A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema.
To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design. Randomized, double-masked, 36-week, 3-period crossover clinical trial. Fifty-six subjects with DME involving the center of the macula in one or both eyes. Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg). Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model. Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was -89 μm for bevacizumab and -137 μm for ranibizumab (difference, 48 μm; P < 0.001). Incorporating cumulative treatment benefit, the model yielded a predicted 36-week (9-month) average improvement in visual acuity of 7.1 letters (95% confidence interval [CI], 5.0-9.2) for bevacizumab and 8.4 letters (95% CI, 6.3-10.5) for ranibizumab, and a change in OCT CSMT of -128 μm (95% CI, -155 to -100) for bevacizumab and -176 μm (95% CI, -202 to -149) for ranibizumab. There was no significant treatment-by-period interaction (i.e., treatment difference was constant in all 3 periods), nor was there a significant differential carryover effect from one period to the next. This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti-vascular endothelial growth factor drugs for DME.


PASylation of Murine Leptin Leads to Extended Plasma Half-Life and Enhanced in Vivo Efficacy.
Leptin plays a central role in the control of energy homeostasis and appetite and, thus, has attracted attention for therapeutic approaches in spite of its limited pharmacological activity owing to the very short circulation in the body. To improve drug delivery and prolong plasma half-life, we have fused murine leptin with Pro/Ala/Ser (PAS) polypeptides of up to 600 residues, which adopt random coil conformation with expanded hydrodynamic volume in solution and, consequently, retard kidney filtration in a similar manner as polyethylene glycol (PEG). Relative to unmodified leptin, size exclusion chromatography and dynamic light scattering revealed an approximately 21-fold increase in apparent size and a much larger molecular diameter of around 18 nm for PAS(600)-leptin. High receptor-binding activity for all PASylated leptin versions was confirmed in BIAcore measurements and cell-based dual-luciferase assays. Pharmacokinetic studies in mice revealed a much extended plasma half-life after ip injection, from 26 min for the unmodified leptin to 19.6 h for the PAS(600) fusion. In vivo activity was investigated after single ip injection of equimolar doses of each leptin version. Strongly increased and prolonged hypothalamic STAT3 phosphorylation was detected for PAS(600)-leptin. Also, a reduction in daily food intake by up to 60% as well as loss in body weight of >10% lasting for >5 days was observed, whereas unmodified leptin was merely effective for 1 day. Notably, application of a PASylated superactive mouse leptin antagonist (SMLA) led to the opposite effects. Thus, PASylated leptin not only provides a promising reagent to study its physiological role in vivo but also may offer a superior drug candidate for clinical therapy.


Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial.
Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.


Social climate profiles in adolescent sports: Associations with enjoyment and intention to continue.
This study explored whether adolescent sports participants' perceptions of the social climate fall into distinct profiles, and whether these profiles are related to enjoyment and intention to continue. A Latent Profile Analysis using 313 Australian sports participants (Mage = 13.03 years) revealed four distinct profiles: positive social climate (45.1%), diminished social climate (19.8%), positive coach relationship quality (19.8%), and positive friendship quality (15.3%). Individuals within the positive social climate and the positive coach relationship quality profiles reported relatively higher levels of enjoyment and intention to continue than individuals in the diminished social climate and the positive friendship quality profiles. Indirect path analyses found the social climate profiles were linked with intention to continue through enjoyment. Results highlight the value of investigating multiple dimensions of the social climate and suggest that the coach may be of particular importance in this age group. Findings have implications for understanding youth sports participation and preventing dropout.


c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met.
Strategies to inhibit the EGF receptor (EGFR) using the tyrosine kinase inhibitor erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). Co-activation of alternative kinases may contribute to erlotinib resistance. We generated HNSCC cells expressing dominant-active c-Src (DA-Src) to determine the contribution of c-Src activation to erlotinib response. Expression of DA-Src conferred resistance to erlotinib in vitro and in vivo compared with vector-transfected control cells. Phospho-Met was strongly upregulated by DA-Src, and DA-Src cells did not produce hepatocyte growth factor (HGF). Knockdown of c-Met enhanced sensitivity to erlotinib in DA-Src cells in vitro, as did combining a c-Met or c-Src inhibitor with erlotinib. Inhibiting EGFR resulted in minimal reduction of phospho-Met in DA-Src cells, whereas complete phospho-Met inhibition was achieved by inhibiting c-Src. A c-Met inhibitor significantly sensitized DA-Src tumors to erlotinib in vivo, resulting in reduced Ki67 labeling and increased apoptosis. In parental cells, knockdown of endogenous c-Src enhanced sensitivity to erlotinib, whereas treatment with HGF to directly induce phospho-Met resulted in erlotinib resistance. The level of endogenous phospho-c-Src in HNSCC cell lines was also significantly correlated with erlotinib resistance. Ligand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src.


Effect of human immunodeficiency virus (HIV) type 1 viral genotype on mother-to-child transmission of HIV-1.
The objective of this study was to determine whether the maternal infecting human immunodeficiency virus (HIV) type 1 clade affects mother-to-child transmission frequency. Mothers in the mother-to-child HIV-1 transmission study in Nairobi, Kenya, were grouped by HIV-1 status of their first enrolled child: uninfected, perinatally infected, or postnatally infected. Restriction fragment length polymorphism (RFLP) analysis was used to determine HIV-1 viral clades of nested polymerase chain reaction products from HIV-1 protease or p24 genes. When inconclusive, sequencing determined the clade. Clade distributions within the groups were compared. The 3 groups displayed a uniform clade distribution. The predominant clades were A (59%) and D (20%). Clades B, C, F, mixed, and recombinant infections comprised the remainder (21%). No significant association was seen between clades A and D and either frequency or mode of vertical transmission. RFLP analysis revealed 2 clade B infections, 9 mixed, and 5 p24/protease recombinant infections in the study population.


The kinetics of E-selectin- and P-selectin-induced intermediate activation of integrin αLβ2 on neutrophils.
Selectins and integrins are key players in the adhesion and signaling cascade that recruits leukocytes to inflamed tissues. Selectin binding induces β2 integrin binding to slow leukocyte rolling. Here, a micropipette was used to characterize neutrophil adhesion to E-selectin and intercellular adhesion molecule-1 (ICAM-1) at room temperature. The time-dependent adhesion frequency displayed two-stage kinetics, with an E-selectin-mediated fast increase to a low plateau followed by a slow increase to a high plateau mediated by intermediate-affinity binding of integrin αLβ2 to ICAM-1. The αLβ2 activation required more than 5 s contact to E-selectin and spleen tyrosine kinase (Syk) activity. A multi-zone channel was used to analyze αLβ2 activation by P-selectin in separate zones of receptors or antibodies, finding an inverse relationship between the rolling velocity on ICAM-1 and P-selectin dose, and a P-selectin dose-dependent change from bent to extended conformations with a closed headpiece that was faster at 37°C than at room temperature. Activation of αLβ2 exhibited different levels of cooperativity and persistent times depending on the strength and duration of selectin stimulation. These results define the precise timing and kinetics of intermediate activation of αLβ2 by E- and P-selectins.


Relationship between sex hormones and anterior knee laxity across the menstrual cycle.
To comprehensively quantify through daily, serial measures changes in knee laxity as a function of changing sex-hormone levels across one complete menstrual cycle. Twenty-five females, 18 - 30 yr, body mass index < or = 30, who reported normal menstrual cycles (28-32 d) over the past 6 months participated. Participants were tested daily across one complete menstrual cycle; 5-7 cc of venous blood were withdrawn to assay serum levels of estradiol, progesterone, and testosterone. Knee laxity was measured as the amount of anterior tibial displacement at 133 N, using a standard knee arthrometer. To evaluate the relationship of knee laxity to changes in sex hormone concentrations, a multiple linear regression model with the possibility of a time delay was performed on each individual subject and the group as a whole. Individual regression equations revealed an average of 63% of the variance in knee laxity was explained by the three hormones and their interactions. All three hormones significantly contributed to the prediction equation, and the amount of variance explained was substantially greater when a time delay was considered. On average, knee laxity changed approximately 3, 4, and 4.5 d after changes in estradiol, progesterone, and testosterone, respectively. When females were analyzed as a group, only 8% of the variance in knee laxity was explained by sex-hormones levels. Changes in sex hormones mediate changes in knee laxity across the menstrual cycle. However, the strength of this relationship, the relative contribution of each hormone, and the associated time delay are highly variable between women. This individual variability is consistent with the variability in menstrual cycle characteristics among women.


