Premature ovarian insufficiency: Pathogenesis and management.
The term premature ovarian insufficiency (POI) describes a continuum of declining ovarian function in a young woman, resulting in an earlier than average menopause. It is a term that reflects the variable nature of the condition and is substantially less emotive than the formerly used "premature ovarian failure" which signaled a single event in time. Contrary to the decline in the age of menarche seen over the last 3-4 decades there has been no similar change in the age of menopause. In developed nations, the average age for cessation of menstrual cycles is 50-52 years. The age is younger among women from developing nations. Much has been written about POI despite a lack of good data on the incidence of this condition. It is believed that 1% of women under the age of 40 years and 0.1% under the age of 30 years will develop POI. Research is increasingly providing information about the pathogenesis and treatments are being developed to better preserve ovarian function during cancer treatment and to improve fertility options. This narrative review summarizes the current literature to provide an approach to best practice management of POI.


Hyaluronic acid slows down collagen membrane degradation in uncontrolled diabetic rats.
To examine the in vitro biokinetics of hyaluronic acid (HA) from a collagen membrane (CM) and to evaluate the in vivo effect of immersion of the CM in HA solution on its degradation in streptozotocin (STZ)-induced diabetes conditions in a rat calvaria subcutaneous model. CM degradation is accelerated in uncontrolled diabetic rats. Immersion of CM in HA has been suggested to decrease their resorption rate without interfering with their tissue integration and structural degradation. However, it is unknown to what extent CM degradation may be influenced by its immersion in HA solution under a condition mimicking a medically compromised situation with an increased inflammatory level such as diabetes. CMs were soaked in cross-linked HA. Protein adsorption and the HA release were quantified by ELISA. Diabetes was induced in sixteen rats, while 16 healthy rats served as control. CM was prepared and labeled prior to implantation with Biotin. Seventeen CM were immersed in HA and 17 CM in PBS. In each animal, one test or one control disk was implanted. In order to compare the collagen content, two similar non-implanted CM were used as baseline. Fourteen days after surgery, thirty-two animals were sacrificed. The entire calvaria including the skin above, was chemically fixed, decalcified, and embedded in paraffin. Five-μm-thick sections were analyzed histologically and histomorphometrically using H&E and avidin-peroxidase staining. The in vitro results demonstrated that the CM adsorbed roughly 80% of the total HA content. After 10 days, 36.3% of the initial HA remained on the CM. The in vivo results demonstrated that diabetes significantly reduced the thickness of the CM, while HA had a significant effect on keeping the membrane thickness. HA increased the residual collagen content in the diabetic group (P < 0.0001) but no such effect was observed in the healthy group. Immersion of CM in HA prior to the implantation delays membrane degradation in uncontrolled diabetic compared with normoglycemic rats.


Selective effects of alpha-methyldopa on myocardial cell components independent of cell size in normotensive and genetically hypertensive rats.
Alpha methyldopa has been shown to modify left ventricular mass and normalize mitochondria/myofibrils volume ratio in spontaneously hypertensive rats (SHR) when administered during the stage of developing cardiac hypertrophy (Tomanek et al., Cardiovas Res 23: 173, 1979). To evaluate the long-term effects of this antihypertensive agent, the drug was administered to SHR and normotensive (WKY) rats between the ages of 1 and 12 months. In another group of SHR and WKY, treatment was delayed until the age of 12 months and the animals were then treated for 3 months. Treatment with alpha-methyldopa had similar effects on systolic blood pressures in both SHR groups; group means (+/- SEM) were 151 +/- 1 in the long-term treatment group and 157 +/- 5 in the delayed treatment group compared to 178 +/- 4 and 176 +/- 3 for their respective controls. While left ventricular weight and cell size were significantly lower after early long-term treatment (compared to nontreated SHR), delayed treatment had no significant effect on these indices of left ventricular mass. Despite the effectiveness of early long-term treatment in modifying left ventricular mass, the relative volumes of mitochondria and myofibrils, as well as other cellular components (sarcoplasm), were not altered. In contrast, delayed treatment caused a significant increase (approximately twofold) in relative sarcoplasmic volume and a decrease in relative myofibrillar volume in both SHR and WKY. These findings indicate that shifts in the relative volumes of intracellular components after alpha-methyldopa are independent of cell size and blood pressure. Furthermore, the data suggest that the effects of alpha-methyldopa on the myocardial cell are dependent on or influenced by factors associated with the development or stabilization of hypertrophy and/or age.


Electronic health record goes personal world-wide.
Increasing patient demand for convenient access to their own healthcare data has led to more personal use of the Electronic Health Record (EHR). With "consumer empowerment" being an important issue of EHR, we are seeing a more "patient-centric" approach of EHR from countries around the world. Researchers have reported on issues in EHR sharing including concerns on privacy and security, consumer empowerment, competition among providers, and content standards. This study attempts to analyze prior research and to synthesize comprehensive, empirically-based conceptual models of EHR for personal use. We use "B2C(2B) " to represent this new behavior of EHR sharing and exchange, with "consumer" in the center stage. Based on different information sharing mechanisms, we summarized the "B2C(2B) " behavior into three models, namely, the Inexpensive data media model, the Internet patient portal model and the Personal portable device model. Models each have their own strengths and weaknesses in their ways to share patient data and to address privacy and security concerns. Personal use of EHR under the B2C(2B) model does look promising based on our study. We started to observe a trend that governments around the world are embarking on related projects. With multiple stake-holders involved, we are only beginning to understand the complexity of such undertakings.


The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS.
RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.


Spontaneous interstitial nephritis in kdkd mice. I. An experimental model of autoimmune renal disease.
Mice of the kdkd strain predictably develop a spontaneous tubulointerstitial nephritis after 8 wk of life. In this report we have examined several aspects of the nephritogenic immune response that seemed potentially relevant to the expression of this progressively destructive renal lesion. Of particular interest is that by direct immunofluorescence we were unable to demonstrate the presence of antibodies to determinants in the tubulointerstitium. Serum and kidney eluates from nephritic mice, furthermore, did not stain any renal structures in normal kidney. We did observe, however, that disease could be transferred through kdkd----CBA/Ca bone marrow chimeras, and prevented, in the reverse direction, by CBA/Ca----kdkd chimeras. The development of the interstitial lesion was markedly inhibited by thymectomy with T cell depletion, but disease could not be adoptively transferred with cells or serum from nephritic mice. The interstitial lesions also did not appear in (kdkd X CBA/Ca)F1 hybrids, and the development of disease in kdkd mice could be inhibited by treatment with adoptively transferred T cells from CBA/Ca mice. With these new findings we now hypothesize that susceptibility to the expression of interstitial nephritis in kdkd mice involves the cellular limb of the immune system, and may be related, in part, to alterations in regulatory T cell function.


Inulin and oligofructose: impact on intestinal diseases and disorders.
A large and diverse variety of bacteria have evolved and adapted to live in the human intestinal habitat in a symbiotic arrangement that influences both physiology and pathology in the host. Symbiosis between host and flora can be optimised by prebiotics. Inulin-type fructans have been shown to improve the metabolic functions of the commensal flora. Clinical and experimental data suggest that they also improve the gut mucosal barrier. Furthermore, modulation of the trophic functions of the flora by these prebiotics could help in the prevention of inflammatory bowel diseases. The anti-inflammatory effects of inulin or oligofructose have been assessed in the rat model of distal colitis induced by dextran sodium sulphate, which histologically resembles human ulcerative colitis, and in the trinitrobenzene sulphonic acid model that resembles human Crohn's disease. Both inulin and oligofructose stimulate colonic production of SCFA and favour the growth of indigenous lactobacilli and/or bifidobacteria. These effects are associated with reduced mucosal inflammation and decreased mucosal lesion scores. Inulin has also been tested in a placebo-controlled clinical trial in patients with relapsing pouchitis. Treatment reduced endoscopic and histological parameters of inflammation of the pouch mucosa. Inulin and oligofructose may offer an opportunity to prevent chronic inflammatory intestinal disorders, and this potential should be tested in further clinical studies.


A vital role for interleukin-21 in the control of a chronic viral infection.
Understanding the factors that regulate the induction, quality, and longevity of antiviral T cell responses is essential for devising rational strategies to prevent or combat infections. In this study, we show that interleukin-21 (IL-21), likely produced by CD4+ T cells, directly influences the generation of polyfunctional CD8+ T cells and that the number of CD4+ T cells that produce IL-21 differs markedly between acute and chronic infections. IL-21 regulates the development of CD8+ T cell exhaustion and the ability to contain chronic lymphocytic choriomeningitis virus infection. Thus, IL-21 serves as a critical helper factor that shapes the functional quality of antiviral CD8+ T cells and is required for viral control.


Treadmill training increases the motor activity and neuron survival of the cerebellum in a mouse model of spinocerebellar ataxia type 1.
Spinocerebellar ataxia (SCA) type 1 (SCA1) is a rare autosomal dominant disorder that is characterized by worsening of disordered coordination, ataxia of the trunk, and other neurological symptoms. Physical activity improves both mobility and the daily living activities of patients with SCA. Intervention with daily regular treadmill exercise may slow the deterioration of cerebellar neurons in SCA1. Therefore, the signal changes and performance of cerebellar neurons after exercise in SCA1 was investigated in this study. We employed a transgenic mouse model of SCA1, generated by amplifying the cytosine-adenine-guanine trinucleotide repeat expansions, and the mice underwent 1 month of moderate daily treadmill exercise for 1 hour. The rotarod test revealed that the motor function of the SCA1 mice that underwent training was superior to that of the control SCA1 mice, which did not undergo training. Moreover, the cerebellar pathology revealed preserved Purkinje neurons stained by carbindin with an increase of the neuronal Per Arnt Sim domain protein 4, a key regulation in the structural and functional plasticity of neurons, in the excised SCA1 mice relative to the controls. The mechanism was related to an increase of phosphorylation of ribosomal protein S6, a downstream target of the mammalian target of rapamycin pathway, but not to autophagy activation. This study determined that regular treadmill exercise may play a crucial role in the viable support of cerebellar neurons in SCA1.


