 0.36 to 1.05, N = 1426, 13 studies, moderate-certainty evidence), and low-certainty evidence indicates that the number of participants who used their devices ≥ 4 hours/night may increase from 601 to 717 per 1000 (odds ratio (OR), 1.68, 95% CI 1.08 to 2.60, N = 376, 2 studies). However, the number of withdrawals may also increase from 136 to 167 per 1000 (OR 1.27, 95% CI 0.97 to 1.66, N = 1702, 11 studies, low-certainty evidence). Participants may experience small improvements in symptoms (ESS score -0.32 points, 95% CI -1.19 to 0.56, N = 470, 5 studies, low-certainty evidence), and we are uncertain whether quality of life improves with supportive interventions, as the certainty of evidence was assessed as very low. When compared with usual care, behavioural interventions produce a clinically-meaningful increase in device usage by 1.31 hours/night (95% CI 0.95 to 1.66, N = 578, 8 studies, high-certainty evidence), probably increase the number of participants who used their machines ≥ 4 hours/night from 371 to 501 per 1000 (OR 1.70, 95% CI 1.20 to 2.41, N = 549, 6 studies, high-certainty evidence), and reduce the number of study withdrawals from 146 to 101 per 1000 (OR 0.66, 95% CI 0.44 to 0.98, N = 939, 10 studies, high-certainty evidence). Behavioural interventions may reduce symptoms (ESS score -2.42 points, 95% CI -4.27 to -0.57, N = 272, 5 studies, low-certainty evidence), but probably have no effect on quality of life (Functional Outcomes of Sleep Questionnaire (FOSQ), standardised mean difference (SMD) 0.00, 0.95% CI -0.26 to 0.26, N = 228, 3 studies, moderate-certainty evidence). We are uncertain whether behavioural interventions improve apnoea hypopnoea index (AHI), as the certainty of evidence was assessed as very low. We are uncertain if mixed interventions improve device usage, increase the number of participants using their machines ≥ 4 hours/night, reduce study withdrawals, improve quality of life, or reduce anxiety symptoms, as the certainty of evidence for these outcomes was assessed to be very low. Symptom scores via the ESS could not be measured due to considerable heterogeneity between studies. AUTHORS' CONCLUSIONS: In CPAP-naïve people with OSA, high-certainty evidence indicates that behavioural interventions yield a clinically-significant increase in hourly device usage when compared with usual care. Moderate certainty evidence shows that supportive interventions increase usage modestly. Very low-certainty evidence shows that educational and mixed interventions may modestly increase CPAP usage. The impact of improved CPAP usage on daytime sleepiness, quality of life, and mood and anxiety scores remains unclear since these outcomes were not assessed in the majority of included studies. Studies addressing the choice of interventions that best match individual patient needs and therefore result in the most successful and cost-effective therapy are needed.

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies.

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated. Objective: To characterize breast cancer risk in relation to recent childbirth. Design: Pooled analysis of individual-level data from 15 prospective cohort studies. Setting: The international Premenopausal Breast Cancer Collaborative Group. Participants: Women younger than 55 years. Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression. Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns. Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited. Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women. Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

Nasal Obstruction and Rhinoplasty: A Focused Literature Review.

BACKGROUND: There is a significant variation in the assessment, treatment, and outcomes of nasal airway obstruction and management in the published literature. This study aimed to: (1) define key components of the nasal airway, (2) identify frequent causes of nasal obstruction, and (3) review existing treatment methods. METHODS: A systematic review of the literature was performed, and 135 studies were included via the following criteria: English, human subjects, and a primary endpoint of nasal airway improvement. Exclusion criteria were: abstract only, no airway data, pediatric patients, cleft rhinoplasty, sleep apnea, isolated traumatic nasal reconstruction, and cadaveric-only or animal studies. RESULTS: The relevant obstructive sites include the ENV, septum, inferior turbinates, INV, and nasal bones. Addressing the alar rim alone may be insufficient, and inspection of the lateral wall and crura may be indicated. Correction of septal deviation involves attention to the bony base. Mucosal sparing treatment of inferior turbinates improves outcomes. INVs are a major source of nasal obstruction, and treatment includes spreader grafts. The bony nasal vault can contribute to nasal obstruction, including due to surgical osteotomies. CONCLUSIONS: Anatomic causes of airway obstruction include the alar rims and lateral nasal walls, deviated nasal septum, inferior turbinate hypertrophy, decreased INV angle, and narrowed nasal bones. Treatments include graft placement; septoplasty; mucosal sparing turbinectomy; and lateral wall support. Pitfalls include failing to address the bony septum, over-resection of inferior turbinates, and narrowing of the nasal vault. Appreciation of airway management during rhinoplasty will improve functional outcomes. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Night shift work and risk of breast cancer in women: the Generations Study cohort.