The challenge of durable brain control in patients with brain-only metastases from breast cancer.
The vast majority of patients with brain metastases from breast cancer have extracranial metastases, e.g., in the liver, lungs or bones, with serious impact on prognosis. Limited research has been performed on patients with brain-only disease. We analyzed patterns of treatment, brain control and survival in uni- and multivariate analyses. All 25 patients with brain-only disease were treated with radiotherapy (whole-brain radiotherapy (WBRT) with or without stereotactic radiotherapy/radiosurgery (SRS) or surgical resection) and most patients with systemic treatment later during the disease trajectory. Only a minority of patients remained free from brain progression at 1 year after their initial therapy, regardless of initial treatment approach (median brain progression-free survival 6.2 months). However, overall survival was significantly better after initial surgical resection/SRS as compared to upfront WBRT (median 24.1 and 5.2 months, respectively). For all patients combined, median survival was 11.7 months (2-year survival rate 28 %). Several prognostic factors for shorter survival were identified in multivariate regression analysis: lower KPS, triple-negative tumor, coordination deficit, older age, lack of upfront surgical resection or SRS, and lack of endocrine or HER2-directed therapy after brain metastases treatment. Although durable brain control and long-term survival beyond 5 years could be achieved in a subset of patients (largely after successful salvage), progression of brain metastases during the first year after diagnosis was common. Prognosis was influenced by patient-, disease- and treatment-related factors.


[Administration of prostaglandin E1 in diabetics and non-diabetic patients with severe Fontaine stage IIb arterial occlusive disease].
The success in therapy of prostaglandin E1 intra-arterially and intravenously applied to diabetics and non-diabetics with PAOD, stages IIb-IV according to Fontaine, was scrutinized in a city hospital primarily concerned with geriatrics, metabolism, and angiology. All the patients included were examined in retrospective studies with regard to the improvement of their situations during their stays in hospital and--in addition to that--a part of them prospectively some time after their stays in hospital. In all, 99 patients were included in the retrospective examination of which there were 60 diabetics and 39 non-diabetics. Of the 60 diabetics 53 were in stage IV, 5 in stage III, and 2 in stage IIb while in case of non-diabetics 26 were in stage IV, 10 in stage III, and 3 in stage IIb. 50 of the diabetics and 27 of the non-diabetics were treated intra-arterially. The prospectively orientated post-observation included 38 diabetics and 24 non-diabetics. The results of the retrospective examination revealed a significantly superior efficiency of intra-arterially applied PGE1 compared with the intravenous application, both, with regard to the reduction of needed analgesics and the improvement of the clinical situation. A comparison between intra-arterially treated diabetics and non-diabetics showed a significantly higher rate of success of the diabetics regarding to the improvement of the clinical situation. Concerning the prospective post-examination: due to their PAOD the diabetics took significantly more often analgesics at the time of their post-examination than the non-diabetics. Also concerning the development of their clinical situations the diabetics turned out to have worse results than the non-diabetics, however, the differences were not significant in this case.


New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.


Paradoxical severe decrease in high-density lipoprotein cholesterol due to rosiglitazone-fenofibrate interaction.
To determine whether the marked decrease in high-density lipoprotein cholesterol (HDL-C) occasionally associated with combination fibrate-thiazolidinedione therapy results from interaction between the 2 drugs or is solely the result of fibrate administration, a previously recognized cause. We prospectively followed the clinical course of 2 patients receiving fenofibrate and rosiglitazone and reviewed the relevant literature, searching PubMed for reports describing striking reductions in HDL-C associated with fibrate administration alone and in conjunction with rosiglitazone and statins. Additional references were obtained from the bibliography of each identified article. Each of the 2 patients demonstrated a Drug Interaction Probability Score score of 9, indicating a highly probable likelihood of interaction. Critical review of all reported cases of concurrent fenofibrate-rosiglitazone-associated decreases in HDL-C failed to show conclusive evidence that the HDL-C decrease could be due to an interaction between the 2 drugs as opposed to either drug being given alone. In at least some patients who experience marked HDL-C decrease when given a combination of fenofibrate and rosiglitazone, this severe adverse effect is the result of a drug interaction between the 2 pharmaceutical agents and is not reproduced by the administration of either drug singly.


Influence of geometry on polychromatic speckle contrast.
Understanding speckle behavior is very important in speckle metrology application. The contrast of a polychromatic speckle depends not only on surface roughness and the coherence length of a light source, as shown in previous works, but also on optical geometry. We applied the Fresnel approach of diffraction theory for the free-space geometry and derived a simple analytical relationship between contrast, coherence length, size of illuminated spot, and distances between source, object, and observation plane. The effect of contrast reduction is found to be significant for low-coherence light sources.


Differential access to care: The role of age, insurance, and income on race/ethnicity-related disparities in adult perforated appendix admission rates.
Differences in perforated appendix admission rates (PAAR) are an ambulatory-sensitive measure of access to care. While pediatric studies report disparities in PAAR, initial adult investigations suggest a lack of racial/ethnic inequity. The objectives of this study were to (1) assess for risk-adjusted, racial/ethnic differences in PAAR among adults on a national scale, (2) consider the extent to which variations (or lack thereof) are explained by age, insurance, and income, and (3) compare results within the United States population to a national segment of the population who are completely insured. According to the Agency for Healthcare Research and Quality definition of PAAR, adults (aged 18-64 years) in the 2006-2010 Nationwide Inpatient Sample were queried for the occurrence and perforation of acute appendicitis. Risk-adjusted differences were compared by race/ethnicity over 5-year age increments using logistic regression with reweighted estimating equations. Noting disparate outcomes between younger (aged 18-34 years) versus older (aged 35-64 years) adults, age-stratified variations were further considered. Results were compared relative to differences among national military/civilian-dependent patients with universal insurance and were assessed for the extent to which disparities could be explained by variations in insurance and income. A total of 129,257 (weighted: 638,452) patients were included. Despite a lack of differences overall, significantly worse outcomes among younger (odds ratio point-estimates ranged from 1.11-1.32) and better outcomes among older (0.78-0.93) minority patients were found. This observation contrasted a lack of differences among completely insured military/civilian-dependent patients (n = 12,154). A total of 22.4% (non-Hispanic black versus non-Hispanic white) and 39.0% (Hispanic versus non-Hispanic white) of younger adult differences were explained by insurance-12.2% and 13.6% by income, 29.8% and 44.0% combined. This national assessment of differences in access to care among adults with acute appendicitis demonstrated the existence of racial/ethnic disparities in PAAR that varied with age and were partially, although incompletely, explained by variations in insurance and income.


Novel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases.
A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease.


Consumer alcohol exposure in supermarkets: legislatively adherent, but a societal problem.
The Sale and Supply of Alcohol Act 2012 came into force to promote the safe and responsible sale, supply, and consumption of alcohol in New Zealand. The Act was intended to minimise harm caused by excessive consumption of alcohol and reduce exposure to alcohol promotion. This study assessed supermarket adherence to sections 112-114 of the Act related to the display and advertisement of alcohol. It also assessed consumer exposure to alcohol marketing in these businesses. This paper reports on an audit of nine supermarkets in a major New Zealand city. Supermarkets exhibited high average adherence with the Act (86% adherence across audit fields); despite this, exposure to alcohol displays, promotions and advertisements remained an issue regardless of supermarket geographic location, size or chain affiliation. Supermarkets are an increasingly popular source of off-licence alcohol sales. Exposure to alcohol marketing in these businesses will likely influence consumer purchasing behaviour. Implications for public health: As an important public health challenge, based on this study, it would appear that supermarkets mostly meet the provisions of the Sale and Supply of Alcohol Act 2012, but not the intent. Additional work is required to strengthen their response to the Act.


PivotPaths: Strolling through Faceted Information Spaces.
We present PivotPaths, an interactive visualization for exploring faceted information resources. During both work and leisure, we increasingly interact with information spaces that contain multiple facets and relations, such as authors, keywords, and citations of academic publications, or actors and genres of movies. To navigate these interlinked resources today, one typically selects items from facet lists resulting in abrupt changes from one subset of data to another. While filtering is useful to retrieve results matching specific criteria, it can be difficult to see how facets and items relate and to comprehend the effect of filter operations. In contrast, the PivotPaths interface exposes faceted relations as visual paths in arrangements that invite the viewer to `take a stroll' through an information space. PivotPaths supports pivot operations as lightweight interaction techniques that trigger gradual transitions between views. We designed the interface to allow for casual traversal of large collections in an aesthetically pleasing manner that encourages exploration and serendipitous discoveries. This paper shares the findings from our iterative design-and-evaluation process that included semi-structured interviews and a two-week deployment of PivotPaths applied to a large database of academic publications.