Topical Sphenopalatine Ganglion Block Compared With Epidural Blood Patch for Postdural Puncture Headache Management in Postpartum Patients: A Retrospective Review.
Postdural puncture headache (PDPH) is a severe and debilitating complication of unintentional dural puncture. The criterion-standard treatment for PDPH has been epidural blood patch (EBP), but it is an invasive intervention with the potential for severe complications, such as meningitis and paralysis. We believe this is the first ever 17-year retrospective chart review in which we compare the effectiveness of sphenopalatine ganglion block (SPGB) to EBP for PDPH treatment in postpartum patients. We conducted a chart review of the first authors' obstetric patients who experienced PDPH from an unintentional dural puncture from a 17-gauge Tuohy needle for labor epidural from January 1997 to July 2014. Demographic characteristics, headache severity, and associated symptoms were collected prior to treatment. Forty-two patients who received SPGB and 39 patients who received EBP were identified. Residual headache, recovery from associated symptoms, and new treatment complications were compared between the 2 groups at 30 minutes, 1 hour, 24 hours, 48 hours, and 1 week posttreatment. A greater number of patients showed significant relief in their PDPH and associated symptoms at 30 and 60 minutes after treatment with SPGB than after treatment with EBP (P < 0.01). Only the EBP patients complained of posttreatment complications, which all resolved in 48 hours. A greater number of patients experienced a quicker onset of headache relief, without any new complications, from treatment with SPGB versus EBP. We believe that SPGB is a safe, inexpensive, and well-tolerated treatment. We hope that clinical trials will be conducted in the future that will confirm our findings and allow us to recommend SPGB for PDPH treatment prior to offering patients EBP.


Serum 25-hydroxyvitamin D and hypertension in premenopausal and postmenopausal women: National Health and Nutrition Examination Surveys 2007-2010.
A recent meta-analysis suggested that the association between vitamin D and risk of hypertension was markedly stronger in women aged <55 years in observational data, while the association became null in women aged ≥55 years. We therefore hypothesized that this difference in associations might potentially be caused by the change in oestrogen around menopause. Our objective was to investigate associations between vitamin D status and hypertension risk and to evaluate those associations as they may differ according to menopausal status. A cross-sectional population survey conducted by the US Centers for Disease Control and Prevention, National Center for Health Statistics. The National Health and Nutrition Examination Surveys (NHANES) 2007-2010 formed the setting for the present study. We analysed data from 2098 premenopausal women and 2298 postmenopausal women. After adjustment for sociodemographic, behavioural and dietary factors, higher concentrations both of serum total 25-hydroxyvitamin D (25(OH)D) and serum 25-hydroxycholecalciferol (25(OH)D3) revealed significant dose-dependent trends with lower risk of hypertension (Ptrend = 0·005 and 0·014, respectively) in premenopausal women. In those women, 25(OH)D ≥ 50 nmol/l (sufficient; in contrast to deficient, vitamin D < 30 nmol/l) appeared to have a protective effect against hypertension (OR = 0·64, 95 % CI 0·39, 1·02 for total 25(OH)D and OR = 0·60, 95 % CI 0·36, 1·00 for 25(OH)D3). Neither association with hypertension was observed in postmenopausal women. Serum 25(OH)D concentrations were associated with lower risk of hypertension in premenopausal women, but not in postmenopausal women.


Fertilization is not a new beginning: the relationship between sperm longevity and offspring performance.
Sperm are the most diverse cell type known: varying not only among- and within- species, but also among- and within-ejaculates of a single male. Recently, the causes and consequences of variability in sperm phenotypes have received much attention, but the importance of within-ejaculate variability remains largely unknown. Correlative evidence suggests that reduced within-ejaculate variation in sperm phenotype increases a male's fertilization success in competitive conditions; but the transgenerational consequences of within-ejaculate variation in sperm phenotype remain relatively unexplored. Here we examine the relationship between sperm longevity and offspring performance in a marine invertebrate with external fertilization, Styela plicata. Offspring sired by longer-lived sperm had higher performance compared to offspring sired by freshly-extracted sperm of the same ejaculate, both in the laboratory and the field. This indicates that within-ejaculate differences in sperm longevity can influence offspring fitness - a source of variability in offspring phenotypes that has not previously been considered. Links between sperm phenotype and offspring performance may constrain responses to selection on either sperm or offspring traits, with broad ecological and evolutionary implications.


Prevalence of and risks for internal contamination among hospital staff caring for a patient contaminated with a fatal dose of polonium-210.
Alexander Litvinenko died on November 23, 2006, from acute radiation sickness syndrome caused by ingestion of polonium-210 (²¹⁰Po). The objective was to assess the prevalence of and risk factors for internal contamination with ²¹⁰Po in healthcare workers (HCWs) caring for the contaminated patient. Hospital. HCWs who had direct contact with the patient. We interviewed 43 HCWs and enquired about their activities and use of personal protective equipment (PPE). Internal contamination was defined as urinary ²¹⁰Po excretion above 20 mBq within 24 hours. We obtained risk ratios (RRs) for internal contamination using Poisson regression. Thirty-seven HCWs (86%) responded, and 8 (22%) showed evidence of internal contamination, all at very low levels that were unlikely to cause adverse health outcomes. Daily care of the patient (washing and toileting the patient) was the main risk factor (RR, 3.6 [95% confidence interval (CI), 1.1-11.6]). In contrast, planned invasive procedures were not associated with a higher risk. There was some evidence of a higher risk associated with handling blood samples (RR, 3.5 [95% CI, 0.8-15.6]) and changing urine bags and/or collecting urine samples (RR, 2.7 [95% CI, 0.8-9.5]). There was also some evidence that those who reported not always using standard PPE were at higher risk than were others (RR, 2.5 [95% CI, 0.8-8.1]). The sensitive quantitative measurement enabled us to identify factors associated with contamination, which by analogy to other conditions with similar transmission mechanisms may help improve protection and preparedness in staff dealing with an ill patient who experiences an unknown illness.


How feedback biases give ineffective medical treatments a good reputation.
Medical treatments with no direct effect (like homeopathy) or that cause harm (like bloodletting) are common across cultures and throughout history. How do such treatments spread and persist? Most medical treatments result in a range of outcomes: some people improve while others deteriorate. If the people who improve are more inclined to tell others about their experiences than the people who deteriorate, ineffective or even harmful treatments can maintain a good reputation. The intent of this study was to test the hypothesis that positive outcomes are overrepresented in online medical product reviews, to examine if this reputational distortion is large enough to bias people's decisions, and to explore the implications of this bias for the cultural evolution of medical treatments. We compared outcomes of weight loss treatments and fertility treatments in clinical trials to outcomes reported in 1901 reviews on Amazon. Then, in a series of experiments, we evaluated people's choice of weight loss diet after reading different reviews. Finally, a mathematical model was used to examine if this bias could result in less effective treatments having a better reputation than more effective treatments. Data are consistent with the hypothesis that people with better outcomes are more inclined to write reviews. After 6 months on the diet, 93% (64/69) of online reviewers reported a weight loss of 10 kg or more while just 27% (19/71) of clinical trial participants experienced this level of weight change. A similar positive distortion was found in fertility treatment reviews. In a series of experiments, we show that people are more inclined to begin a diet with many positive reviews, than a diet with reviews that are representative of the diet's true effect. A mathematical model of medical cultural evolution shows that the size of the positive distortion critically depends on the shape of the outcome distribution. Online reviews overestimate the benefits of medical treatments, probably because people with negative outcomes are less inclined to tell others about their experiences. This bias can enable ineffective medical treatments to maintain a good reputation.


Lessons from SADHART, ENRICHD, and other trials.
Depression is highly prevalent in patients with cardiovascular disease and is independently associated with a poor prognosis when present. A very important aspect of continued therapeutic advances in this field will be the ability to show a convincing connection between the treatment of depression in patients with heart disease and a reduction in morbidity and mortality associated with the co-occurrence of these conditions. The recent SADHART (Sertraline AntiDepressant Heart Attack Trial) investigation demonstrated that sertraline is safe and efficacious in depressed patients with ischemic heart disease but was underpowered to detect a mortality difference between sertraline and placebo. The ENRICHD (ENhancing Recovery in Coronary Heart Disease) trial showed that cognitive-behavioral therapy is effective for treating depression but had no impact on cardiovascular morbidity or mortality. There are a number of methodologic complexities associated with research regarding depression and cardiovascular disease, including difficulties in the definition and measurement of depression, complexities in the conduction of large-scale trials, ethical considerations surrounding the use of placebo, and interpretation of trial results. In addition, the lack of certainty regarding the pathophysiologic link between depression and cardiovascular disease means that there is a lack of pharmacotherapy targeted specifically at the dysregulated physiology that might explain the increased morbidity and mortality seen when these two conditions occur together.


Linear accelerator-based single-fraction stereotactic radiosurgery versus hypofractionated stereotactic radiotherapy for intact and resected brain metastases up to 3 cm: A multi-institutional retrospective analysis.
Single-fraction stereotactic radiosurgery (SF-SRS) is typically used to provide local control of brain metastases. Recently, hypofractionated stereotactic radiotherapy (HF-SRT) has been utilized for large brain metastases. Data comparing these two modalities are limited for brain metastases ≤3 cm. Patients with brain metastases receiving linear accelerator-based SF-SRS or HF-SRT were identified at three institutions. Local progression-free survival (LPFS), intracranial progression-free survival (ICPFS), overall survival (OS), and radionecrosis-free survival (RNFS) were determined from time of treatment. 108 patients (76 intact, 32 resected) with 184 brain metastases (142 intact, 42 resected) were included. There were no significant differences between SF-SRS and HF-SRT for intact metastases in 1-year LPFS (62.8% vs. 58.5%, p=0.631), ICPFS (56.9% vs. 55.3%, p=0.300), and OS (71.6% vs. 70.6%, p=0.096), or for resected metastases in 1-year LPFS (67.3% vs. 57.8%, p=0.288), ICPFS (64.8% vs. 57%, p=0.291), and OS (64.8% vs. 66.1%, p=0.603). There were also no significant differences in 1-year RNFS between SF-SRS and HF-SRT (92% vs. 92%, p=0.325). There were no significant differences in LPFS, ICPFS, OS, and RNFS between SF-SRS and HF-SRT for brain metastases ≤3 cm suggesting SF-SRS may be preferred due to similar outcomes and reduced number of fractions.