BACKGROUND: It is plausible that night shift work could affect breast cancer risk, possibly by melatonin suppression or circadian clock disruption, but epidemiological evidence is inconclusive. METHODS: Using serial questionnaires from the Generations Study cohort, we estimated hazard ratios (HR) and 95% confidence intervals (95%CI) for breast cancer in relation to being a night shift worker within the last 10 years, adjusted for potential confounders. RESULTS: Among 102,869 women recruited in 2003-2014, median follow-up 9.5 years, 2059 developed invasive breast cancer. The HR in relation to night shift work was 1.00 (95%CI: 0.86-1.15). There was a significant trend with average hours of night work per week (P = 0.035), but no significantly raised risks for hours worked per night, nights worked per week, average hours worked per week, cumulative years of employment, cumulative hours, time since cessation, type of occupation, age starting night shift work, or age starting in relation to first pregnancy. CONCLUSIONS: The lack of overall association, and no association with all but one measure of dose, duration, and intensity in our data, does not support an increased risk of breast cancer from night shift work in women.

FLUORESCEIN ANGIOGRAPHIC EVALUATION OF PERIPHERAL RETINAL VASCULATURE AFTER PRIMARY INTRAVITREAL RANIBIZUMAB FOR RETINOPATHY OF PREMATURITY.

PURPOSE: To evaluate angiographic findings in neonates up to 150 weeks postmenstrual age who received intravitreal ranibizumab for primary treatment of Type 1 retinopathy of prematurity. METHODS: Retrospective evaluation of fluorescein angiogram findings was completed for 30 eyes of 16 neonates who received intravitreal ranibizumab as primary treatment for Type 1 retinopathy of prematurity between April 2013 and January 2015. Outcome measures included maturity to Zone III, vascular blunting, vascular loops, vascular dilatation, capillary dropout, and vascular fluorescein leakage. RESULTS: Mean gestational age was 24 weeks and mean postmenstrual age at time of intravitreal ranibizumab treatment was 35 weeks. Fluorescein angiograms performed at 44 weeks to 150 weeks postmenstrual age showed only 50% of eyes reached vascularization to Zone III; 40% had persistent vascular leakage; and ≥90% exhibited vascular blunting, vascular dilatation, and/or capillary dropout. CONCLUSION: Although intravitreal ranibizumab is effective in initial cessation of Type 1 retinopathy of prematurity, vascularization to Zone III was only achieved in 50% of eyes in our series and most eyes had fluorescein angiography evidence of vascular anomalies. If future studies are performed comparing treatment with laser photocoagulation to anti-vascular endothelial growth factor, fluorescein angiographic studies should be considered to assess the status of the peripheral retinal vasculature to determine treatment effect.

Use of Digital Photography With Newcomer Immigrant and Refugee Youth to Examine Behaviors and Promote Health.

This project examined health behaviors of newly arrived immigrant and refugee youth through digital photography as part of a health promotion intervention. Students (n = 23) aged 12 to 17 years at a school for newcomer youth in North Carolina used digital cameras to record dietary and physical activity behaviors, barriers, and promoters in their home environment. Eighteen participants completed individual photography projects that revealed consumption of soda, processed foods, limited calcium-rich foods, and limited evidence of physical activity. Photography project results and topics from nutrition education provided during the program were used to tailor health promotion resources. Students used digital cameras and props to create visual health-promoting materials (e.g., large posters for school hallways) that included and represented the wide range of cultures and ethnicities at the school. Facilitated discussion analysis revealed students preferred positive health promotion messages (health benefits of fruits and vegetables) versus negative (sugar or salt content of foods). Students reported they enjoyed using the cameras and developing materials and that as result of their experience they want to increase fruit and vegetable consumption, reduce sugar sweetened beverages, and increase physical activity. Digital photography shows promise as a tool to identify health behaviors and environmental barriers and to tailor health messages, especially with populations experiencing language, literacy, and/or cultural barriers.

