Use of transcranial low-intensity focused ultrasound for targeted delivery of stem cell-derived exosomes to the brain.

The blood-brain barrier (BBB) presents a significant challenge for targeted drug delivery. A proposed method to improve drug delivery across the BBB is focused ultrasound (fUS), which delivers ultrasound waves to a targeted location in the brain and is hypothesized to open the BBB. Furthermore, stem cell-derived exosomes have been suggested as a possible anti-inflammatory molecule that may have neural benefits, if able to pass the BBB. In the present study, transcranial low-intensity focused ultrasound (LIFU), without the use of intravenous microbubbles, was assessed for both (1) its ability to influence the BBB, as well as (2) its ability to increase the localization of intravenously administered small molecules to a specific region in the brain. In vivo rat studies were conducted with a rodent-customized 2 MHz LIFU probe (peak pressure = 1.5 MPa), and injection of labeled stem cell-derived exosomes. The results suggested that LIFU (without microbubbles) did not appear to open the BBB after exposure times of 20, 40, or 60 min; instead, there appeared to be an increase in transcytosis of the dextran tracer. Furthermore, the imaging results of the exosome study showed an increase in exosome localization in the right hippocampus following 60 min of targeted LIFU.

Life history, climate and biogeography interactively affect worldwide genetic diversity of plant and animal populations.

Understanding how biological and environmental factors interactively shape the global distribution of plant and animal genetic diversity is fundamental to biodiversity conservation. Genetic diversity measured in local populations (GDP) is correspondingly assumed representative for population fitness and eco-evolutionary dynamics. For 8356 populations across the globe, we report that plants systematically display much lower GDP than animals, and that life history traits shape GDP patterns both directly (animal longevity and size), and indirectly by mediating core-periphery patterns (animal fecundity and plant dispersal). Particularly in some plant groups, peripheral populations can sustain similar GDP as core populations, emphasizing their potential conservation value. We further find surprisingly weak support for general latitudinal GDP trends. Finally, contemporary rather than past climate contributes to the spatial distribution of GDP, suggesting that contemporary environmental changes affect global patterns of GDP. Our findings generate new perspectives for the conservation of genetic resources at worldwide and taxonomic-wide scales.

Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer.

BACKGROUND: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk. PATIENTS AND METHODS: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models. RESULTS: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI ≥35.0 kg/m2 with 21-22.9 kg/m2. When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI <25.0 kg/m2 in early adulthood and BMI ≥30.0 kg/m2 at baseline compared with BMI <25.0 kg/m2 in early adulthood and BMI <30.0 kg/m2 at baseline. Baseline waist circumference, comparing ≥110 cm with <90 cm, and waist-to-hip ratio, comparing ≥1.00 with <0.90, were associated with significant 14%-16% increases in high-grade prostate cancer risk and suggestive or significant 20%-39% increases in prostate cancer mortality risk. Height was associated with suggestive or significant 33%-56% risks of advanced or advanced restricted prostate cancer and prostate cancer mortality, comparing ≥1.90 m with <1.65 m. CONCLUSION: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3).

BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3).

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.

Holmium-doped 2.1 µm waveguide chip laser with an output power > 1 W.

We demonstrate the increasing applicability of compact ultra-fast laser inscribed glass guided-wave lasers and report the highest-power glass waveguide laser with over 1.1 W of output power in monolithic operation in the short-infrared near 2070 nm achieved (51% incident slope efficiency). The holmium doped ZBLAN chip laser is in-band pumped by a 1945 nm thulium fiber laser. When operated in an extended-cavity configuration, over 1 W of output power is realized in a linearly polarized beam. Broad and continuous tunability of the extended-cavity laser is demonstrated from 2004 nm to 2099 nm. Considering its excellent beam quality of M² = 1.08, this laser shows potential as a flexible master oscillator for single frequency and mode-locking applications.

Psychosocial predictors of weight loss by race and sex.

This paper examined the psychosocial predictors of weight loss among race and sex subgroups. Analyses included overweight and obese participants from the PREMIER study, a previously published randomized trial that examined the effects of two multi-component lifestyle interventions on blood pressure among pre-hypertensive and stage 1 hypertensive adults. Both intervention conditions received behavioural recommendations for weight loss and group sessions. Weight and psychosocial measures of self-efficacy and social support for diet and exercise were assessed at baseline and at 6 months. There were 157 African-American (AA) women, 46 AA men, 203 non-AA women and 182 non-AA men with an average age of 50 years and average body mass index of 34 at baseline. Multiple predictor regression models were performed individually by race and sex subgroup. Among AA women, increases in diet self-efficacy were associated with weight loss. Among AA men, increases in diet-related social support and self-efficacy, along with increases in family support to exercise, were associated with weight loss (all Ps <0.05). Among non-AA women, increases in friends' support to exercise and exercise-related self-efficacy were associated with weight loss, and among non-AA men only increases in diet self-efficacy were associated with weight loss (all Ps <0.05). These results emphasize the need for targeted interventions based on race and sex to optimize the impact of lifestyle-based weight loss programmes.