A Review of Nonpharmacological Strategies in the Treatment of Relative Energy Deficiency in Sport.
Relative energy deficiency in sport (RED-S) can result in negative health and performance outcomes in both male and female athletes. The underlying etiology of RED-S is low energy availability (LEA), which occurs when there is insufficient dietary energy intake to meet exercise energy expenditure, corrected for fat-free mass, leaving inadequate energy available to ensure homeostasis and adequate energy turnover (optimize normal bodily functions to positively impact health), but also optimizing recovery, training adaptations, and performance. As such, treatment of RED-S involves increasing energy intake and/or decreasing exercise energy expenditure to address the underlying LEA. Clinically, however, the time burden and methodological errors associated with the quantification of energy intake, exercise energy expenditure, and fat-free mass to assess energy availability in free-living conditions make it difficult for the practitioner to implement in everyday practice. Furthermore, interpretation is complicated by the lack of validated energy availability thresholds, which can result in compromised health and performance outcomes in male and female athletes across various stages of maturation, ethnic races, and different types of sports. This narrative review focuses on pragmatic nonpharmacological strategies in the treatment of RED-S, featuring factors such as low carbohydrate availability, within-day prolonged periods of LEA, insufficient intake of bone-building nutrients, lack of mechanical bone stress, and/or psychogenic stress. This includes the implementation of strategies that address exacerbating factors of LEA, as well as novel treatment methods and underlying mechanisms of action, while highlighting areas of further research.


Increased breast cancer prevalence among female orthopedic surgeons.
As a result of low-dose ionizing radiation exposure during clinical practice, female orthopaedic surgeons may be at increased risk for breast cancer. The 2009 American Academy of Orthopaedic Surgeons (AAOS) membership directory was used to mail a survey to all female AAOS fellows. Survey responses were collected between June 2009 and June 2010 among 505 (69.7%) of the eligible women. We calculated standardized prevalence ratios (SPRs) and 95% confidence intervals (CIs) by dividing the observed number of cancers among female orthopaedic surgeons by the expected number, based on the gender-specific, age-specific, and race-specific cancer prevalence statistics in the general U.S. population. We compared the distribution of breast cancer risk factors in our study population to that of the women in the 2007 California Health Interview Survey (CHIS, n=30,541). Twenty-four women reported a prior diagnosis of invasive cancer. Female orthopaedic surgeons had a prevalence of cancer that was 85% higher than that of the general U.S. female population (SPR 1.85, 95% CI 1.19-2.76). Orthopaedic surgeons in our study also had a statistically significant 2.9-fold higher prevalence of breast cancer compared to the general U.S. female population (SPR 2.9, 95% CI 1.66-4.71). Survey respondents had a higher prevalence of both protective and predisposing breast cancer factors compared to California women. Our findings confirm that breast cancer prevalence is elevated among female orthopaedic surgeons. Although further research is needed to determine the factors behind this population's hypothesized increased risk, taken together, our results and others suggest that the orthopaedic community consider educating current practitioners of the use of protective shielding and other modifiable breast cancer risk factors.


Sources of error in total knee arthroplasty.
The purpose of this study was to identify the procedural steps in a total knee arthroplasty (TKA) in which technical errors occur and to quantify the magnitude of these errors. Forty-nine consecutive TKAs were performed using a traditional exposure and manual instrumentation. An image-free computer navigation system (OrthoPilot; Aesculap AG, Tuttlingen, Germany) was used to measure and compare femoral and tibial alignment at specific procedural points during the TKA; this data was then used to evaluate possible sources of error in the procedure. The femoral cut tended to be made in hyperextension, the tibial cut tended to be made in hyperextension and valgus, and the tibial component tended to be implanted in valgus. This study identified specific points during the performance of a TKA where technical errors occur. This information suggests technical considerations that can help a surgeon achieve more reproducible, durable, and successful outcomes for his or her patients.


A smart theranostic platform for photoacoustic and magnetic resonance dual-imaging-guided photothermal-enhanced chemodynamic therapy.
The use of smart theranostic agents in multimodal imaging and treatment is a promising strategy to overcome the limitations of single mode diagnosis and treatment, and can greatly improve the diagnosis and effects of treatment. In this study, a gold@manganese dioxide (Au@MnO2) core-shell nanostructure was designed as a glutathione (GSH)-triggered smart theranostic agent for photoacoustic and magnetic resonance (MR) dual-imaging-guided photothermal-enhanced chemodynamic therapy. Both in vitro and in vivo experiments demonstrated not only that the photoacoustic and MR imaging function of Au@MnO2 could be activated by a high endogenous GSH concentration, but also that after being triggered by the endogenous GSH, Au@MnO2 had an excellent synergistic treatment effect in photothermal-enhanced chemodynamic therapy under the guidance of photoacoustic and MR imaging. This study demonstrated that the use of GSH-triggered Au@MnO2 in photoacoustic and MR dual-imaging-guided photothermal-enhanced chemodynamic therapy is a smart theranostic nanoplatform for the accurate diagnosis and efficient treatment of cancer.


Dynamics of indigenous bacterial communities associated with crude oil degradation in soil microcosms during nutrient-enhanced bioremediation.
Bacterial population dynamics were examined during bioremediation of an African soil contaminated with Arabian light crude oil and nutrient enrichment (biostimulation). Polymerase chain reaction followed by denaturing gradient gel electrophoresis (DGGE) were used to generate bacterial community fingerprints of the different treatments employing the 16S ribosomal ribonucleic acid (rRNA) gene as molecular marker. The DGGE patterns of the nutrient-amended soils indicated the presence of distinguishable bands corresponding to the oil-contaminated-nutrient-enriched soils, which were not present in the oil-contaminated and pristine control soils. Further characterization of the dominant DGGE bands after excision, reamplification and sequencing revealed that Corynebacterium spp., Dietzia spp., Rhodococcus erythropolis sp., Nocardioides sp., Low G+C (guanine plus cytosine) Gram positive bacterial clones and several uncultured bacterial clones were the dominant bacterial groups after biostimulation. Prominent Corynebacterium sp. IC10 sequence was detected across all nutrient-amended soils but not in oil-contaminated control soil. Total heterotrophic and hydrocarbon utilizing bacterial counts increased significantly in the nutrient-amended soils 2 weeks post contamination whereas oil-contaminated and pristine control soils remained fairly stable throughout the experimental period. Gas chromatographic analysis of residual hydrocarbons in biostimulated soils showed marked attenuation of contaminants starting from the second to the sixth week after contamination whereas no significant reduction in hydrocarbon peaks were seen in the oil-contaminated control soil throughout the 6-week experimental period. Results obtained indicated that nutrient amendment of oil-contaminated soil selected and enriched the bacterial communities mainly of the Actinobacteria phylogenetic group capable of surviving in toxic contamination with concomitant biodegradation of the hydrocarbons. The present study therefore demonstrated that the soil investigated harbours hydrocarbon-degrading bacterial populations which can be biostimulated to achieve effective bioremediation of oil-contaminated soil.


Can screening and brief intervention lead to population-level reductions in alcohol-related harm?
A distinction is made between the clinical and public health justifications for screening and brief intervention (SBI) against hazardous and harmful alcohol consumption. Early claims for a public health benefit of SBI derived from research on general medical practitioners' (GPs') advice on smoking cessation, but these claims have not been realized, mainly because GPs have not incorporated SBI into their routine practice. A recent modeling exercise estimated that, if all GPs in England screened every patient at their next consultation, 96% of the general population would be screened over 10 years, with 70-79% of excessive drinkers receiving brief interventions (BI); assuming a 10% success rate, this would probably amount to a population-level effect of SBI. Thus, a public health benefit for SBI presupposes widespread screening; but recent government policy in England favors targeted versus universal screening, and in Scotland screening is based on new registrations and clinical presentation. A recent proposal for a national screening program was rejected by the UK National Health Service's National Screening Committee because 1) there was no good evidence that SBI led to reductions in mortality or morbidity, and 2) a safe, simple, precise, and validated screening test was not available. Even in countries like Sweden and Finland, where expensive national programs to disseminate SBI have been implemented, only a minority of the population has been asked about drinking during health-care visits, and a minority of excessive drinkers has been advised to cut down. Although there has been research on the relationship between treatment for alcohol problems and population-level effects, there has been no such research for SBI, nor have there been experimental investigations of its relationship with population-level measures of alcohol-related harm. These are strongly recommended. In this article, conditions that would allow a population-level effect of SBI to occur are reviewed, including their political acceptability. It is tentatively concluded that widespread dissemination of SBI, without the implementation of alcohol control measures, might have indirect influences on levels of consumption and harm but would be unlikely on its own to result in public health benefits. However, if and when alcohol control measures were introduced, SBI would still have an important role in the battle against alcohol-related harm.


Stüve-Wiedemann syndrome in children surviving infancy: clinical and radiological features.
We report three children from two inbred Arab families with Stüve-Wiedemann syndrome who have survived the first year of life (ages are 6 years, 2.8 years and 2 years). All exhibited a characteristic phenotype resembling that described by Chen et al.[(2001). Am J Med Genet 101:240-245]. In all three children the skeletal abnormalities progressed to severe bowing of the long bones with prominent joints and severe spinal deformity. Neurological symptoms were present in all of them. These included temperature instability with excessive sweating, reduced pain sensation with repeated injury to the tongue and limbs, absent corneal reflexes and a smooth tongue. Mentality was normal in all of them. Radiological changes included under tubulation of the diaphyses, rarefaction and striation of metaphyses, destruction of the femoral heads and spinal deformity. We confirm that survival in this syndrome is possible and that the prognosis improves after the first year of life. This should be taken into consideration when counselling parents of affected children. This report further supports the existence of a characteristic phenotype in Stüve-Wiedemann syndrome survivors which include, in addition to the skeletal abnormalities and distinctive radiological features, neurological symptoms reminiscent of dysautonomia.