Inorganic nanoparticle thin film that suppresses flammability of polyurethane with only a single electrostatically-assembled bilayer.
In an effort to reduce the flammability of polyurethane foam, a thin film of renewable inorganic nanoparticles (i.e., anionic vermiculite [VMT] and cationic boehmite [BMT]) was deposited on polyurethane foam via layer-by-layer (LbL) assembly. One, two, and three bilayers (BL) of BMT-VMT resulted in foam with retained shape after being exposed to a butane flame for 10 s, while uncoated foam was completely consumed. Cone calorimetry confirmed that the coated foam exhibited a 55% reduction in peak heat release rate with only a single bilayer deposited. Moreover, this protective nanocoating reduced total smoke release by 50% relative to untreated foam. This study revealed that 1 BL, adding just 4.5 wt % to PU foam, is an effective and conformal flame retardant coating. These results demonstrate one of the most efficient and renewable nanocoatings prepared using LbL assembly, taking this technology another step closer to commercial viability.


Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents.
The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9- and 13-HODE and their metabolites, 9- and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs.


Mutation-rate plasticity and the germline of unicellular organisms.
The mutation rate is a fundamental factor in evolutionary genetics. Recently, mutation rates were found to be strongly reduced at high density in a wide range of unicellular organisms, prokaryotic and eukaryotic. Independently, cell division was found to become more asymmetrical at increasing density in diverse organisms; some 'mother' cells continue dividing, while their 'offspring' cells do not divide further. Here, we investigate how this increased asymmetry in cell division at high density can be reconciled with reduced mutation-rate estimates. We calculated the expected number of mutant cells due to replication errors under various modes of segregation of template-DNA strands and copy-DNA strands, both under symmetrical (exponential) and asymmetrical (linear) growth. We show that the observed reduction in the mutation rate at high density can be explained if mother cells preferentially retain the template-DNA strands, since new mutations are then confined to non-dividing daughter cells, thus reducing the spread of mutant cells. Any other inheritance mode results in an increase in the number of mutant cells at higher density. The proposed hypothesis that patterns of DNA-strand segregation are density-dependent fundamentally challenges our current understanding of mutation-rate estimates and extends the distinction between germline and soma to unicellular organisms.


Results of Database Studies in Spine Surgery Can Be Influenced by Missing Data.
National databases are increasingly being used for research in spine surgery; however, one limitation of such databases that has received sparse mention is the frequency of missing data. Studies using these databases often do not emphasize the percentage of missing data for each variable used and do not specify how patients with missing data are incorporated into analyses. This study uses the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to examine whether different treatments of missing data can influence the results of spine studies. (1) What is the frequency of missing data fields for demographics, medical comorbidities, preoperative laboratory values, operating room times, and length of stay recorded in ACS-NSQIP? (2) Using three common approaches to handling missing data, how frequently do those approaches agree in terms of finding particular variables to be associated with adverse events? (3) Do different approaches to handling missing data influence the outcomes and effect sizes of an analysis testing for an association with these variables with occurrence of adverse events? Patients who underwent spine surgery between 2005 and 2013 were identified from the ACS-NSQIP database. A total of 88,471 patients undergoing spine surgery were identified. The most common procedures were anterior cervical discectomy and fusion, lumbar decompression, and lumbar fusion. Demographics, comorbidities, and perioperative laboratory values were tabulated for each patient, and the percent of missing data was noted for each variable. These variables were tested for an association with "any adverse event" using three separate multivariate regressions that used the most common treatments for missing data. In the first regression, patients with any missing data were excluded. In the second regression, missing data were treated as a negative or "reference" value; for continuous variables, the mean of each variable's reference range was computed and imputed. In the third regression, any variables with > 10% rate of missing data were removed from the regression; among variables with ≤ 10% missing data, individual cases with missing values were excluded. The results of these regressions were compared to determine how the different treatments of missing data could affect the results of spine studies using the ACS-NSQIP database. Of the 88,471 patients, as many as 4441 (5%) had missing elements among demographic data, 69,184 (72%) among comorbidities, 70,892 (80%) among preoperative laboratory values, and 56,551 (64%) among operating room times. Considering the three different treatments of missing data, we found different risk factors for adverse events. Of 44 risk factors found to be associated with adverse events in any analysis, only 15 (34%) of these risk factors were common among the three regressions. The second treatment of missing data (assuming "normal" value) found the most risk factors (40) to be associated with any adverse event, whereas the first treatment (deleting patients with missing data) found the fewest associations at 20. Among the risk factors associated with any adverse event, the 10 with the greatest effect size (odds ratio) by each regression were ranked. Of the 15 variables in the top 10 for any regression, six of these were common among all three lists. Differing treatments of missing data can influence the results of spine studies using the ACS-NSQIP. The current study highlights the importance of considering how such missing data are handled. Until there are better guidelines on the best approaches to handle missing data, investigators should report how missing data were handled to increase the quality and transparency of orthopaedic database research. Readers of large database studies should note whether handling of missing data was addressed and consider potential bias with high rates or unspecified or weak methods for handling missing data.


Poor glycemic control and posterior circulation ischemic stroke.
This study aimed at determining whether diabetes or glucose metabolism is associated with ischemic stroke in the posterior circulation. We included 10,245 patients with acute ischemic stroke (mean age 72.7 ± 12.5 years, men 59.5%) who were enrolled in a multicenter hospital-based stroke registry in Fukuoka, Japan, between June 2007 and August 2016. Posterior circulation ischemic stroke (PCIS) was defined as brain infarction in the territory of the posterior cerebral artery and vertebro-basilar arteries. We investigated the associations between diabetes or glycemic parameters, including plasma glucose concentrations, hemoglobin A1c, and the homeostatic model assessment of insulin resistance (HOMA-IR), and PCIS using logistic regression analysis. To improve covariate imbalance, we further evaluated associations after propensity score matching using 1:1 nearest neighbor matching and inverse probability weighting. Diabetes was significantly associated with PCIS even after adjusting for multiple confounding factors (odds ratio-OR [95% confidence interval], 1.37 [1.25-1.50]). Similarly, fasting (1.07 [1.02-1.12]/SD), casual plasma glucose (1.16 [1.11-1.20]/SD) concentrations, and hemoglobin A1c (1.12 [1.08-1.17]/SD), but not HOMA-IR (1.02 [0.97-1.07]/SD), were associated with PCIS. These associations were maintained in patients with ischemic stroke because of thrombotic etiology and were unchanged even after the propensity score matching methods. In patients with diabetes, the ORs of PCIS further increased with an increase in hemoglobin A1c and the presence of microvascular complications. Poor glycemic control may be associated with an increased risk of thrombotic infarction that occurs preferentially in the posterior circulation of the brain.


Multicenter clinical trial of mitoxantrone in non-Hodgkin's lymphoma and Hodgkin's disease.
In this phase II multicenter trial, the efficacy and safety of mitoxantrone (Novantrone; Lederle Laboratories, Wayne, NJ) were evaluated in the treatment of 206 patients with relapsed non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) previously treated with other agents. Sixty-nine percent of the patients had received prior therapy with doxorubicin. The patients received 14 mg/m2 of mitoxantrone every 3 weeks. Nineteen (12%) of the NHL patients and two (7%) of the HD patients had complete responses (CRs). The combined CR and partial response (PR) rates were 37% (60 of 163) for NHL patients and 36% (10 of 28) for HD patients; the median duration of response was 323 days for NHL patients and 209 days for HD patients. The median survival times were 337 days for patients with NHL and 469 days for patients with HD. The median survival time for patients with low-grade NHL was 589 days compared with 298 days for patients with intermediate-grade NHL and 167 days for patients with high-grade NHL. The median time to treatment failure was 73 days for NHL patients and 98 days for HD patients. The major toxicity was myelosuppression, which was moderate and reversible. Nausea, vomiting, and alopecia were mild. There were two cases of congestive heart failure (CHF) considered related to treatment; both patients had received prior treatment with doxorubicin. In this group of heavily pretreated patients, mitoxantrone was effective and well tolerated. Responses were seen with mitoxantrone in patients who had relapsed after prior therapy with doxorubicin and in patients who had failed to respond to prior therapy with doxorubicin. Mitoxantrone should be evaluated in less heavily pretreated patients and should be considered for incorporation into combination chemotherapeutic regimens for the treatment of malignant lymphoma.