A stochastic movement simulator improves estimates of landscape connectivity.

Conservation actions often focus on restoration or creation of natural areas designed to facilitate the movements of organisms among populations. To be efficient, these actions need to be based on reliable estimates or predictions of landscape connectivity. While circuit theory and least-cost paths (LCPs) are increasingly being used to estimate connectivity, these methods also have proven limitations. We compared their performance in predicting genetic connectivity with that of an alternative approach based on a simple, individual-based "stochastic movement simulator" (SMS). SMS predicts dispersal of organisms using the same landscape representation as LCPs and circuit theory-based estimates (i.e., a cost surface), while relaxing key LCP assumptions, namely individual omniscience of the landscape (by incorporating perceptual range) and the optimality of individual movements (by including stochasticity in simulated movements). The performance of the three estimators was assessed by the degree to which they correlated with genetic estimates of connectivity in two species with contrasting movement abilities (Cabanis's Greenbul, an Afrotropical forest bird species, and natterjack toad, an amphibian restricted to European sandy and heathland areas). For both species, the correlation between dispersal model and genetic data was substantially higher when SMS was used. Importantly, the results also demonstrate that the improvement gained by using SMS is robust both to variation in spatial resolution of the landscape and to uncertainty in the perceptual range model parameter. Integration of this individual-based approach with other developing methods in the field of connectivity research, such as graph theory, can yield rapid progress towards more robust connectivity indices and more effective recommendations for land management.

Evolutionary processes driving spatial patterns of intraspecific genetic diversity in river ecosystems.

Describing, understanding and predicting the spatial distribution of genetic diversity is a central issue in biological sciences. In river landscapes, it is generally predicted that neutral genetic diversity should increase downstream, but there have been few attempts to test and validate this assumption across taxonomic groups. Moreover, it is still unclear what are the evolutionary processes that may generate this apparent spatial pattern of diversity. Here, we quantitatively synthesized published results from diverse taxa living in river ecosystems, and we performed a meta-analysis to show that a downstream increase in intraspecific genetic diversity (DIGD) actually constitutes a general spatial pattern of biodiversity that is repeatable across taxa. We further demonstrated that DIGD was stronger for strictly waterborne dispersing than for overland dispersing species. However, for a restricted data set focusing on fishes, there was no evidence that DIGD was related to particular species traits. We then searched for general processes underlying DIGD by simulating genetic data in dendritic-like river systems. Simulations revealed that the three processes we considered (downstream-biased dispersal, increase in habitat availability downstream and upstream-directed colonization) might generate DIGD. Using random forest models, we identified from simulations a set of highly informative summary statistics allowing discriminating among the processes causing DIGD. Finally, combining these discriminant statistics and approximate Bayesian computations on a set of twelve empirical case studies, we hypothesized that DIGD were most likely due to the interaction of two of these three processes and that contrary to expectation, they were not solely caused by downstream-biased dispersal.

Women's attitudes towards a pre-conception healthy lifestyle programme.

Nearly half of US women begin pregnancy overweight or obese and more than half of overweight or obese pregnant women experience excessive gestational weight gain. Recent lifestyle intervention programmes have helped women avoid excessive weight gain during pregnancy, but helping women lose weight before pregnancy may be a more effective way to improve pregnancy outcomes. This study assessed women's attitudes towards pre-conception diet and weight management interventions. An anonymous survey was conducted in patients waiting in a health maintenance organization's obstetrics and primary care waiting rooms. It focused on attitudes towards participating in a pre-conception, lifestyle change programme. Eighty percent of the 126 women surveyed were pregnant or considering pregnancy within 5 years. Of the 126 respondents, 60 (48%) were overweight or obese. Of these, 96% rated healthy diet and healthy weight before pregnancy as very important or important and 77% favoured a healthy lifestyle programme (diet, weight management and physical activity) before becoming pregnant. Likewise, overweight or obese women reported being likely or highly likely to participate in specific intervention programme aspects such as keeping phone appointments (77%), using a programme website (70%) and keeping food and exercise records (63%). Survey results show that women in this population believe that adopting a healthy lifestyle and losing weight are important before pregnancy and that they are enthusiastic about programmes that will help them achieve those goals in preparation for pregnancy.

Inpatient costs, mortality and 30-day re-admission in patients with central-line-associated bloodstream infections.