Protein kinase A-dependent step(s) in hepatitis C virus entry and infectivity.
Viruses exploit signaling pathways to their advantage during multiple stages of their life cycle. We demonstrate a role for protein kinase A (PKA) in the hepatitis C virus (HCV) life cycle. The inhibition of PKA with H89, cyclic AMP (cAMP) antagonists, or the protein kinase inhibitor peptide reduced HCV entry into Huh-7.5 hepatoma cells. Bioluminescence resonance energy transfer methodology allowed us to investigate the PKA isoform specificity of the cAMP antagonists in Huh-7.5 cells, suggesting a role for PKA type II in HCV internalization. Since viral entry is dependent on the host cell expression of CD81, scavenger receptor BI, and claudin-1 (CLDN1), we studied the role of PKA in regulating viral receptor localization by confocal imaging and fluorescence resonance energy transfer (FRET) analysis. Inhibiting PKA activity in Huh-7.5 cells induced a reorganization of CLDN1 from the plasma membrane to an intracellular vesicular location(s) and disrupted FRET between CLDN1 and CD81, demonstrating the importance of CLDN1 expression at the plasma membrane for viral receptor activity. Inhibiting PKA activity in Huh-7.5 cells reduced the infectivity of extracellular virus without modulating the level of cell-free HCV RNA, suggesting that particle secretion was not affected but that specific infectivity was reduced. Viral particles released from H89-treated cells displayed the same range of buoyant densities as did those from control cells, suggesting that viral protein association with lipoproteins is not regulated by PKA. HCV infection of Huh-7.5 cells increased cAMP levels and phosphorylated PKA substrates, supporting a model where infection activates PKA in a cAMP-dependent manner to promote virus release and transmission.


A former amino terminal signal sequence engineered to an internal location directs translocation of both flanking protein domains.
To determine whether a functional amino terminal signal sequence can be active at an internal position, a hybrid gene was constructed in which the entire coding region of bovine preprolactin cDNA was inserted into chimpanzee alpha-globin cDNA 109 codons downstream from the initiation codon of globin. When RNA synthesized in vitro from this plasmid (pSPGP1) was translated in the rabbit reticulocyte cell-free system, a 32-kD protein was produced that was both prolactin and globin immunoreactive. When microsomal membranes were present during translation (but not when added posttranslationally), a 26-kD and a 14-kD product were also observed. By immunoreactivity and electrophoretic mobility, the 26-kD protein was identical to mature prolactin, and the 14-kD protein appeared to be the globin domain with the prolactin signal sequence attached at its carboxy terminus. From (a) posttranslational proteolysis in the presence and absence of detergent, (b) sedimentation of vesicles in the presence and absence of sodium carbonate pH 11.5, and (c) N-linked glycosylation of the globin-immunoreactive fragment after insertion of an Asn-X-Ser N-linked glycosylation site into the globin coding region of pSPGP1, it appears that all of the 26-kD and some of the 14-kD products, but none of the 32-kD precursor, have been translocated to the lumen of the membrane vesicles. Thus, when engineered to an internal position, the prolactin signal sequence is able to translocate both flanking protein domains. These data have implications for the understanding of translocation of proteins across the membrane of the endoplasmic reticulum.


MERS-CoV diagnosis: An update.
Diagnosis of MERS-Cov still a major concern in most of daignostic laboratories. To date the Real-time Polymerase Chain reaction (RT-PCR) is the mainstay for diagnosis of MERS-CoV. RT-PCR has limitations, including a long turnaround time and lack of common measurements and correlations with Viral Load (VL). It is recommended to screen for MERS-CoV using RT-PCR of the upstream of envelope gene (upE) followed by confirmation of the presence of one of the following genes; open reading frame 1A, 1B genes or nucleocapsid (N) gene. Scientists are looking to implement viral sequencing on all negative samples by RT-PCR and they beleive that can be exposed to another level of testing using sequencing of the RNA-dependent RNA polymerase (RdRp) gene or N gene and in this case a positive result is diagnostic. It is also very important to maintain a contineous and random sequencing for MERS-Cov samples to be able to pick early viral mutations. Serological assays still not widely or routinely performed, and a lot of studies looking to implement such method in routine patient's testings.


Effective induction of death in mesothelioma cells with magnetite nanoparticles under an alternating magnetic field.
With the objective of finding an avenue for development of magnetic hyperthermia as an effective mesothelioma treatment, the influence of heating by magnetite nanoparticles (MNPs) with a diameter of ~40nm, which were incorporated into cells and then subjected to AC magnetic field, on induction of cell death was investigated in all three histological subtypes of human mesothelioma cells (i.e., epithelioid NCI-H28, sarcomatoid NCI-H2052, and biphasic MSTO-211H cells). Cellular uptake of MNPs was observed in all cell types, but the amount of MNPs incorporated per cell into MSTO-211H cells was smaller than in NCI-H28 and NCI-H2052 cells. On the other hand, cell death induced by cellular uptake of MNPs was observed specifically in MSTO-211H cells. Hence, when cells are heated by intracellular MNPs under AC magnetic field, a high degree of cell mortality in NCI-H28 and NCI-H2052 cells is induced by the temperature increase derived from the high amount of intracellular MNPs, but the combination of intracellular heating and cell-type-specific toxicity of MNPs induced high rates of cell death in MSTO-211H cells even at a lower temperature. Almost all of the heated cells were dead after 24-h incubation at 37°C in all histological subtypes. Additionally, higher mortalities were observed in all three types of mesothelioma cells after MNPs-heating, as compared to the heating with a thermostatic bath. Herein, the significance of cellular uptake of MNPs for effectively inducing cell death in mesothelioma has been demonstrated in vitro.


DAVID: Database for Annotation, Visualization, and Integrated Discovery.
Functional annotation of differentially expressed genes is a necessary and critical step in the analysis of microarray data. The distributed nature of biological knowledge frequently requires researchers to navigate through numerous web-accessible databases gathering information one gene at a time. A more judicious approach is to provide query-based access to an integrated database that disseminates biologically rich information across large datasets and displays graphic summaries of functional information. Database for Annotation, Visualization, and Integrated Discovery (DAVID; http://www.david.niaid.nih.gov) addresses this need via four web-based analysis modules: 1) Annotation Tool - rapidly appends descriptive data from several public databases to lists of genes; 2) GoCharts - assigns genes to Gene Ontology functional categories based on user selected classifications and term specificity level; 3) KeggCharts - assigns genes to KEGG metabolic processes and enables users to view genes in the context of biochemical pathway maps; and 4) DomainCharts - groups genes according to PFAM conserved protein domains. Analysis results and graphical displays remain dynamically linked to primary data and external data repositories, thereby furnishing in-depth as well as broad-based data coverage. The functionality provided by DAVID accelerates the analysis of genome-scale datasets by facilitating the transition from data collection to biological meaning.


Pregabalin Does Not Increase Risk of Heart Failure Exacerbation in Patients With Pre-existing Heart Failure.
Through actions of calcium channel trafficking inhibition and sodium/water retention, pregabalin may increase the risk of acute heart failure (AHF). The objective of this study was to determine the prevalence of heart failure (HF) acute exacerbations, measured by a composite of emergency department (ED) visits, per-patient per-year (PPPY) hospitalizations, time-to first ED admission, and time-to hospitalizations in pre-existing HF patients taking pregabalin compared with those who were pregabalin-naive. A retrospective cohort study of pregabalin users with HF were propensity score-matched to pregabalin-naïve patients with HF to evaluate the composite of ED admissions or PPPY hospitalizations, time-to first ED admission, and time-to hospitalizations during the 365 days post-index. Doubly robust generalized linear regression and Cox-proportional hazard regression modeling were undertaken for analysis of differences between groups. The matched cohort of 385 pregabalin users and 3460 pregabalin nonusers were principally middle-aged, equally gender distributed, and primary Caucasian. Most patients were on guideline-directed HF medical therapy. The estimated cumulative incidence of the primary outcome was a hazard ratio of 1.099 (95% CI: 0.789-1.530; P = 0.58). This large, single-center, cohort study shows pregabalin is not associated with an increased risk of AHF events in patients with pre-existing HF.


Liposomal Curcumin is Better than Curcumin to Alleviate Complications in Experimental Diabetic Mellitus.
Curcumin (CC) is known to have anti-inflammatory and anti-oxidative properties and has already been tested for its efficiency in different diseases including diabetes mellitus (DM). New formulations and route administration were designed to obtain products with higher bioavailability. Our study aimed to test the effect of intraperitoneal (i.p.) administration of liposomal curcumin (lCC) as pre-treatment in streptozotocin(STZ)-induced DM in rats on oxidative stress, liver, and pancreatic functional parameters. Forty-two Wistar-Bratislava rats were randomly divided into six groups (seven animals/group): control (no diabetes), control-STZ (STZ-induced DM -60 mg/100g body weight a single dose intraperitoneal administration, and no CC pre-treatment), two groups with DM and CC pre-treatment (1mg/100g bw-STZ + CC1, 2 mg/100g bw-STZ + CC2), and two groups with DM and lCC pre-treatment (1 mg/100g bw-STZ + lCC1, 2 mg/100g bw-STZ + lCC1). Intraperitoneal administration of Curcumin in diabetic rats showed a significant reduction of nitric oxide, malondialdehyde, total oxidative stress, and catalase for both evaluated formulations (CC and lCC) compared to control group (p < 0.005), with higher efficacy of lCC formulation compared to CC solution (p < 0.002, excepting catalase for STZ + CC2vs. STZ + lCC1when p = 0.0845). The CC and lCC showed hepatoprotective and hypoglycemic effects, a decrease in oxidative stress and improvement in anti-oxidative capacity status against STZ-induced DM in rats (p < 0.002). The lCC also proved better efficacy on MMP-2, and -9 plasma levels as compared to CC (p < 0.003, excepting STZ + CC2 vs. STZ + lCC1 comparison with p = 0.0553). The lCC demonstrated significantly better efficacy as compared to curcumin solution on all serum levels of the investigated markers, sustaining its possible use as adjuvant therapy in DM.