Decreased Chromosomal Damage in Lymphocytes of Obese Patients After Bariatric Surgery.
The number of bariatric surgeries being performed worldwide has markedly risen. While the improvement in obesity-associated comorbidities after bariatric surgery is well-established, very little is known about its impact on cancer risk. The peripheral lymphocyte micronucleus test is a widely used method for the monitoring of chromosomal damage levels in vivo, and micronucleus frequency positively correlates with cancer risk. Therefore, the aim of this study was to compare the micronucleus frequency before and after bariatric surgery in obese subjects. Peripheral blood mononuclear cells were collected from 45 obese subjects before and at two time-points after bariatric surgery (6 and 12 months) to assess spontaneous micronucleus frequency. Consistent with the increased cancer risk previously shown, bariatric surgery-induced weight loss led to a significant reduction in lymphocyte micronucleus frequency after 12 months. Interestingly, comorbidities such as type 2 diabetes mellitus and metabolic syndrome further seemed to have an impact on the lymphocyte micronucleus frequency. Our findings may indicate a successful reduction of cancer risk in patients following weight loss caused by bariatric surgery.


Analysis of multiple association studies provides evidence of an expression QTL hub in gene-gene interaction network affecting HDL cholesterol levels.
Epistasis has been suggested to underlie part of the missing heritability in genome-wide association studies. In this study, we first report an analysis of gene-gene interactions affecting HDL cholesterol (HDL-C) levels in a candidate gene study of 2,091 individuals with mixed dyslipidemia from a clinical trial. Two additional studies, the Atherosclerosis Risk in Communities study (ARIC; n = 9,713) and the Multi-Ethnic Study of Atherosclerosis (MESA; n = 2,685), were considered for replication. We identified a gene-gene interaction between rs1532085 and rs12980554 (P = 7.1 × 10(-7)) in their effect on HDL-C levels, which is significant after Bonferroni correction (P(c) = 0.017) for the number of SNP pairs tested. The interaction successfully replicated in the ARIC study (P = 7.0 × 10(-4); P(c) = 0.02). Rs1532085, an expression QTL (eQTL) of LIPC, is one of the two SNPs involved in another, well-replicated gene-gene interaction underlying HDL-C levels. To further investigate the role of this eQTL SNP in gene-gene interactions affecting HDL-C, we tested in the ARIC study for interaction between this SNP and any other SNP genome-wide. We found the eQTL to be involved in a few suggestive interactions, one of which significantly replicated in MESA. Importantly, these gene-gene interactions, involving only rs1532085, explain an additional 1.4% variation of HDL-C, on top of the 0.65% explained by rs1532085 alone. LIPC plays a key role in the lipid metabolism pathway and it, and rs1532085 in particular, has been associated with HDL-C and other lipid levels. Collectively, we discovered several novel gene-gene interactions, all involving an eQTL of LIPC, thus suggesting a hub role of LIPC in the gene-gene interaction network that regulates HDL-C levels, which in turn raises the hypothesis that LIPC's contribution is largely via interactions with other lipid metabolism related genes.


Identification of hepatocellular carcinoma-related genes with a machine learning and network analysis.
Liver cancer is one of the leading causes of cancer mortality worldwide. Hepatocellular carcinoma (HCC) is the main type of liver cancer. We applied a machine learning approach with maximum-relevance-minimum-redundancy (mRMR) algorithm followed by incremental feature selection (IFS) to a set of microarray data generated from 43 tumor and 52 nontumor samples. With the machine learning approach, we identified 117 gene probes that could optimally separate tumor and nontumor samples. These genes not only include known HCC-relevant genes such as MT1X, BMI1, and CAP2, but also include cancer genes that were not found previously to be closely related to HCC, such as TACSTD2. Then, we constructed a molecular interaction network based on the protein-protein interaction (PPI) data from the STRING database and identified 187 genes on the shortest paths among the genes identified with the machine learning approach. Network analysis reveals new potential roles of ubiquitin C in the pathogenesis of HCC. Based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, we showed that the identified subnetwork is significantly enriched in biological processes related to cell death. These results bring new insights of understanding the process of HCC.


Nocardioides koreensis sp. nov., Nocardioides bigeumensis sp. nov. and Nocardioides agariphilus sp. nov., isolated from soil from Bigeum Island, Korea.
Three Gram-positive, coccoid to rod-shaped actinobacteria, designated strains MSL-09(T), MSL-19(T) and MSL-28(T), were isolated from a soil sample collected from Bigeum Island in Korea, and were subjected to a polyphasic taxonomic analysis. All three isolates grew optimally at pH 7.5-9.0 and 28-30 degrees C. 16S rRNA gene analysis revealed that all three strains belonged to the genus Nocardioides, with strains MSL-09(T), MSL-19(T) and MSL-28(T) respectively showing the highest sequence similarity to Nocardioides aquaticus DSM 11439(T) (96.25 %), Nocardioides aquiterrae GW-9(T) (95.75 %) and Nocardioides terrigena DS-17(T) (95.61 %). Chemotaxonomically, they contain LL-2,6-diaminopimelic acid in the cell-wall peptidoglycan, MK-8(H(4)) as the predominant menaquinone and diphosphatidylglycerol, phosphatidylglycerol and some unknown lipids as the polar lipids found in the cell wall. iso-C(16 : 0) is a major fatty acid. The G+C content of the DNA was respectively 69.9, 69.3 and 69.4 mol% for strains MSL-09(T), MSL-19(T) and MSL-28(T). Based on morphological, physiological, biochemical and chemotaxonomic characters presented in this study, the three strains represent novel species of the genus Nocardioides. The names Nocardioides koreensis sp. nov. (type strain MSL-09(T) =KCTC 19272(T) =DSM 19266(T)), Nocardioides bigeumensis sp. nov. (type strain MSL-19(T) =KCTC 19290(T) =DSM 19320(T)) and Nocardioides agariphilus sp. nov. (type strain MSL-28(T) =KCTC 19276(T) =DSM 19323(T)) are proposed.


Anxiety Associated with Asthma Exacerbations and Overuse of Medication: The Role of Cultural Competency.
Toshi, a 14-year-old Japanese boy, had uncontrolled asthma after relocating from Japan with his family 1 year ago. In Japan, he was diagnosed with moderate, persistent asthma, which was controlled with salmeterol and albuterol on an as needed basis. Since moving to the United States, Toshi complained of frequent dyspnea.Initially, he was seen by a Japanese physician who prescribed 200 mg of fluticasone 3 times a day and albuterol nebulization as needed. When Toshi came to the Pediatric Primary Care Clinic, he reported using his nebulizer up to 25 times daily. A physical examination revealed a thin, anxious, jittery, hypertensive, and tachycardic adolescent with hyperreflexia and dysmetria. Toshi complained of difficulty breathing, in the absence of wheezing or respiratory distress; peak flow recordings in the office were normal. Furthermore, he had a history of "panic attacks," being a "worrier," and stopped attending school, playing sports, and socializing over the past 6 months due to his "breathing difficulties."Citalopram was prescribed for anxiety, but the family's apprehension about mental health disorders led to resistance to treatment recommendations. With motivational interviewing and negotiation, Toshi and his family agreed to a trial of citalopram. Three months later, he no longer took fluticasone or albuterol. The tachycardia, hypertension, and neurological symptoms improved. As he gained weight and improved his strength, he attended classes and participated in sports.A few months later, with improvement of his health, Toshi and his parents decided to discontinue citalopram. He then developed behaviors consistent with generalized anxiety and obsessive-compulsive disorder. Currently, his symptoms associated with anxiety have worsened, but he and his family are resistant to medication or initiating cognitive behavioral therapy due to their cultural beliefs regarding mental health disorders.