Maternal breast cancer risk in relation to birthweight and gestation of her offspring.

BACKGROUND: Parity and age at first pregnancy are well-established risk factors for breast cancer, but the effects of other characteristics of pregnancies are uncertain and the literature is inconsistent. METHODS: In a cohort of 83,451 parous women from the general population of the UK, which collected detailed information on each pregnancy and a wide range of potential confounders, we investigated the associations of length of gestation and birthweight of offspring in a woman's pregnancies with her breast cancer risk, adjusting for a full range of non-reproductive as well as reproductive risk factors unlike in previous large studies. RESULTS: Gestation of the first-born offspring was significantly inversely related to the risk of pre-menopausal breast cancer (p trend = 0.03; hazard ratio (HR) for 26-31 compared with 40-41 weeks, the baseline group, = 2.38, 95% confidence interval (CI) 1.26-4.49), and was borderline significantly related to risk of breast cancer overall (p trend = 0.05). Risk was significantly raised in mothers of high birthweight first-born (HR for breast cancer overall = 1.53, 95% CI 1.06-2.21 for ≥ 4500 g compared with 3000-3499 g, the baseline group). For gestation and birthweight of most recent birth, there were no clear effects. Analyses without adjustment for confounders (other than age) gave similar results. CONCLUSIONS: Our data add to evidence that short gestation pregnancies may increase the risk of breast cancer, at least pre-menopausally, perhaps by hormonal stimulation and breast proliferation early in pregnancy without the opportunity for the differentiation that occurs in late pregnancy. High birthweight first pregnancies may increase breast cancer risk, possibly through the association of birthweight with oestrogen and insulin-like growth factor 1 levels.

Breast cancer risk in relation to history of preeclampsia and hyperemesis gravidarum: Prospective analysis in the Generations Study.

Preeclampsia and hyperemesis gravidarum are pregnancy complications associated with altered sex hormone levels. Previous studies suggest preeclampsia may be associated with a decreased risk of subsequent breast cancer and hyperemesis with an increased risk, but the evidence remains unclear. We used data from the Generations Study, a large prospective study of women in the United Kingdom, to estimate relative risks of breast cancer in relation to a history of preeclampsia and hyperemesis using Cox regression adjusting for known breast cancer risk factors. During 7.5 years average follow-up of 82,053 parous women, 1,969 were diagnosed with invasive or in situ breast cancer. Women who had experienced preeclampsia during pregnancy had a significantly decreased risk of premenopausal breast cancer (hazard ratio (HR) =0.67, 95% confidence interval (CI): 0.49-0.90) and of HER2-enriched tumours (HR = 0.33, 95% CI: 0.12-0.91), but there was no association with overall (HR = 0.90, 95% CI: 0.80-1.02) or postmenopausal (HR = 0.97, 95% CI: 0.85-1.12) breast cancer risk. Risk reductions among premenopausal women were strongest within 20 years since the last pregnancy with preeclampsia. Hyperemesis was associated with a significantly increased risk of HER2-enriched tumours (HR = 1.76, 95% CI: 1.07-2.87), but not with other intrinsic subtypes or breast cancer risk overall. These results provide evidence that preeclampsia is associated with a decreased risk of premenopausal and HER2-enriched breast cancer and that hyperemesis, although not associated with breast cancer risk overall, may be associated with raised risk of HER2-enriched tumours.

Hepatic artery stenosis after liver transplant: Donation after cardiac death donor vs donation after brain death donor grafts.

BACKGROUND: Hepatic artery stenosis (HAS) after liver transplant (LT) is a source of significant morbidity. Some reports have suggested higher arterial complications in patients who receive donation after cardiac death (DCD) livers. METHODS: A total of 2860 consecutive LT were reviewed from a prospectively collected database. All angiograms performed in LT recipients were reviewed and primary patency rates determined by need for further intervention or graft loss due to HAT. RESULTS: Hepatic artery stenosis was seen in 4.6% of DCD and donation after brain death (DBD) recipients. Recipient male gender, age at transplant, complex donor hepatic artery anatomy, and prolonged operative time were all associated with HAS, but not DCD status. While HAS in recipients of DCD grafts required more stents (1.7% vs 0.6%, P = 0.04) and had worse primary patency rates (logrank, P = 0.02), outcomes as defined by HAT, patient and graft survival were not significantly different between the recipients of DCD or DBD grafts. CONCLUSION: We observed no significant difference in the incidence of hepatic artery complications, patient survival, or graft survival in recipients of DCD or DBD grafts. However, HAS in DCD recipients had worse primary patency and a higher need for stent placement.