Decreases in thymopoiesis of astronauts returning from space flight.
Following the advent of molecular assays that measure T cell receptor excision circles (TRECs) present in recent thymic emigrants, it has been conclusively shown that thymopoiesis persists in most adults, but that functional output decreases with age, influencing the maintenance of a diverse and functional T cell receptor (TCR) repertoire. Space flight has been shown to result in a variety of phenotypic and functional changes in human T cells and in the reactivation of latent viruses. While space flight has been shown to influence thymic architecture in rodents, thymopoiesis has not previously been assessed in astronauts. Here, we assessed thymopoiesis longitudinally over a 1-year period prior to and after long-term space flight (median duration, 184 days) in 16 astronauts. While preflight assessments of thymopoiesis remained quite stable in individual astronauts, we detected significant suppression of thymopoiesis in all subjects upon return from space flight. We also found significant increases in urine and plasma levels of endogenous glucocorticoids coincident with the suppression of thymopoiesis. The glucocorticoid induction and thymopoiesis suppression were transient, and they normalized shortly after return to Earth. This is the first report to our knowledge to prospectively demonstrate a significant change in thymopoiesis in healthy individuals in association with a defined physiologic emotional and physical stress event. These results suggest that suppression of thymopoiesis has the potential to influence the maintenance of the TCR repertoire during extended space travel. Further studies of thymopoiesis and endogenous glucocorticoids in other stress states, including illness, are warranted.


Assessing cultural appropriateness of three translated cancer-related fatigue instruments.
The purpose of this study was to evaluate the cultural appropriateness (ie, semantic equivalence, content equivalence, and conceptual equivalence) of 3 translated fatigue instruments (the Cancer Fatigue Scale, the Fatigue Symptom Inventory, and the Schwartz Cancer Fatigue Scale-revised) by using 2 phases: (a) establishment of semantic and content equivalencies by the rigorous process of translation and back-translation, and (b) evaluation of content equivalence and conceptual equivalence by testing on monolingual subjects with the translated fatigue scales and a questionnaire with fatigue terms list and open-ended questions. Convenience sampling was used to recruit subjects at a chemotherapy treatment center for outpatients in Taiwan. The results indicated that the content in the 3 scales were relevant to the experience of fatigue among Taiwanese from the view of patients, but only the fatigue domains in the Cancer Fatigue Scale-Chinese version was similar to the original construct based on the exploratory factor analysis. However, the results for examining the content equivalencies by the fatigue terms list showed that only 4 items in the list were used to describe fatigue by more than 50% of the patients. Therefore, the contents of the chosen scales might not represent the whole concept of fatigue in Taiwan. Exploration of the content and construct of fatigue in Taiwan and further testing of the translated scales are recommended. In addition, the result in this study is helpful for clinical nurses to understand expressions of fatigue in cancer patients within the Chinese culture but the meaning of fatigue still needs to be further explored.


Toward automated nucleic acid enzyme selection.
Methods for automation of nucleic acid selections are being developed. The selection of aptamers has been successfully automated using a Biomek 2000 workstation. Several binding species with nanomolar affinities were isolated from diverse populations. Automation of a deoxyribozyme ligase selection is in progress. The process requires eleven times more robotic manipulations than an aptamer selection. The random sequence pool contained a 5' iodine residue and the ligation substrate contained a 3' phosphorothioate. Initially, a manual deoxyribozyme ligase selection was performed. Thirteen rounds of selection yielded ligators with a 400-fold increase in activity over the initial pool. Several difficulties were encountered during the automation of DNA catalyst selection, including effectively washing bead-bound DNA, pipetting 50% glycerol solutions, purifying single strand DNA, and monitoring the progress of the selection as it is performed. Nonetheless, automated selection experiments for deoxyribozyme ligases were carried out starting from either a naive pool or round eight of the manually selected pool. In both instances, the first round of selection revealed an increase in ligase activity. However, this activity was lost in subsequent rounds. A possible cause could be mispriming during the unmonitored PCR reactions. Potential solutions include pool redesign, fewer PCR cycles, and integration of a fluorescence microtiter plate reader to allow robotic 'observation' of the selections as they progress.


Niche opportunities and invasion dynamics in a desert annual community.
Although many factors influence the ability of exotics to invade successfully, most studies focus on only a few variables to explain invasion; attempts at theoretical synthesis are largely untested. The niche opportunities framework proposes that the demographic success of an invader is largely affected by the availability of resources and the abundance of its enemies. Here, we use a 31-year study from a desert ecosystem to examine the niche opportunities framework via the invasion of the annual plant Erodium cicutarium. While the invader remained rare for two decades, a decline in granivory combined with an ideal climate window created an opportunity for E. cicutarium to escape control and become the dominant annual plant in the community. We show that fluctuations in consumption and resources can create niche opportunities for invaders and highlight the need for additional long-term studies to track the influence of changing climate and community dynamics on invasions.


Vibrio cyclotrophicus sp. nov., a polycyclic aromatic hydrocarbon (PAH)-degrading marine bacterium.
Strain P-2P44T was isolated from creosote-contaminated marine sediments by using a most-probable number procedure in which phenanthrene was the sole carbon and energy source. Growth experiments showed that P-2P44T utilized several two- and three-ring polycyclic aromatic hydrocarbons (PAHs) as substrates, including naphthalene, 2-methylnaphthalene and phenanthrene. Additionally, gas-chromatography experiments showed that P-2P44T degraded several other PAHs, though it was unable to use them as sole sources of carbon and energy. Phylogenetic analyses confirmed that strain P-2P44T is a member of the genus Vibrio, most closely related to Vibrio splendidus. However, strain P-2P44T shared only 98.3% 16S rDNA identity and 35% DNA-DNA reassociation with the type strain of V. splendidus. Strain P-2P44T differed phenotypically from V. splendidus. Together, these differences indicated that strain P-2P44T represents a novel species in the genus Vibrio, for which the name Vibrio cyclotrophicus sp. nov. is proposed; the type strain is P-2P44T (= ATCC 700982T = PICC 106644T).


Assessing family resources: validation of the Swedish version of the Family Hardiness Index.
All families face normative transitions. Some are perceived as stressful and calls for family resources to maintain or restore family well-being. In times of illness, families also need to develop strengths and capabilities to enhance family well-being. The way these are developed is related to family hardiness. Family hardiness is thus seen as a family resource, and the Family Hardiness Index (FHI) was developed to measure family stress resistance and adaptation resources. The index was not available in Swedish and no extensive international psychometric evaluation was found. Therefore, the aim was to translate and validate the Swedish version of the FHI. The study was approved by a Regional Ethical Review Board. Data from 174 Swedish participants, family members to persons with cognitive dysfunctions (n = 95) and nursing students (n = 79) were included. Family members were enrolled in outpatient clinics in primary care and rehabilitation, and nursing students at a nursing school. Psychometric properties were evaluated through calculations of missing data, distributions of item and scale scores, item correlations, Cronbach's alpha, confirmatory factor analyses and correlations with theoretically related constructs. Sample scores had acceptable data quality, internal consistency for the FHI total scale was satisfactory (α = 0.86), and construct validity was supported. Our findings cast some doubt on the intended interpretation since confirmatory factor analyses showed that a modified four-subscale version, excluding one subscale, showed best fit. The Control subscale lacked important psychometric properties in terms of homogeneity, internal consistency and construct validity. The sample size was probably sufficiently large for the factor analyses, but the subgroup analyses should be treated with caution. The conclusion is that the Swedish version of the FHI is a promising scale for assessing family hardiness, but more solid evidence for the factor structure in various Swedish and international samples is needed.


Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos.
In situ hybridization with 35S-labelled RNA probes was used to study the distribution of transcripts of genes coding for the retinoic acid receptors, RAR-alpha, -beta and -gamma, and the cellular binding proteins for retinoic acid (CRABP I) and retinol (CRBP I), in mouse embryos during the period of early morphogenesis. Primary mesenchyme formation was associated with CRBP I labelling of both epiblast and mesenchyme of the primitive streak, while the CRABP probe labelled the migrating primary mesenchyme cells. Neural crest cell emigration and migration were associated with CRABP labelling of both neural epithelium (excluding the floor plate) and neural crest cells, while CRBP I expression was restricted to basal and apical regions of the epithelium (excluding the floor plate). The strongest neuroepithelial signal for CRABP was in the preoptic hindbrain. RAR-beta was present in presomitic stage embryos, being expressed at highest levels in the lateral regions. RAR-alpha was associated with crest cell emigration and migration, while RAR-gamma was present in the primitive streak region throughout the period of neurulation. There was a change from RAR-beta to RAR-gamma expression at the junction between closed and open neural epithelium at the caudal neuropore. RAR-alpha and RAR-beta were expressed at specific levels of the hindbrain and in the spinal cord. These distribution patterns are discussed in relation to segmental expression patterns of other genes, and to maturational changes in the caudal neuropore region. The CRABP transcript distribution patterns correlated well with known target tissues of excess retinoid-induced teratogenesis (migrating primary mesenchyme and neural crest cells, preoptic hindbrain), providing further support for our hypothesis that cells expressing CRABP are those that cannot tolerate high levels of RA for their normal developmental function.


Functional and molecular characterisation of EO771.LMB tumours, a new C57BL/6-mouse-derived model of spontaneously metastatic mammary cancer.
The translation of basic research into improved therapies for breast cancer patients requires relevant preclinical models that incorporate spontaneous metastasis. We have completed a functional and molecular characterisation of a new isogenic C57BL/6 mouse model of breast cancer metastasis, comparing and contrasting it with the established BALB/c 4T1 model. Metastatic EO771.LMB tumours were derived from poorly metastatic parental EO771 mammary tumours. Functional differences were evaluated using both in vitro assays and spontaneous metastasis assays in mice. Results were compared to non-metastatic 67NR and metastatic 4T1.2 tumours of the 4T1 model. Protein and transcript levels of markers of human breast cancer molecular subtypes were measured in the four tumour lines, as well as p53 (Tp53) tumour-suppressor gene status and responses to tamoxifen in vivo and in vitro. Array-based expression profiling of whole tumours identified genes and pathways that were deregulated in metastatic tumours. EO771.LMB cells metastasised spontaneously to lung in C57BL/6 mice and displayed increased invasive capacity compared with parental EO771. By immunohistochemical assessment, EO771 and EO771.LMB were basal-like, as was the 4T1.2 tumour, whereas 67NR had a luminal phenotype. Primary tumours from all lines were negative for progesterone receptor, Erb-b2/Neu and cytokeratin 5/6, but positive for epidermal growth factor receptor (EGFR). Only 67NR displayed nuclear estrogen receptor alpha (ERα) positivity. EO771 and EO771.LMB expressed mutant p53, whereas 67NR and 4T1.2 were p53-null. Integrated molecular analysis of both the EO771/EO771.LMB and 67NR/4T1.2 pairs indicated that upregulation of matrix metalloproteinase-3 (MMP-3), parathyroid hormone-like hormone (Pthlh) and S100 calcium binding protein A8 (S100a8) and downregulation of the thrombospondin receptor (Cd36) might be causally involved in metastatic dissemination of breast cancer.