Chronic Monosodium Glutamate Administration Induced Hyperalgesia in Mice.
Monosodium glutamate (MSG) is a widely used food additive. Although it is generally considered safe, some questions regarding the impact of its use on general health have arisen. Several reports correlate MSG consumption with a series of unwanted reactions, including headaches and mechanical sensitivity in pericranial muscles. Endogenous glutamate plays a significant role in nociceptive processing, this neurotransmitter being associated with hyperalgesia and central sensitization. One of the mechanisms underlying these phenomena is the stimulation of Ca2+/calmodulin sensitive nitric oxide synthase, and a subsequent increase in nitric oxide production. This molecule is a key player in nociceptive processing, with implications in acute and chronic pain states. Our purpose was to investigate the effect of this food additive on the nociceptive threshold when given orally to mice. Hot-plate and formalin tests were used to assess nociceptive behaviour. We also tried to determine if a correlation between chronic administration of MSG and variations in central nitric oxide (NO) concentration could be established. We found that a dose of 300 mg/kg MSG given for 21 days reduces the pain threshold and is associated with a significant increase in brain NO level. The implications of these findings on food additive-drug interaction, and on pain perception in healthy humans, as well as in those suffering from affections involving chronic pain, are still to be investigated.


Anti-inflammatory peptide-functionalized hydrogels for insulin-secreting cell encapsulation.
Pancreatic islet encapsulation within semi-permeable materials has been proposed for transplantation therapy of type I diabetes mellitus. Polymer hydrogel networks used for this purpose have been shown to provide protection from islet destruction by immunoreactive cells and antibodies. However, one of the fundamental deficiencies with current encapsulation methods is that the permselective barriers cannot protect islets from cytotoxic molecules of low molecular weight that are diffusible into the capsule material, which subsequently results in beta-cell destruction. Use of materials that can locally inhibit the interaction between the permeable small cytotoxic factors and islet cells may prolong the viability and function of encapsulated islet grafts. Here we report the design of anti-inflammatory hydrogels supporting islet cell survival in the presence of diffusible pro-inflammatory cytokines. We demonstrated that a poly(ethylene glycol)-containing hydrogel network, formed by native chemical ligation and presenting an inhibitory peptide for islet cell surface IL-1 receptor, was able to maintain the viability of encapsulated islet cells in the presence of a combination of cytokines including IL-1 beta, TNF-alpha, and INF-gamma. In stark contrast, cells encapsulated in unmodified hydrogels were mostly destroyed by cytokines which diffused into the capsules. At the same time, these peptide-modified hydrogels were able to efficiently protect encapsulated cells against beta-cell specific T-lymphocytes and maintain glucose-stimulated insulin release by islet cells. With further development, the approach of encapsulating cells and tissues within hydrogels presenting anti-inflammatory agents may represent a new strategy to improve cell and tissue graft function in transplantation and tissue engineering applications.


Information authentication system using interference of two beams in gyrator transform domain.
A novel information authentication system, i.e., an asymmetric optical interference of two beams in the gyrator transform (GT) domain, is proposed. In this algorithm, the input color image is divided into R, G, and B channels. The complex field of each channel is constructed by the inverse Fourier transform of the channel attached with a random phase function. The phase-only mask (POM) and amplitude-only mask (AOM) are analytically derived from the complex field. The POM and AOM are separately gyrator transformed. The two asymmetric phase keys and two encrypted images are obtained by the amplitude truncations and phase truncations of the transform images, respectively. Finally, the encoded image is produced by the interference of two encrypted images. The two asymmetric keys and two angle parameters of the GT are regarded as additional keys for each channel to enhance the security level of the cryptosystem. The noniterative authentication procedure is devoid of any silhouette problem. The proposed system can be implemented digitally or optically, and its architecture is free from optical misalignment problems. The theoretical analysis and numerical simulation results both validate the proposed technique.


Micronucleus index of rats treated with sodium nitrite can be amplified by sodium chloride.
The possible effect of sodium chloride as an amplifier of sodium nitrite co-carcinogenicity was assayed by in vivo experiments. 18 male rats who matched for age and weight were tested for this experiment. They were at age of 8 weeks and weight of them was around 190 grams. They were exposed to the same environmental conditions, and they were divided into 3 groups: 1--The unexposed rats who were not under any special treatment (C group) 2--Rats who were treated twice with sodium nitrite in a dose of 5.18 mg/kg body weight, with an interval of 24 hours (N group). 3--Rats who were given sodium nitrite the same as second group, 24 hours after a single application of 1 ml of saturated sodium chloride solution (29 percent) (SN group). The bone marrow samplings were performed and the micronuclei index was evaluated in all three groups. Sodium chloride combined with nitrite induced the significant elevation of micronuclei count in the SN group (p < 0.001). But sodium nitrite without sodium chloride did not have the same effect. The data offers a possible amplification of sodium nitrite's co-carcinogenicity by sodium chloride in rats.


Multi-trait analysis of genome-wide association summary statistics using MTAG.
We introduce multi-trait analysis of GWAS (MTAG), a method for joint analysis of summary statistics from genome-wide association studies (GWAS) of different traits, possibly from overlapping samples. We apply MTAG to summary statistics for depressive symptoms (N eff = 354,862), neuroticism (N = 168,105), and subjective well-being (N = 388,538). As compared to the 32, 9, and 13 genome-wide significant loci identified in the single-trait GWAS (most of which are themselves novel), MTAG increases the number of associated loci to 64, 37, and 49, respectively. Moreover, association statistics from MTAG yield more informative bioinformatics analyses and increase the variance explained by polygenic scores by approximately 25%, matching theoretical expectations.


Activation mechanism of the human Smoothened receptor.
Smoothened (SMO) is a membrane protein of the class F subfamily of G protein-coupled receptors (GPCRs) and maintains homeostasis of cellular differentiation. SMO undergoes conformational change during activation, transmitting the signal across the membrane, making it amenable to bind to its intracellular signaling partner. Receptor activation has been studied at length for class A receptors, but the mechanism of class F receptor activation remains unknown. Agonists and antagonists bound to SMO at sites in the transmembrane domain (TMD) and the cysteine-rich domain have been characterized, giving a static view of the various conformations SMO adopts. Although the structures of the inactive and active SMO outline the residue-level transitions, a kinetic view of the overall activation process remains unexplored for class F receptors. We describe SMO's activation process in atomistic detail by performing 300 μs of molecular dynamics simulations and combining it with Markov state model theory. A molecular switch, conserved across class F and analogous to the activation-mediating D-R-Y motif in class A receptors, is observed to break during activation. We also show that this transition occurs in a stage-wise movement of the transmembrane helices: TM6 first, followed by TM5. To see how modulators affect SMO activity, we simulated agonist and antagonist-bound SMO. We observed that agonist-bound SMO has an expanded hydrophobic tunnel in SMO's core TMD, whereas antagonist-bound SMO shrinks this tunnel, further supporting the hypothesis that cholesterol travels through a tunnel inside Smoothened to activate it. In summary, this study elucidates the distinct activation mechanism of class F GPCRs and shows that SMO's activation process rearranges the core TMD to open a hydrophobic conduit for cholesterol transport.


Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling.
Extracts of Cannabis sativa have been used for their calming and sedative effects for centuries. Recent developments in drug discovery have suggested that modulation of neuronal endogenous cannabinoid signaling systems could represent a novel approach to the treatment of anxiety-related disorders while minimizing the adverse effects of direct acting cannabinoid receptor agonists. In this study, we evaluated the effects of direct cannabinoid receptor agonists and antagonists and endocannabinoid-modulating drugs on anxiety-like behavior in mice using the elevated-plus maze. We found that the direct CB1 receptor agonists (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP 55,940) (0.001-0.3 mg/kg) and 2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate) (WIN 55212-2) (0.3-10 mg/kg) increased time spent on the open arms (To) at low doses only. At the highest doses tested, both compounds altered overall locomotor activity. In contrast, Delta9-tetrahydrocannabinol (0.25-10 mg/kg) produced a dose-dependent reduction in To. The endocannabinoid uptake/catabolism inhibitor 4-hydroxyphenylarachidonylamide (AM404) (0.3-10 mg/kg) produced an increase in To at low doses and had no effect at the highest dose tested. The fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597) (0.03-0.3 mg/kg) produced a monophasic, dose-dependent increase in To. The CB1 receptor antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716) (1-10 mg/kg) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (1-10 mg/kg) produced dose-related decreases in To. These data indicate that activation of CB1 cannabinoid receptors reduces anxiety-like behaviors in mice and further support an anxiolytic role for endogenous cannabinoid signaling. These results suggest that pharmacological modulation of this system could represent a new approach to the treatment of anxiety-related psychiatric disorders.