Botulinum Toxin Therapy: Is Syringe Type Related to Cost-Effectiveness?

INTRODUCTION: Clostridium botulinum toxin is effective through cleaving presynaptic proteins at the neuromuscular junction, which prevents the release of acetylcholine and inhibits muscle contraction. Several serotypes of botulinum toxin (BT) exist; however, only 2 types have been approved by the US Food and Drug Administration for commercial and medical use, A and B. Both types of BT must be administered intramuscularly with a syringe, but the type of syringe is the injector's preference. Which syringe type is most efficient in minimizing product waste and most cost-effective for the patient and provider? METHODS: We performed a single-center, open-label, analytical study using BT therapy and 2 types of syringes for analytics of cost-effectiveness. OnabotulinumtoxinA was the neuromodulator used in this report. Vials (100 U) of BT A were each reconstituted with 2.5 mL of 0.9% sodium chloride, for a final concentration of 4 U/0.1 mL. High-dead-space syringes are compared with low-dead-space syringes: 1-mL tuberculin (TB) luer slip syringe with detachable 25-gauge needle and 1-mL ultrafine insulin syringe with an attached 31-gauge needle, respectively. After each syringe was evacuated, the TB syringe was noted to contain 0.05 mL of the remaining product in the hub. RESULTS: Providers are discarding approximately 2 U of BT per TB syringe product injection. If the physician uses 30 syringes per day, 3 days a week, for 1 year, it equals to a lost revenue of approximately $155,500 per year. To individualize the cost-effective analysis, average quantity of syringes used per patient and overall patient volume must be considered, with corresponding adjustment of cost and units discarded. DISCUSSION: The American Society of Plastic Surgeons reported that the use of neuromodulators has increased by approximately 797% from 2000 to 2016. During that period, the price of neuromodulators has also increased by approximately 85%. Considering these statistics, the type of syringe used for BT neuromodular injection is a thought-provoking concept but surrounded by a paucity of data. Overall, our data suggest that the use of ultrafine insulin syringes for injection of BT reduces product waste and is cost-effective for the patient and the provider.

Gender as a Moderator of Descriptive Norms and Substance Use among Latino College Students.

This study addresses gaps in the literature by testing gender differences in the associations between substance use norms and substance use among Latino college students. Secondary data analysis was conducted using data from the 2009 National College Health Assessment. Participants selected for this study were 4,336 Latino undergraduates. Linear mixed modeling was used to test gender as a moderator of the relationship between alcohol use norms and alcohol use as well as marijuana use norms and marijuana use. Results indicated that the strength of the relationships between norms and substance use was stronger for males than for females. Substance use rates and gender roles differ for Latinos and Latinas and may partially account for the stronger relationship between these constructs for males. Implications for future research and prevention are discussed.

Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance.

Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the mitochondrial calcium uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca2+ in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analyzed from several models of obese and diabetic rodents and in 72 patients with obesity as well as in vitro insulin-resistant adipocytes. Genetic manipulation of MCU activity in 3T3-L1 adipocytes allowed the investigation of the role of mitochondrial calcium uptake. In insulin-resistant adipocytes, mitochondrial calcium uptake increased and several MCU components were upregulated. Similar results were observed in mouse and human visceral adipose tissue (VAT) during the progression of obesity and diabetes. Intriguingly, subcutaneous adipose tissue (SAT) was spared from overt MCU fluctuations. Furthermore, MCU expression returned to physiological levels in VAT of patients after weight loss by bariatric surgery. Genetic manipulation of mitochondrial calcium uptake in 3T3-L1 adipocytes demonstrated that changes in mitochondrial calcium concentration ([Ca2+]mt) can affect mitochondrial metabolism, including oxidative enzyme activity, mitochondrial respiration, membrane potential, and reactive oxygen species formation. Finally, our data suggest a strong relationship between [Ca2+]mt and the release of IL-6 and TNFα in adipocytes. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of VAT and SAT.