Effects of stress and dietary tryptophan enhancement on craving for alcohol in binge and non-binge heavy drinkers.
Stress is known to play an important role in alcohol abuse, whereas binge drinking may increase individuals' susceptibility to the development of alcohol dependence. We set out to investigate whether binge drinkers (BDs) or non-BDs (NBDs) are at a greater risk of an increase in their desire for alcohol following experimental stress induction (modified Trier Social Stress Test; Experiment 1) and to explore the biological mechanisms underlying such an effect (Experiment 2). Preclinical evidence suggests that serotonin may mediate stress-induced reinstatement of alcohol intake. We therefore tested whether dietary tryptophan (TRP) enhancement would modulate stress-induced desire for alcohol and whether it would affect the two populations (BD/NBD) differently. In Experiment 1 (14 NBDs, 10 BDs; mean weekly alcohol intake 50.64 U), stress induction selectively increased strong desire for alcohol compared with the nonstressful condition in BDs. Throughout the experiment, BDs reported greater negative reinforcement type of craving than NBDs, but also a higher expectancy of alcohol-induced negative effects. In Experiment 2, 41 participants (22 NBDs, 19 BDs; mean alcohol intake 38.81 U) were given either the TRP-rich (TRP+; 9 BDs, 11 NBD) or the control (CTR; 10 BD, 11 NBD) diet before undergoing stress induction. In BDs, the TRP+ diet prevented the stress-induced increase in strong desire that was observed in individuals receiving the CTR diet. In NBDs, the TRP+ diet appeared to facilitate an increase in strong desire. These findings suggest that BDs may indeed be at a greater risk than NBDs of an increase in their craving for alcohol when stressed. Furthermore, whereas enhancement of 5-hydroxytryptamine function may moderate the impact of stress on craving in BDs, it seems to facilitate stress-induced craving in NBDs, suggesting that the serotonergic system may be differentially involved depending on individual binge drinking status.


Hyperspectral Reflectance-Derived Relationship Matrices for Genomic Prediction of Grain Yield in Wheat.
Hyperspectral reflectance phenotyping and genomic selection are two emerging technologies that have the potential to increase plant breeding efficiency by improving prediction accuracy for grain yield. Hyperspectral cameras quantify canopy reflectance across a wide range of wavelengths that are associated with numerous biophysical and biochemical processes in plants. Genomic selection models utilize genome-wide marker or pedigree information to predict the genetic values of breeding lines. In this study, we propose a multi-kernel GBLUP approach to genomic selection that uses genomic marker-, pedigree-, and hyperspectral reflectance-derived relationship matrices to model the genetic main effects and genotype × environment (G × E) interactions across environments within a bread wheat (Triticum aestivum L.) breeding program. We utilized an airplane equipped with a hyperspectral camera to phenotype five differentially managed treatments of the yield trials conducted by the Bread Wheat Improvement Program of the International Maize and Wheat Improvement Center (CIMMYT) at Ciudad Obregón, México over four breeding cycles. We observed that single-kernel models using hyperspectral reflectance-derived relationship matrices performed similarly or superior to marker- and pedigree-based genomic selection models when predicting within and across environments. Multi-kernel models combining marker/pedigree information with hyperspectral reflectance phentoypes had the highest prediction accuracies; however, improvements in accuracy over marker- and pedigree-based models were marginal when correcting for days to heading. Our results demonstrate the potential of using hyperspectral imaging to predict grain yield within a multi-environment context and also support further studies on the integration of hyperspectral reflectance phenotyping into breeding programs.


Dissecting the Mechanisms Underlying Unusually Successful Human Health Span and Life Span.
Humans age at different rates and families with exceptional survival provide the opportunity to understand why some people age slower than others. Unique features exhibited by centenarians include a family history of longevity, compression of morbidity with resultant extension of health span, and biomarkers such as low-circulating insulin-like growth factor 1 (IGF-1) and elevated high-density lipoprotein (HDL) cholesterol levels. Given the rarity of the centenarian phenotype, it has not been surprising that the use of discovery methods that relied on common population single nucleotide polymorphisms (SNPs) to unlock the genetic determinants of exceptional longevity have not yielded significant results. Conversely, gene sequencing has resulted in discoveries of functional gene variants that support several of the centenarian phenotypes. These discoveries have led to the strategic developments of drugs that may delay aging and prolong health span.


Bactericidal activity of propylene glycol, glycerine, polyethylene glycol 400, and polyethylene glycol 1000 against selected microorganisms.
The aim of the present study was to evaluate the bactericidal activity of propylene glycol, glycerine, polyethylene glycol 400 (PEG 400), and polyethylene glycol 1000 (PEG 1000) against selected microorganisms in vitro. Five vehicles, namely propylene glycol, glycerine, PEG 400, PEG 1000, and combination of propylene glycol with PEG 400, were tested for their bactericidal activity. The minimum bactericidal concentration was noted against four standard strains of organisms, i.e. Streptococcus mutans American Type Culture Collection (ATCC) 25175, Streptococcus mutans ATCC 12598, Enterococcus faecalis ATCC 35550, and Escherichia coli ATCC 25922, using broth dilution assay. Successful endodontic therapy depends upon thorough disinfection of root canals. In some refractory cases, routine endodontic therapy is not sufficient, so intracanal medicaments are used for proper disinfection of canals. Intracanal medicaments are dispensed with vehicles which aid in increased diffusion through the dentinal tubules and improve their efficacy. Among the various vehicles used, glycerine is easily available, whereas others like propylene glycol and polyethylene glycol have to be procured from appropriate sources. Also, these vehicles, being viscous, aid in sustained release of the medicaments and improve their handling properties. The most commonly used intracanal medicaments like calcium hydroxide are ineffective on many microorganisms, while most of the other medicaments like MTAD (Mixture of Tetracycline, an Acid, and a Detergent) and Triple Antibiotic Paste (TAP) consist of antibiotics which can lead to development of antibiotic resistance among microorganisms. Thus, in order to use safer and equally effective intracanal medicaments, newer alternatives like chlorhexidine gluconate, ozonized water, etc., are being explored. Similarly, the five vehicles mentioned above are being tested for their antimicrobial activity in this study. All vehicles exhibited bactericidal activity at 100% concentration. Propylene glycol was effective against three organisms namely S. mutans E. faecalis and E. coli and its bactericidal activity was at 50%, 25% and 50% respectively. PEG 1000 was effective against S. mutans and E. coli at 25%. Hence propylene glycol was effective on more number of organisms of which E. faecalis is a known resistant species. PEG 1000 was bactericidal at a lower concentration but was effective on two organisms only.


Mental health service use among high school students exposed to interpersonal violence.
Violence-exposed youth rarely receive mental health services, even though exposure increases risk for academic and psychosocial problems. This study examines the association between violence exposure and mental health service contact. The 4 forms of violence exposure were peer, family, sexual, and witnessing. Data are from 1534 Boston public high school students who participated in a 2008 self-report survey of violence exposure and its correlates. Multivariate logistic regressions estimated associations between each form of violence with service contact, then examined whether associations persisted when controlling for suicidality and self-injurious behaviors. In unadjusted models, violence-exposed students more often reported service contact than their peers. However, in multivariate models, only exposure to family (odds ratio [OR] = 1.69, 95% confidence interval [CI] = 1.23-2.31) and sexual violence (OR = 2.34, 95% CI = 1.29-4.20) were associated with service contact. Associations attenuated when controlling for suicidality and self-injurious behaviors, indicating they were largely explained by self-harm. Sexual violence alone remained associated with mental health service contact in fully adjusted models, but only for girls (OR=3.32, 95% CI=1.30-8.45), suggesting sex-specific pathways. Associations between adolescent violence exposure and mental health service contact vary by forms of exposure. Outreach to a broader set of exposed youth may reduce the impact of violence and its consequences for vulnerable students.


Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation.
The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1. This results in the decrease of GATA1 targets such as ZFPM1 and NFE2, leading to expansion of megakaryocytic progenitors with concomitant inhibition of maturation of megakaryocytes. The down-regulation of GATA1 further decreases CCND1 and increases CDKN2A expression. Overexpression of GATA1 abrogated the effects of the immunomodulatory drugs and restored maturation of megakaryocytic progenitors. Our data not only provide the mechanism for the immunomodulatory drugs induced thrombocytopenia but also help to explain the higher risk of secondary malignancies and long-term cytopenia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.


Implementing EEG hyperscanning setups.
Hyperscanning refers to obtaining simultaneous neural recordings from more than one person (Montage et al., 2002 [1]), that can be used to study interactive situations. In particular, hyperscanning with Electroencephalography (EEG) is becoming increasingly popular since it allows researchers to explore the interactive brain with a high temporal resolution. Notably, there is a 40-year gap between the first instance that simultaneous measurement of EEG activity was mentioned in the literature (Duane and Behrendt, 1965 [2]), and the first actual description of an EEG hyperscanning setup being implemented (Babiloni et al., 2006 [3]). To date, specific EEG hyperscanning devices have not yet been developed and EEG hyperscanning setups are not usually described with sufficient detail to be easily reproduced. Here, we offer a step-by-step description of solutions to many of these technological challenges. Specifically, we describe and provide customized implementations of EEG hyperscanning setups using hardware and software from different companies: Brain Products, ANT, EGI, and BioSemi. •Necessary details to set up a functioning EEG hyperscanning protocol are provided.•The setups allow independent measures and measures of synchronization between the signals of two different brains.•Individual electrical Ground and Reference is obtained in all discussed systems.