Evaluating drug-drug interaction information in NDF-RT and DrugBank.
There is limited consensus among drug information sources on what constitutes drug-drug interactions (DDIs). We investigate DDI information in two publicly available sources, NDF-RT and DrugBank. We acquire drug-drug interactions from NDF-RT and DrugBank, and normalize the drugs to RxNorm. We compare interactions between NDF-RT and DrugBank and evaluate both sources against a reference list of 360 critical interactions. We compare the interactions detected with NDF-RT and DrugBank on a large prescription dataset. Finally, we contrast NDF-RT and DrugBank against a commercial source. DrugBank drug-drug interaction information has limited overlap with NDF-RT (24-30%). The coverage of the reference set by both sources is about 60%. Applied to a prescription dataset of 35.5M pairs of co-prescribed systemic clinical drugs, NDF-RT would have identified 808,285 interactions, while DrugBank would have identified 1,170,693. Of these, 382,833 are common. The commercial source Multum provides a more systematic coverage (91%) of the reference list. This investigation confirms the limited overlap of DDI information between NDF-RT and DrugBank. Additional research is required to determine which source is better, if any. Usage of any of these sources in clinical decision systems should disclose these limitations.


Meating Conflict: Toward a Model of Ambivalence-Motivated Reduction of Meat Consumption.
An increasing number of people are concerned about eating meat, despite enjoying doing so. In the present research, we examined whether the desire to resolve this ambivalence about eating meat leads to a reduction in meat consumption. Our model of ambivalence-motivated meat reduction proposes that the pervasive nature of evaluative conflict motivates meat avoidance, and we highlight two potential mechanisms involved: the anticipation of ambivalence reduction through behavioral change, and information seeking for contents that facilitate meat reduction. Study 1 drew on a cross-sectional 6-day food diary with 7485 observations in a quota sample to investigate why meat-related ambivalence arises and to demonstrate the correlation of ambivalence with meat reduction. Two experiments investigated the causal direction of this association by showing that ambivalence-induced discomfort motivated participants to eat less meat when they introspected on their preexisting incongruent evaluations (Study 2 and 3), which was mediated by the aforementioned mechanisms involved (Study 3; preregistered). The studies utilized diverse samples from Germany, England, and the US (total N = 1192) and support the proposed model by indicating that behavioral change is an important coping strategy to resolve ambivalent discomfort in the context of meat consumption. Our model of ambivalence-motivated meat reduction contributes to theorizing on the consequences of ambivalence and the psychology of (not) eating meat.


Nipping early risk factors in the bud: preventing substance abuse, delinquency, and violence in adolescence through interventions targeted at young children (0-8 years).
This bulletin describes state-of-the-art universal and selective prevention programs designed to promote parent and teacher competencies and to prevent conduct problems. In addition, it describes indicated interventions designed for children who already have been diagnosed with oppositional defiant disorder and/or conduct disorder. Emphasis is placed on empirically supported programs that have identified key malleable risk factors in children, families, and schools, which have been shown in longitudinal research to be related to later development of substance abuse, delinquency, and violence. We have targeted preschool and primary grade children, ages 0-8 years, in this review because research suggests that the most effective interventions can nip in the bud risk behaviors in the early years, before antisocial behaviors become crystallized. Guidelines for selecting effective interventions are provided.


Viral load drives disease in humans experimentally infected with respiratory syncytial virus.
Respiratory syncytial virus (RSV) is the leading cause of childhood lower respiratory infection, yet viable therapies are lacking. Two major challenges have stalled antiviral development: ethical difficulties in performing pediatric proof-of-concept studies and the prevailing concept that the disease is immune-mediated rather than being driven by viral load. The development of a human experimental wild-type RSV infection model to address these challenges. Healthy volunteers (n = 35), in five cohorts, received increasing quantities (3.0-5.4 log plaque-forming units/person) of wild-type RSV-A intranasally. Overall, 77% of volunteers consistently shed virus. Infection rate, viral loads, disease severity, and safety were similar between cohorts and were unrelated to quantity of RSV received. Symptoms began near the time of initial viral detection, peaked in severity near when viral load peaked, and subsided as viral loads (measured by real-time polymerase chain reaction) slowly declined. Viral loads correlated significantly with intranasal proinflammatory cytokine concentrations (IL-6 and IL-8). Increased viral load correlated consistently with increases in multiple different disease measurements (symptoms, physical examination, and amount of nasal mucus). Viral load appears to drive disease manifestations in humans with RSV infection. The observed parallel viral and disease kinetics support a potential clinical benefit of RSV antivirals. This reproducible model facilitates the development of future RSV therapeutics.


APOL1 renal risk variants promote cholesterol accumulation in tissues and cultured macrophages from APOL1 transgenic mice.
Apolipoprotein L1 (APOL1) genetic variants G1 and G2, compared to the common allele G0, are major risk factors for non-diabetic kidney disease in African descent populations. APOL1 is a minor protein component of HDL, as well as being expressed in podocytes and vascular cells. Reverse cholesterol transport involves the transport of cholesterol to HDL by cellular ATP-binding cassette; ABCA1 and ABCG1 with subsequent delivery from peripheral tissues to the liver. With impaired reverse cholesterol transport, lipid accumulation occurs and macrophages morphologically transform into foam cells, releasing inflammatory factors. We asked whether the APOL1 risk variants alter peripheral cholesterol metabolism and specifically affect macrophage cholesterol efflux. Tissues and bone marrow (BM)-derived monocytes were isolated from wild-type mice (WT) and from BAC/APOL1 transgenic (APOL1-G0, APOL1-G1, and APOL1-G2) mice, which carry a bacterial artificial chromosome that contains the human APOL1 genomic region. Monocytes were differentiated into macrophages using M-CSF, and then polarized into M1 and M2 macrophages. Cholesterol content, cholesterol efflux, and ABCA1 and ABCG1 mRNA expression were measured. Kidney, spleen, and bone marrow-derived macrophages from APOL1-G1 and -G2 mice showed increased cholesterol accumulation and decreased ABCA1 and ABCG1 mRNA levels. BM-derived macrophages from APOL1-G1 and -G2 mice showed significantly reduced cholesterol efflux compared to WT or APOL1-G0 macrophages. Taken together, the evidence suggests that APOL1-G1 and -G2 risk variants impaired reverse cholesterol transport through decreased expression of cholesterol efflux transporters suggesting a possible mechanism to promote macrophage foam cell formation, driving inflammation in the glomerulus and renal interstitium.


Hope Matters: Developing and Validating a Measure of Future Expectations Among Young Women in a High HIV Prevalence Setting in Rural South Africa (HPTN 068).
Hope is a future expectancy characterized by an individual's perception that a desirable future outcome can be achieved. Though scales exist to measure hope, they may have limited relevance in low resource, high HIV prevalence settings. We developed and validated a hope scale among young women living in rural South Africa. We conducted formative interviews to identify the key elements of hope. Using items developed from these interviews, we administered the hope scale to 2533 young women enrolled in an HIV-prevention trial. Women endorsed scale items highly and the scale proved to be unidimensional in the sample. Hope scores were significantly correlated with hypothesized psycholosocial correlates with the exception of life stressors. Overall, our hope measure was found to have excellent reliability and to show encouraging preliminary indications of validity in this population. This study presents a promising measure to assess hope among young women in South Africa.


The assimilation of Western medicine into a semi-nomadic healthcare system: a case study of the Indigenous Aeta Magbukún, Philippines.
The Aeta Magbukún are a genetically and culturally distinct group of Indigenous people living in an isolated mountain forest in the municipality of Mariveles, in the province of Bataan, Philippines. This research aims to document some healthcare related information of the people, inform future decisions regarding maximising benefits of modern conveniences, and minimise negative consequences on their culture and health. Using an ethnographic approach, data were collated from a community health survey in combination with field notes from three of the co-authors while living with the Aetas. Despite major implications from rapid ecological and cultural changes, traditional ethnomedical systems continue to be revered as an essential healing practice, although they are increasingly used in conjunction with Western medicines and healthcare. At the Aeta village level, the changing socio-political influence among the kagun (traditional healer), the NGOs, and the Municipal Council in terms of healthcare provision is pivotal, as the kagun has chosen to integrate the Western medicine and healthcare services into their traditional healthcare system, without simply rejecting them. In turn, Western-style healthcare interventions have the potential to be carefully managed to integrate traditional Aeta Magbukún socio-political structures, healthcare, and cultural continuity. The cumulative influence of numerous other novel aspects to Aeta life (e.g., permanent housing, a highway through the village, literacy, cash economies, energy-dense foods, communication/entertainment devices, etc.) will place additional pressure on the traditional ethnomedical healthcare system. However, enabling the continuity of access to appropriate healthcare knowledge (both the transfer of knowledge from Western medicine to the Aeta Magbukún, and vice versa) can assist many cultures through the inherent stresses of increasingly rapid acculturation and development.