Smoking and risk of breast cancer in the Generations Study cohort.

BACKGROUND: Plausible biological reasons exist regarding why smoking could affect breast cancer risk, but epidemiological evidence is inconsistent. METHODS: We used serial questionnaire information from the Generations Study cohort (United Kingdom) to estimate HRs for breast cancer in relation to smoking adjusted for potentially confounding factors, including alcohol intake. RESULTS: Among 102,927 women recruited 2003-2013, with an average of 7.7 years of follow-up, 1815 developed invasive breast cancer. The HR (reference group was never smokers) was 1.14 (95% CI 1.03-1.25; P = 0.010) for ever smokers, 1.24 (95% CI 1.08-1.43; P = 0.002) for starting smoking at ages < 17 years, and 1.23 (1.07-1.41; P = 0.004) for starting smoking 1-4 years after menarche. Breast cancer risk was not statistically associated with interval from initiation of smoking to first birth (P-trend = 0.97). Women with a family history of breast cancer (ever smoker vs never smoker HR 1.35; 95% CI 1.12-1.62; P = 0.002) had a significantly larger HR in relation to ever smokers (P for interaction = 0.039) than women without (ever smoker vs never smoker HR 1.07; 95% CI 0.96-1.20; P = 0.22). The interaction was prominent for age at starting smoking (P = 0.003) and starting smoking relative to age at menarche (P = 0.0001). CONCLUSIONS: Smoking was associated with a modest but significantly increased risk of breast cancer, particularly among women who started smoking at adolescent or peri-menarcheal ages. The relative risk of breast cancer associated with smoking was greater for women with a family history of the disease.

Prescription Drug Misuse and Arrest History.

BACKGROUND: Prescription drug misuse is widely acknowledged as a major public health issue in the United States. Surprisingly little research examines the association between prescription drug misuse and history of arrest among adults. METHODS: We use data from the 2013 National Survey on Drug Use and Health to examine this association. Arrest was self-reported and separated into three categories: any, property crime, or violent crime. Prescription drug misuse was defined as use without a prescription or solely for the feeling or experience caused by the drug. We looked at the misuse of any prescription drug and also separate classes of misuse (pain relievers, sedatives, tranquilizers, and stimulants). Several multivariate logistic regression models were estimated to examine the association between prescription drug misuse and arrest. RESULTS: Findings showed that 8.62% of respondents reported prescription drug misuse and 3.55% reported any arrest. In multivariate models that included demographic characteristics and measures of alcohol and other drug use, respondents who reported prescription drug misuse were at increased odds of arrest. CONCLUSIONS: The current research shows that prescription drug misuse is significantly associated with arrest, but more research is needed on the causal nature of this association. The criminal justice and drug treatment systems must develop treatment and rehabilitation services that understand the close association between prescription drug misuse and arrest.

Psychological stress, adverse life events and breast cancer incidence: a cohort investigation in 106,000 women in the United Kingdom.

BACKGROUND: Women diagnosed with breast cancer frequently attribute their cancer to psychological stress, but scientific evidence is inconclusive. We investigated whether experienced frequency of stress and adverse life events affect subsequent breast cancer risk. METHODS: Breast cancer incidence was analysed with respect to stress variables collected at enrolment in a prospective cohort study of 106,000 women in the United Kingdom, with 1783 incident breast cancer cases. Relative risks (RR) were obtained as hazard ratios using Cox proportional hazards models. RESULTS: There was no association of breast cancer risk overall with experienced frequency of stress. Risk was reduced for death of a close relative during the 5 years preceding study entry (RR = 0.87, 95 % confidence interval (CI): 0.78-0.97), but not for death of a spouse/partner or close friend, personal illness/injury, or divorce/separation. There was a positive association of divorce with oestrogen-receptor-negative (RR = 1.54, 95 % CI: 1.01-2.34), but not with oestrogen-receptor-positive breast cancer. Risk was raised in women who were under age 20 at the death of their mother (RR = 1.31, 95 % CI: 1.02-1.67), but not of their father, and the effect was attenuated after excluding mothers with breast or ovarian cancer (RR = 1.17, 95 % CI: 0.85-1.61). CONCLUSIONS: This large prospective study did not show consistent evidence for an association of breast cancer risk with perceived stress levels or adverse life events in the preceding 5 years, or loss of parents during childhood and adolescence.