Clinical experience with the Bendit steerable microcatheter: a new paradigm for endovascular treatment.
Vessel tortuosity poses a challenge during endovascular treatment of neurovascular lesions. Bendit Technologies (Petah Tikva, Israel) has developed flexible, steerable microcatheters designed with unique bending and torquing capabilities. To describe our first-in-human trial of Bendit21. Bendit21 was used in our exploratory, prospective, multicenter, open-label, single-arm clinical study, and in two compassionate use cases. Procedures were conducted at four centers in Austria, Germany, Israel, and the United States between May 2021 and March 2022, in patients with neurovascular conditions. The primary endpoints were device-related safety events, successful navigation through the neurovasculature, and, when intended, successful delivery of contrast or therapy. Two patients with giant aneurysms were treated successfully under compassionate use approval. The clinical study included 25 patients (mean age: 63.4±11.8 years; 32.0% female). Fourteen patients (56.0%) had aneurysms, two had arteriovenous malformations/fistulas (8.0%), one had a stroke (4.0%), four (16.0%) had intracranial stenosis, and four (16.0%) had other conditions. Bendit21 was used without a guidewire in 12/25 (48.0%) procedures. Bendit21 was successfully navigated through the vasculature without delays or spasms in all cases (100%). Contrast was delivered as intended in 7/7 (100%) cases. Therapeutic devices were delivered successfully with Bendit as intended in 14/18 (77.8%) cases; four deficiencies occurred in three patients with aneurysms, in whom delivery of coils, an intrasaccular device, or a flow diverter was attempted. There were no device-related safety events or mortalities. Our initial clinical experience with the Bendit21 microcatheter demonstrates its usefulness in achieving technical success in patients with challenging neurovascular conditions.


Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesis.
Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disease characterized by microcephaly, growth retardation, immunodeficiency, chromosomal instability, and predisposition to cancer. Heterozygous NBS patients show increased chromosomal instability and are suspected to be at a high risk for cancer. To study the impact of NBS1 heterozygosity on malignancy susceptibility, we disrupted the murine homologue (Nbn) of NBS1 in mice using gene targeting techniques. While null mutation in the Nbn gene resulted in embryonic lethality at the blastocyst stage because of growth retardation and increased apoptosis, heterozygous knockout (Nbn(+/-)) mice developed a wide array of tumors affecting the liver, mammary gland, prostate, and lung, in addition to lymphomas. Moreover, gamma-irradiation enhanced tumor development in Nbn(+/-) mice, giving rise to a high frequency of epithelial tumors, mostly in the thyroid and lung, as well as lymphomas. These mice also developed numerous tumors in the ovary and testis. Southern and Western blot analyses showed a remaining wild-type allele and nibrin expression in Nbn(+/-) tumors. Sequencing analysis confirmed no mutation in the Nbn cDNA derived from these tumors. Cytogenetic analysis revealed that primary Nbn(+/-) embryonic fibroblasts and tumor cells exhibit increased chromosomal aberrations. These data suggest that haploinsufficiency, not loss of heterozygosity, of Nbn could be the mechanism underlying the tumor development. Taken together, our heterozygous Nbn-knockout mice represent a novel model to study the consequences of NBS1 heterozygosity on tumor development.


Structural insights into +1 frameshifting promoted by expanded or modification-deficient anticodon stem loops.
Maintenance of the correct reading frame on the ribosome is essential for accurate protein synthesis. Here, we report structures of the 70S ribosome bound to frameshift suppressor tRNA(SufA6) and N1-methylguanosine at position 37 (m(1)G37) modification-deficient anticodon stem loop(Pro), both of which cause the ribosome to decode 4 rather than 3 nucleotides, resulting in a +1 reading frame. Our results reveal that decoding at +1 suppressible codons causes suppressor tRNA(SufA6) to undergo a rearrangement of its 5' stem that destabilizes U32, thereby disrupting the conserved U32-A38 base pair. Unexpectedly, the removal of the m(1)G37 modification of tRNA(Pro) also disrupts U32-A38 pairing in a structurally analogous manner. The lack of U32-A38 pairing provides a structural correlation between the transition from canonical translation and a +1 reading of the mRNA. Our structures clarify the molecular mechanism behind suppressor tRNA-induced +1 frameshifting and advance our understanding of the role played by the ribosome in maintaining the correct translational reading frame.


Risks, values, and decision making surrounding pregnancy.
Assessing, communicating, and managing risk are among the most challenging tasks in the practice of medicine and are particularly difficult in the context of pregnancy. We analyze common scenarios in medical decision making around pregnancy, from reproductive health policy and clinical care to research protections. We describe three tendencies in these scenarios: 1) to consider the probabilities of undesirable outcomes alone, in isolation from women's values and social contexts, as determinative of individual clinical decisions and health policy; 2) to regard any risk to the fetus, including incremental risks that would in other contexts be regarded as acceptable, as trumping considerations that may be substantially more important to the wellbeing of the pregnant woman; and 3) to focus on the risks associated with undertaking medical interventions during pregnancy to the exclusion of demonstrable risks to both woman and fetus of failing to intervene. These tendencies in the perception, communication, and management of risk can lead to care that is neither evidence-based nor patient-centered, often to the detriment of both women and infants.


Acousto-optic effect compensation for optical determination of the normal velocity distribution associated with acoustic transducer radiation.
The acousto-optic effect, in which an acoustic wave causes variations in the optical index of refraction, imposes a fundamental limitation on the determination of the normal velocity, or normal displacement, distribution on the surface of an acoustic transducer or optically reflecting pellicle by a scanning heterodyne, or homodyne, laser interferometer. A general method of compensation is developed for a pulsed harmonic pressure field, transmitted by an acoustic transducer, in which the laser beam can transit the transducer nearfield. By representing the pressure field by the Rayleigh integral, the basic equation for the unknown normal velocity on the surface of the transducer or pellicle is transformed into a Fredholm equation of the second kind. A numerical solution is immediate when the scanned points on the surface correspond to those of the surface area discretization. Compensation is also made for oblique angles of incidence by the scanning laser beam. The present compensation method neglects edge waves, or those due to boundary diffraction, as well as effects due to baffles, if present. By allowing measurement in the nearfield of the radiating transducer, the method can enable quantification of edge-wave and baffle effects on transducer radiation. A verification experiment has been designed.


Effect of tryptophan insertions on the properties of the human group IIA phospholipase A2: mutagenesis produces an enzyme with characteristics similar to those of the human group V phospholipase A2.
An important characteristic of the human group IIA secreted phospholipase A(2) (IIA PLA(2)) is the extremely low activity of this enzyme with phosphatidylcholine (PC) vesicles, mammalian cell membranes, and serum lipoproteins. This characteristic is reflected in the lack of ability of this enzyme to bind productively to zwitterionic interfaces. Part of the molecular basis for this lack of activity is an absence of tryptophan, a residue with a known preference for residing in the interfacial region of zwitterionic phospholipid bilayers. In this paper we have replaced the eight residues that make up the hydrophobic collar on the interfacial binding surface of the enzyme with tryptophan. The catalytic and interfacial binding properties of these mutants have been investigated, particularly those properties associated with binding to and hydrolysis of zwitterionic interfaces. Only the insertion of a tryptophan at position 3 or 31 produces mutants that significantly enhance the activity of the human IIA enzyme against zwitterionic interfaces and intact cell membranes. Importantly, the ability of the enzyme mutants to hydrolyze PC-rich interfaces such as the outer plasma membrane of mammalian cells was paralleled by enhanced interfacial binding to zwitterionic interfaces. The corresponding double tryptophan mutant (V3,31W) displays a specific activity on PC vesicles comparable to that of the human group V sPLA2. This enhanced activity includes the ability to interact with human embryonic kidney HEK293 cells, previously reported for the group V enzyme [Kim, Y. J., Kim, K. P., Rhee, H. J., Das, S., Rafter, J. D., Oh, Y. S., and Cho, W. (2002) J. Biol. Chem. 277, 9358-9365].


Regulation of human cell engraftment and development of EBV-related lymphoproliferative disorders in Hu-PBL-scid mice.
Human PBMC engraft in mice homozygous for the severe combined immunodeficiency (Prkdcscid) mutation (Hu-PBL-scid mice). Hu-PBL-NOD-scid mice generate 5- to 10-fold higher levels of human cells than do Hu-PBL-C.B-17-scid mice, and Hu-PBL-NOD-scid beta2-microglobulin-null (NOD-scid-B2mnull) mice support even higher levels of engraftment, particularly CD4+ T cells. The basis for increased engraftment of human PBMC and the functional capabilities of these cells in NOD-scid and NOD-scid-B2mnull mice are unknown. We now report that human cell proliferation in NOD-scid mice increased after in vivo depletion of NK cells. Human cell engraftment depended on CD4+ cells and required CD40-CD154 interaction, but engrafted CD4+ cells rapidly became nonresponsive to anti-CD3 Ab stimulation. Depletion of human CD8+ cells led to increased human CD4+ and CD20+ cell engraftment and increased levels of human Ig. We further document that Hu-PBL-NOD-scid mice are resistant to development of human EBV-related lymphoproliferative disorders. These disorders, however, develop rapidly following depletion of human CD8+ cells and are prevented by re-engraftment of CD8+ T cells. These data demonstrate that 1) murine NK cells regulate human cell engraftment in scid recipients; 2) human CD4+ cells are required for human CD8+ cell engraftment; and 3) once engrafted, human CD8+ cells regulate human CD4+ and CD20+ cell expansion, Ig levels, and outgrowth of EBV-related lymphoproliferative disorders. We propose that the Hu-PBL-NOD-scid model is suitable for the in vivo analysis of immunoregulatory interactions between human CD4+ and CD8+ cells.