Hepatitis C virus infection in nonliver solid organ transplant candidates and recipients.
Transplantation is the best treatment for many patients with end-stage organ failure. Hepatitis C infection is prevalent among solid organ candidates and recipients and continues to represent a major source of morbidity and mortality. Prior interferon (IFN)-based therapies have been associated with limited efficacy and high rates of adverse events. Furthermore, prior IFN-based regimens are associated with high rates of allograft rejection limiting their use post-transplant. This review will outline the limited experience with current treatment regimens and how to incorporate the new hepatitis C virus (HCV) treatment regimens. The introduction of new direct-acting antiviral (DAA) agents against HCV has dramatically altered the landscape of treatment for HCV. Different all-oral regimens are currently available and are rapidly becoming the standard for treating patients with chronic hepatitis C. Excluding patients with liver disease or those who received liver transplant, those regimens have not been studied in patients awaiting solid organ transplant, or those transplanted. The safety and efficacy of DAAs in patients awaiting liver transplant and liver transplant recipients provide us with some insight and guidance on how to use those all-oral IFN-free regimens to allow effective treatment for patients who received or are awaiting nonliver solid organ transplants.


Transition Metal (Fe, Co, Ni) Nanoparticles on Selective Amino-N-Doped Carbon as High-Performance Oxygen Reduction Reaction Electrocatalyst.
Metal-air batteries are attracting increasing attention as a superior renewable energy conversion device due to their high performance and strong potential. However, the high cost and low stability of the current Pt catalyst is the main obstacle preventing wide industrial application. In this work, we applied a plasma process to fabricate aniline and a transition metals electrode (Fe, Co, Ni) as the carbon-nitrogen and the metal nanoparticle (NP) precursors, respectively, for selective metal/amino-N-doped carbon catalysts. All three as-synthesized catalysts exhibited dominant amino-N as the major C-N bonding state. In electrochemical testing, Co/amino-N-doped carbon showed positive E1/2 potential (0.83 V vs. Reversible Hydrogen Electrode (RHE)). In addition, the calculated electron transfer number (n) of Co/amino-N-doped carbon at 0.5 V vs. RHE was 3.81, which was only slightly less than that of commercial Pt/C (3.97). This superior performance of transition metal/amino-N-doped carbon promotes it as an economical oxygen reduction reaction (ORR) electrocatalyst to replace expensive Pt/C in metal-air batteries.


Population Impact and Efficiency of Improvements to HIV PrEP Under Conditions of High ART Coverage Among San Francisco Men Who Have Sex With Men.
Key components of Ending the HIV Epidemic (EHE) plan include increasing HIV antiretroviral therapy (ART) and HIV pre-exposure prophylaxis (PrEP) coverage. One complication to addressing this service delivery challenge is the wide heterogeneity of HIV burden and health care access across the United States. It is unclear how the effectiveness and efficiency of expanded PrEP will depend on different baseline ART coverage. We used a network-based model of HIV transmission for men who have sex with men (MSM) in San Francisco. Model scenarios increased varying levels of PrEP coverage relative under current empirical levels of baseline ART coverage and 2 counterfactual levels. We assessed the effectiveness of PrEP with the cumulative percentage of infections averted (PIA) over the next decade and efficiency with the number of additional person-years needed to treat (NNT) by PrEP required to avert one HIV infection. In our projections, only the highest levels of combined PrEP and ART coverage achieved the EHE goals. Increasing PrEP coverage up to 75% showed that PrEP effectiveness was higher at higher baseline ART coverage. Indeed, the PIA was 61% in the lowest baseline ART coverage population and 75% in the highest. The efficiency declined with increasing ART (NNT range from 41 to 113). Improving both PrEP and ART coverage would have a synergistic impact on HIV prevention even in a high baseline coverage city such as San Francisco. Efforts should focus on narrowing the implementation gaps to achieve higher levels of PrEP retention and ART sustained viral suppression.


Anal plugs for the management of fecal incontinence in children and adults: a randomized control trial.
To evaluate the contribution of the anal plug to the management of fecal incontinence in children and adults. Effective management of fecal incontinence remains problematic. Previous studies of an anal plug have yielded conflicting results. A randomized controlled trial was conducted. The intervention was the Conveen anal plug (Coloplast Limited) used for 12 months. Outcomes measures included: generic measures of child health [Functional Status II-R, Child Health Questionnaire (CHQ-PF50) and Dartmouth Primary Care Cooperative Information Project Charts]; generic measures of adult health for patients and carers (the SF-36, and Patient Generated and Carer Generated indices); condition-specific measures for adults and children; qualitative interviews, bowel charts, and diaries. The main outcome measure was a condition-specific score on a 0 to 100 scale, where 0 was the most severe and 100 was the least severe incontinence. Thirty-one intervention and 17 control patients were recruited. Fecal incontinence was due to 1 of 3 reasons: congenital, acquired, and neurogenic. At baseline, patients managed their condition preemptively or protectively. Intervention patients used the plug as a complete management substitute or as an adjunct to existing management. The majority of intervention respondents retained the plug most of the time. There was greater improvement from baseline in mean condition-specific score in intervention group compared with control group but this difference was not statistically significant (t test P=0.053). Complete data analysis using analysis of covariance showed the mean difference between the treatment groups in condition-specific score of 9.9 (95% confidence interval-1.4, 21.1). Intention to treat analyses using imputation showed similar results. There was generally greater improvement in intervention groups subjects using other measures for children, adults, and carers. The anal plug is of benefit to the majority of patients. It does not suit all eligible patients with in situ plug retention being a problem for some.


To be dinuclear or not: Z-DNA induction by nickel complexes.
The left-handed Z-DNA has been identified as a gene regulating element. Therefore the generation of Z-DNA through metal complexes might be an innovative way for the regulation of gene expression. Use of the new dinuclear complex N,N,N',N'-tetrakis-[2-(3,5-dimethylpyrazol-1-yl)ethyl]-1,3-propylenediamine-bis(nickel(II) dinitrate) (2) reversibly induced Z-DNA formation. However, when a 1:1 ratio of metal/dinucleating ligand was used as a control, the midpoint of the B- to Z-DNA transition was at the same nickel concentration as in case of the dinuclear complex. The novel mononuclear analogue, N-methyl-N,N-bis-[2-(3,5-dimethylpyrazol-1-yl)ethyl]amine-nickel(II)-dinitrate (3) was inducing the Z-DNA at a similar ratio versus nucleotides as free nickel(II) itself. For the first time, proton and nickel binding constants for the bis-[2-(pyrazol-1-yl)ethyl]amine ligand system are reported and discussed. Both nickel complexes 2 and 3 were structurally characterized by single crystal analysis. Furthermore, the synthesis of the two new ligands, N,N,N',N'-tetrakis-[2-(3,5-dimethylpyrazol-1-yl)ethyl]-1,2-propylenediamine (4) and N-methyl-N,N-bis-[2-(3,5-dimethylpyrazol-1-yl)ethyl]amine (5) is described. The two major synthetic pathways leading to polypyrazoyl amines in general are critically discussed with respect to yield, reproducibility and handling of the intermediates.


A two-step strategy for the complementation of M. tuberculosis mutants.
The sequence of Mycobacterium tuberculosis, completed in 1998, facilitated both the development of genomic tools, and the creation of a number of mycobacterial mutants. These mutants have a wide range of phenotypes, from attenuated to hypervirulent strains. These phenotypes must be confirmed, to rule out possible secondary mutations that may arise during the generation of mutant strains. This may occur during the amplification of target genes or during the generation of the mutation, thus constructing a complementation strain, which expresses the wild-type copy of the gene in the mutant strain, becomes necessary. In this study we have introduced a two-step strategy to construct complementation strains using the Ag85 promoter. We have constitutively expressed dosR and have shown dosR expression is restored to wild-type level.