Previous work has suggested that central-line-associated bloodstream infection (CLABSI) is associated with increased costs and risk of mortality; however, no studies have looked at both total and variable costs, and information on outcomes outside of the intensive-care unit (ICU) is sparse. The aim of this study was to determine the excess in-hospital mortality and costs attributable to CLABSI in ICU and non-ICU patients. We conducted a retrospective cohort and cost-of-illness study from the hospital perspective of 398 patients at a tertiary-care academic medical centre from 1 January 2008 to 31 December 2010. All CLABSI patients and a simple random sample drawn from a list of all central lines inserted during the study period were included. Generalized linear models with log link and gamma distribution were used to model costs as a function of CLABSI and important covariates. Costs were adjusted to 2010 US dollars by use of the personal consumption expenditures for medical care index. We used multivariable logistic regression to identify independent predictors of in-hospital mortality. Among both ICU and non-ICU patients, adjusted variable costs for patients with CLABSI were c. $32 000 (2010 US dollars) higher on average than for patients without CLABSI. After we controlled for severity of illness and other healthcare-associated infections, CLABSI was associated with a 2.27-fold (95% CI 1.15-4.46) increased risk of mortality. Other healthcare-associated infections were also significantly associated with greater costs and mortality. Overall, CLABSI was associated with significantly higher adjusted in-hospital mortality and total and variable costs than those for patients without CLABSI.

Behavioral mediators of treatment effects in the weight loss maintenance trial.

BACKGROUND: The Weight Loss Maintenance Trial tested strategies for maintenance of weight loss. Personal contact was superior to interactive technology and self-directed conditions. PURPOSE: We aimed to identify behavioral mediators of the superior effect of personal contact vs. interactive technology and of personal contact vs. self-directed arms. METHODS: Overweight/obese adults at risk for cardiovascular disease (n = 1,032) who lost at least 4 kg were randomized to personal contact, interactive technology, or self-directed. After 30 months, 880 participants had data on weight and behavioral strategies. RESULTS: Reported increase of intake of fruits and vegetables and physical activity and more frequent self-weighing met criteria as mediators of the better outcome of personal contact vs. interactive technology. Increased intake of fruits and vegetables, more frequent self-weighing, and decreased dessert consumption were mediators of the difference between personal contact vs. self-directed. CONCLUSION: Inducing changes in the identified behaviors might yield better outcomes in future weight loss maintenance trials.

Complex interactions between paternal and maternal effects: parental experience and age at reproduction affect fecundity and offspring performance in a butterfly.

Parental effects can greatly affect offspring performance and are thus expected to impact population dynamics and evolutionary trajectories. Most studies have focused on maternal effects, whereas fathers are also likely to influence offspring phenotype, for instance when males transfer nutrients to females during mating. Moreover, although the separate effects of maternal age and the environment have been documented as a source of parental effects in many species, their combined effects have not been investigated. In the present study, we analyzed the combined effects of maternal and paternal age at reproduction and a mobility treatment in stressful conditions on offspring performance in the butterfly Pieris brassicae. Both paternal and maternal effects affected progeny traits but always via interactions between age and mobility treatment. Moreover, parental effects shifted from male effects expressed at the larval stage to maternal effects at the adult stage. Indeed, egg survival until adult emergence significantly decreased with father age at mating only for fathers having experienced the mobility treatment, whereas offspring adult life span decreased with increasing mother age at laying only for females that did not experience the mobility treatment. Overall, our results demonstrate that both parents' phenotypes influence offspring performance through nongenetic effects, their relative contribution varying over the course of progeny's life.

Impact of sleep, screen time, depression and stress on weight change in the intensive weight loss phase of the LIFE study.

BACKGROUND: The LIFE study is a two-phase randomized clinical trial comparing two approaches to maintaining weight loss following guided weight loss. Phase I provided a nonrandomized intensive 6-month behavioral weight loss intervention to 472 obese (body mass index 30-50) adult participants. Phase II is the randomized weight loss maintenance portion of the study. This paper focuses on Phase I measures of sleep, screen time, depression and stress. METHODS: The Phase I intervention consisted of 22 group sessions led over 26 weeks by behavioral counselors. Recommendations included reducing dietary intake by 500 calories per day, adopting the Dietary Approaches to Stop Hypertension (DASH) dietary pattern and increasing physical exercise to at least 180 min per week. Measures reported here are sleep time, insomnia, screen time, depression and stress at entry and post-weight loss intervention follow-up. RESULTS: The mean weight loss for all participants over the intensive Phase I weight loss intervention was 6.3 kg (s.d. 7.1). Sixty percent (N=285) of participants lost at least 4.5 kg (10 lbs) and were randomized into Phase II. Participants (N=472) attended a mean of 73.1% (s.d. 26.7) of sessions, completed 5.1 (s.d. 1.9) daily food records/week, and reported 195.1 min (s.d. 123.1) of exercise per week. Using logistic regression, sleep time (quadratic trend, P=0.030) and lower stress (P=0.024) at entry predicted success in the weight loss program, and lower stress predicted greater weight loss during Phase I (P=0.021). In addition, weight loss was significantly correlated with declines in stress (P=0.048) and depression (P=0.035). CONCLUSION: Results suggest that clinicians and investigators might consider targeting sleep, depression and stress as part of a behavioral weight loss intervention.

Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss.

AIMS/HYPOTHESIS: Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss. METHODS: Targeted mass spectrometry-based profiling of 60 metabolites, plus biochemical assays of NEFA, ß-hydroxybutyrate, ketones, insulin and glucose were performed in baseline and 6 month plasma samples from 500 participants who had lost ≥4 kg during Phase I of the Weight Loss Maintenance (WLM) trial. Homeostatic model assessment of insulin resistance (HOMA-IR) and change in HOMA-IR with weight loss (∆HOMA-IR) were calculated. Principal components analysis (PCA) and mixed models adjusted for race, sex, baseline weight, and amount of weight loss were used; findings were validated in an independent cohort of patients (n = 22). RESULTS: Mean weight loss was 8.67 ± 4.28 kg; mean ∆HOMA-IR was -0.80 ± 1.73, range -28.9 to 4.82). Baseline PCA-derived factor 3 (branched chain amino acids [BCAAs] and associated catabolites) correlated with baseline HOMA-IR (r = 0.50, p < 0.0001) and independently associated with ∆HOMA-IR (p < 0.0001). ∆HOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ∆HOMA-IR (r = 0.24). These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ∆HOMA-IR (p = 0.007). CONCLUSIONS/INTERPRETATION: A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.

Experimental studies of the role of the little raven (Corvus mellori) in surveillance for West Nile virus in Australia.

OBJECTIVE: To study the potential role of an Australian corvid, the little raven (Corvus mellori), in the surveillance for exotic West Nile virus (WNV) in Australia. METHOD: In a series of trials, little ravens were infected with WNV (strain 4132 New York 1999) and Kunjin virus (strain K42886) by the intramuscular route. They were observed for 20 days during which blood and swab samples were taken for virus isolation. Tissue samples were taken from ravens humanely killed during the acute infection period, and at the termination of the trials, for virus isolation, histopathology and immunohistochemistry. RESULTS: Ravens infected with WNV became mildly ill, but all recovered and seroconverted. Blood virus titres peaked around 3 to 4 days after inoculation at levels between 10(3.0) to 10(7.5) plaque forming units/mL. Virus or viral antigen was detected in spleen, liver, lung, kidney, intestine, testis and ovary by virus isolation and/or immunohistochemistry. WNV was detected in oral and cloacal swabs from 2 to 7 days post inoculation. The molecular and pathogenic characteristics of the inocula were consistent with them being of high virulence, as expected for this isolate. Ravens infected with Kunjin virus developed viraemia and seroconverted, although they did not develop disease. CONCLUSIONS: Little ravens do not develop severe disease in response to virulent WNV infection and for this reason may not be important sentinel hosts in the event of an outbreak of WNV, as in North America. However, as they have relatively high viraemias, they may be able to support virus cycles.

Maternal fumonisin exposure as a risk factor for neural tube defects.

Fumonisins are mycotoxins produced by the fungus F. verticillioides, a common contaminant of maize (corn) worldwide. Maternal consumption of fumonisin B(1)-contaminated maize during early pregnancy has recently been associated with increased risk for neural tube defects (NTDs) in human populations that rely heavily on maize as a dietary staple. Experimental administration of purified fumonisin to mice early in gestation also results in an increased incidence of NTDs in exposed offspring. Fumonisin inhibits the enzyme ceramide synthase in de novo sphingolipid biosynthesis, resulting in an elevation of free sphingoid bases and depletion of downstream glycosphingolipids. Increased sphingoid base metabolites (i.e., sphinganine-1-phosphate) may perturb signaling cascades involved in embryonic morphogenesis by functioning as ligands for sphingosine-1-P (S1P) receptors, a family of G-protein-coupled receptors that regulate key biological processes such as cell survival/proliferation, differentiation and migration. Fumonisin-induced depletion of glycosphingolipids impairs expression and function of the GPI-anchored folate receptor (Folr1), which may also contribute to adverse pregnancy outcomes. NTDs appear to be multifactorial in origin, involving complex gene-nutrient-environment interactions. Vitamin supplements containing folic acid have been shown to reduce the occurrence of NTDs, and may help protect the developing fetus from environmental teratogens. Fumonisins appear to be an environmental risk factor for birth defects, although other aspects of maternal nutrition and genetics play interactive roles in determining pregnancy outcome. Minimizing exposures to mycotoxins through enhanced agricultural practices, identifying biomarkers of exposure, characterizing mechanisms of toxicity, and improving maternal nutrition are all important strategies for reducing the NTD burden in susceptible human populations.