Surfactant analysis during Pneumocystis carinii pneumonia in HIV-infected patients.
Pulmonary surfactant is altered in experimental Pneumocystis carinii pneumonia. Although P carinii is a major causative agent of pneumonia in immunocompromised patients, the pathophysiology of lung injury caused by this organism is poorly understood. Therefore, we studied bronchoalveolar lavage specimens obtained from 19 HIV-infected subjects with PCP compared with specimens from ten healthy control subjects. As iterative BAL was performed, 37 BAL specimens were analyzed for protein and phospholipid. The BAL samples were divided into two groups as follows: 22 BAL samples with the presence of P carinii and 15 BAL samples without P carinii. Compared to control subjects, HIV+ BAL presented a significant increase of PR and a decrease of total PL in both P carinii+ and P carinii- BAL, but in P carinii+ BAL, the fall of PL/PR ratio was significantly more pronounced compared to P carinii- (0.09 +/- 0.02 vs 0.19 +/- 0.04, p less than 0.02). The BAL performed during the recovery of PCP showed an improvement of initial biochemical abnormalities. Surfactant composition was also altered, with a phosphatidylcholine and phosphatidylglycerol drop and a sphingomyelin and lysophosphatidylcholine increase. The presence, even in P carinii- BAL, of less polar compounds of undetermined nature, was revealed. We concluded that in HIV+ patients, abnormalities of pulmonary surfactant were present before PCP, and that the development of PCP enhances these abnormalities. These surfactant alterations may contribute to the saprophyte-pathogen transformation of P carinii, but this hypothesis requires further investigation that is presently in progress.


A Generic Software Architecture for Prognostics (GSAP).
Prognostics is a systems engineering discipline focused on predicting end-of-life of components and systems. As a relatively new and emerging technology, there are few fielded implementations of prognostics, due in part to practitioners perceiving a large hurdle in developing the models, algorithms, architecture, and integration pieces. Similarly, no open software frameworks for applying prognostics currently exist. This paper introduces the Generic Software Architecture for Prognostics (GSAP), an open-source, cross-platform, object-oriented software framework and support library for creating prognostics applications. GSAP was designed to make prognostics more accessible and enable faster adoption and implementation by industry, by reducing the effort and investment required to develop, test, and deploy prognostics. This paper describes the requirements, design, and testing of GSAP. Additionally, a detailed case study involving battery prognostics demonstrates its use.


The microtubule binding drug laulimalide inhibits vascular endothelial growth factor-induced human endothelial cell migration and is synergistic when combined with docetaxel (taxotere).
Laulimalide, a natural product from marine sponges, is a microtubule-stabilizing agent that binds to tubulin at a site distinct from that of the taxoids. In the present study, we found that laulimalide inhibited human umbilical vein endothelial cell (HUVEC) tubule formation and vascular endothelial growth factor (VEGF)-induced HUVEC migration, key components of the angiogenic process. These occurred at concentrations substantially lower than that which inhibited HUVEC proliferation. When combined, laulimalide and docetaxel (Taxotere) synergistically inhibited migration and tubule formation, but their combined effect on proliferation was antagonistic. Possible mechanism(s) by which laulimalide inhibited VEGF-induced HUVEC migration were explored. Similar to docetaxel, laulimalide had no effect on the VEGF-induced tyrosine phosphorylation of the VEGF receptor Flk-1/KDR (VEGFR-2). Low concentrations of laulimalide substantially blocked subsequent VEGFR-2 downstream events, as did docetaxel, including the phosphorylation of the Tyr397 and Tyr407 residues of focal adhesion kinase (FAK), the association of VEGFR-2 with FAK and Hsp90, and the Tyr31 phosphorylation of paxillin. Laulimalide inhibited integrin activation; however, compared with docetaxel, it had a weaker inhibitory effect on the VEGF-induced association of VEGFR-2 with the alpha5beta1 integrin. Compared with docetaxel, laulimalide more potently caused a reduction in the constitutive levels (i.e., in the absence of VEGF) of phosphorylated paxillin and more potently inhibited the association of RhoA with the alpha5beta1 integrin. In conclusion, although both docetaxel and laulimalide inhibited integrin-associated signaling pathways that mediated VEGF-induced cell migration, their actions on the signaling cascade seemed not to be identical. These complementary actions could account for their synergistic effects on HUVEC.


Media Messages and Perceptions of the Affordable Care Act during the Early Phase of Implementation.
Public opinion about the Affordable Care Act (ACA) has been polarized since the law's passage. Past research suggests these conditions would make any media influence on the public limited at best. However, during the early phase of implementation, locally broadcast ACA-related media messages-in the form of paid health insurance and political advertisements and news media stories-abounded as advocates, insurance marketers, and politicians sought to shape the public's perceptions of the law. To what extent did message exposure affect ACA perceptions during the first open enrollment period? We merge data on volumes of messaging at the media market level with nationally representative survey data to examine the relationship between estimated exposure to media messaging and the public's perceptions of how informed they were about and favorable toward the ACA in October 2013. We find that higher volumes of insurance advertising and local news coverage are associated with participants' perceptions of being informed about the law. Volumes of insurance advertising and of local news coverage are also associated with participants' favorability toward the law, but the relationship varies with partisanship, supporting the growing body of research describing partisan perceptual bias.


Methodology to account for uncertainties and tradeoffs in pharmaceutical environmental hazard assessment.
Many pharmaceutical products find their way into receiving waters, giving rise to concerns regarding their environmental impact. A procedure was proposed that enables ranking of the hazard to aquatic species and human health due to such products. In the procedure, hazard assessment is based on five of the pharmaceutical product's individual physico-chemical properties. These properties are aggregated using the weighted Euclidian distance as the utility function. The weights and physico-chemical properties are considered as random variables. Physico-chemical property uncertainty criteria are obtained from a literature review. Weight uncertainty is based on a hazard ranking from a panel of experts, the histogram of which is converted into a continuous probability density function using statistical Kernel smoothing technique. The hazard-ranking procedure was applied to a list of common pharmaceuticals used in Switzerland. The procedure is target-specific. Two rankings were presented: One giving priority to environmental protection and the other to human health. For most substances, the hazard rank depends on the target. For the Swiss case study, the ranking procedure led to the conclusion that the hormones ethinylestradiol and testosterone, along with the antibiotic erythromycin A, should be in all cases included in risk-assessment methodologies, environmental concentration estimates and regular measurement campaigns. The methodology proposed is flexible and can be extrapolated to other substances and groups of experts.


Priority regions for research on dryland cereals and legumes.
Dryland cereals and legumes are important crops in farming systems across the world. Yet they are frequently neglected among the priorities for international agricultural research and development, often due to lack of information on their magnitude and extent. Given what we know about the global distribution of dryland cereals and legumes, what regions should be high priority for research and development to improve livelihoods and food security? This research evaluated the geographic dimensions of these crops and the farming systems where they are found worldwide. The study employed geographic information science and data to assess the key farming systems and regions for these crops. Dryland cereal and legume crops should be given high priority in 18 farming systems worldwide, where their cultivated area comprises more than 160 million ha. These regions include the dryer areas of South Asia, West and East Africa, the Middle East and North Africa, Central America and other parts of Asia. These regions are prone to drought and heat stress, have limiting soil constraints, make up half of the global population and account for 60 percent of the global poor and malnourished. The dryland cereal and legume crops and farming systems merit more research and development attention to improve productivity and address development problems. This project developed an open access dataset and information resource that provides the basis for future analysis of the geographic dimensions of dryland cereals and legumes.


Energy and the u.s. Economy: a biophysical perspective.
A series of hypotheses is presented about the relation of national energy use to national economic activity (both time series and cross-sectional) which offer a different perspective from standard economics for the assessment of historical and current economic events. The analysis incorporates nearly 100 years of time series data and 3 years of cross-sectional data on 87 sectors of the United States economy. Gross national product, labor productivity, and price levels are all correlated closely with various aspects of energy use, and these correlations are improved when corrections are made for energy quality. A large portion of the apparent increase in U.S. energy efficiency has been due to our ability to expand the relative use of high-quality fuels such as petroleum and electricity, and also to relative shifts in fuel use between sectors of the economy. The concept of energy return on investment is introduced as a major driving force in our economy, and data are provided which show a marked decline in energy return on investment for all our principal fuels in recent decades. Future economic growth will depend largely on the net energy yield of alternative fuel sources, and some standard economic models may need to be modified to account for the biophysical constraints on human economic activity.


Convergence of HIV prevalence and inter-racial sexual mixing among men who have sex with men, San Francisco, 2004-2011.
Disparity in HIV prevalence by race/ethnicity has been noted among men who have sex with men for almost 20 years. Research suggests that rather than individual risk behaviors, sexual networks play an important role in HIV prevalence disparity. This analysis uses data from the National HIV Behavioral Surveillance System collected at three time points using time-location sampling in 2004, 2008, 2011. We use Newman's coefficient to assess racial mixing among 1,207 observations. We found significant differences in HIV status across race groups in 2004 and 2008; yet in 2011, there were no significant differences of HIV status by race. Racial mixing across all races increased from 2004 to 2011; in other words, individuals were increasingly more likely to sexually partner outside their own race/ethnicities. Increased racial mixing may explain this convergence, although full social network studies are necessary in order to fully explain these findings.


The self-stigma of depression for women.
Self-stigmatizing women who avoid seeking treatment for depression could believe that they have pragmatic personal reasons for their decision. As a preliminary step towards testing this hypothesis, the aim of this study was to assess diverse, low-income working women for shared self-stigmatizing beliefs about depression. Depression and depression self-stigma were assessed in a targeted sample of African American, Caucasian and Latina women who qualify for public health services and have access to health care services. Depression and self-stigmatizing beliefs about depression were positively correlated (r = .30-.64). Over one third of the women in the study (37.5%) said they would do what they could to keep their depression secret. Over half (55%) indicated that the person they normally would disclose depression to is their best friend. A majority (80%) of the women in the study said they would choose not to disclose personal depression to a health care professional. Pairwise t tests for group differences showed that Caucasian women, women recently seen by a health care professional and women with more years of education had higher self-stigma scores. Self-stigmatizing women who feel depressed could knowingly decide to keep their depression secret with the hope of avoiding loss.