Polymerization kinetics in three-dimensional direct laser writing.
By in-situ measuring the scattered light during microstructure formation, the polymerization kinetics of three-dimensional direct laser writing are investigated in detail. Oxygen quenching, oxygen diffusion, and inhibitor depletion are shown to have substantial impact on the kinetic behavior. For typical photoresists based on multifunctional acrylates, the polymerization occurs in less than a millisecond.


Mate choice, genetic incompatibility, and outbreeding in the ornate dragon lizard, Ctenophorus ornatus.
There has been recent interest in the role genetic incompatibility may play in mate or sperm choice. One source of incompatibility may be too similar or disparate genomes. An isolated population of the ornate dragon lizard, Ctenophorus ornatus, was followed over a breeding season and parentage assigned to the offspring using microsatellites. It was found that the adults in the population had an eight per cent chance of mating with a relative. I examined whether C. ornatus mate (or fertilize their eggs) with respect to genetic similarity. There was no difference in a female's relatedness to the male in whose territory she resided and her average relatedness to all other males. Neither was there a difference in the relatedness of the male that sired a female's offspring and the female's average relatedness to all other males. There was no evidence of a cost to mating with a more genetically similar mate, because offspring survival was not influenced by degree of inbreeding or outbreeding. However, females that were more outbred had fewer offspring survive. In this small population there are two possible explanations for the decreased fitness associated with outbreeding. First, the species may have an evolutionary history of inbreeding and thus may be susceptible to outbreeding depression. Second. as fitter individuals produce more offspring, these offspring have an increased probability of breeding with relatives, leading to an indirect relationship between fitness and outbreeding.


Constructing query-driven dynamic machine learning model with application to protein-ligand binding sites prediction.
We are facing an era with annotated biological data rapidly and continuously generated. How to effectively incorporate new annotated data into the learning step is crucial for enhancing the performance of a bioinformatics prediction model. Although machine-learning-based methods have been extensively used for dealing with various biological problems, existing approaches usually train static prediction models based on fixed training datasets. The static approaches are found having several disadvantages such as low scalability and impractical when training dataset is huge. In view of this, we propose a dynamic learning framework for constructing query-driven prediction models. The key difference between the proposed framework and the existing approaches is that the training set for the machine learning algorithm of the proposed framework is dynamically generated according to the query input, as opposed to training a general model regardless of queries in traditional static methods. Accordingly, a query-driven predictor based on the smaller set of data specifically selected from the entire annotated base dataset will be applied on the query. The new way for constructing the dynamic model enables us capable of updating the annotated base dataset flexibly and using the most relevant core subset as the training set makes the constructed model having better generalization ability on the query, showing "part could be better than all" phenomenon. According to the new framework, we have implemented a dynamic protein-ligand binding sites predictor called OSML (On-site model for ligand binding sites prediction). Computer experiments on 10 different ligand types of three hierarchically organized levels show that OSML outperforms most existing predictors. The results indicate that the current dynamic framework is a promising future direction for bridging the gap between the rapidly accumulated annotated biological data and the effective machine-learning-based predictors. OSML web server and datasets are freely available at: http://www.csbio.sjtu.edu.cn/bioinf/OSML/ for academic use.


How to analyze many contingency tables simultaneously in genetic association studies.
We study exact tests for (2 x 2) and (2 x 3) contingency tables, in particular exact chi-squared tests and exact tests of Fisher type. In practice, these tests are typically carried out without randomization, leading to reproducible results but not exhausting the significance level. We discuss that this can lead to methodological and practical issues in a multiple testing framework when many tables are simultaneously under consideration as in genetic association studies.Realized randomized p-values are proposed as a solution which is especially useful for data-adaptive (plug-in) procedures. These p-values allow to estimate the proportion of true null hypotheses much more accurately than their non-randomized counterparts. Moreover, we address the problem of positively correlated p-values for association by considering techniques to reduce multiplicity by estimating the "effective number of tests" from the correlation structure.An algorithm is provided that bundles all these aspects, efficient computer implementations are made available, a small-scale simulation study is presented and two real data examples are shown.


Micro-flow-injection analysis (μFIA) immunoassay of herbicide residue 2,6-dichlorobenzamide – towards automated at-line monitoring using modular microfluidics.
As a part of developing new systems for continuously monitoring the presence of pesticides in groundwater, a microfluidic amperometric immunosensor was developed for detecting the herbicide residue 2,6-dichlorobenzamide (BAM) in water. A competitive immunosorbent assay served as the sensing mechanism and amperometry was applied for detection. Both the immunoreaction chip (IRC) and detection (D) unit are integrated on a modular microfluidic platform with in-built micro-flow-injection analysis (μFIA) function. The immunosorbent, immobilized in the channel of the IRC, was found to have high long-term stability and withstand many regeneration cycles, both of which are key requirements for systems utilized in continuous monitoring. The IRC was regenerated during 51 cycles in a heterogeneous competitive assay out of which 27 were without the analyte (the highest possible signal level) in order to assess the regeneration capability of the immunosorbent. Detection of BAM standard solutions was performed in the concentration range from 62.5 μg L(-1) to 0.0008 μg L(-1). Non-linear regression of the data using the four-parameter logistic equation generated a sigmoidal standard curve showing an IC50 value (concentration that reduces the signal by 50%) of 0.25 μg L(-1). The strongest signal variation is observed in the concentration range between 0.02 and 2.5 μg L(-1), which includes the 0.1 μg L(-1) threshold limit set by the European Commission for BAM in drinking water. The presented results demonstrate the potential of the constructed μFIA immunosensor as an at-line monitoring system for controlling the quality of ground water supply.


AccessLab: Workshops to broaden access to scientific research.
AccessLabs are workshops with two simultaneous motivations, achieved through direct citizen-scientist pairings: (1) to decentralise research skills so that a broader range of people are able to access/use scientific research, and (2) to expose science researchers to the difficulties of using their research as an outsider, creating new open access advocates. Five trial AccessLabs have taken place for policy makers, media/journalists, marine sector participants, community groups, and artists. The act of pairing science academics with local community members helps build understanding and trust between groups at a time when this relationship appears to be under increasing threat from different political and economic currents in society. Here, we outline the workshop motivations, format, and evaluation, with the aim that others can build on the methods developed.


Remote Access Robotic Facelift Thyroidectomy: A Multi-institutional Experience.
Robotic facelift thyroidectomy (RFT) was developed as a new surgical approach to the thyroid gland using a remote incision site. Early favorable results led to this confirmatory multi-institutional experience. Prospectively collected data on consecutive patients undergoing RFT in five North American academic endocrine surgical practices were compiled. Surgical indications, operative times, final pathology, nodule size, complications, and postoperative management (drain use and length of hospital stay) were evaluated. A total of 102 RFT procedures were undertaken in 90 patients. All but one of the patients (98.9 %) were female, and the mean age was 41.9 ± 13.1 years (range 12-69 years). The indication for surgery was nodular disease in 91.2 % of cases; 8.8 % were completion procedures performed for a diagnosis of cancer. The mean size of the largest nodule was 1.9 cm (range 0-5.6 cm). The mean total operative time for a thyroid lobectomy was 162 min (range 82-265 min). No permanent complications occurred. There were 4 cases (3.9 %) of transient recurrent laryngeal nerve weakness, no cases of hypocalcemia, and 3 (2.9 %) hematomas. There were no conversions to an anterior cervical approach. The majority of patients were managed on an outpatient basis (61.8 %) and without a drain (65.7 %). RFT is technically feasible and safe in selected patients. RFT can continue to be offered to carefully selected patients as a way to avoid a visible cervical scar. Future prospective studies to compare this novel approach to other remote access approaches are warranted.


Osteoporosis in men. New insights into aetiology, pathogenesis, prevention and management.
Osteoporosis is increasingly recognised in men. Low bone mass, risk factors for falling and factors causing fractures in women are likely to cause fractures in men. Bone mass is largely genetically determined, but environmental factors also contribute. Greater muscle strength and physical activity are associated with higher bone mass, while radial bone loss is greater in cigarette smokers or those with a moderate alcohol intake. Sex hormones have important effects on bone physiology. In men, there is no abrupt cessation of testicular function or 'andropause' comparable with the menopause in women; however, both total and free testosterone levels decline with age. A common secondary cause of osteoporosis in men is hypogonadism. There is increasing evidence that estrogens are important in skeletal maintenance in men as well as women. Peripheral aromatisation of androgens to estrogens occurs and osteoblast-like cells can aromatise androgens into estrogens. Human models exist for the effects of estrogens on the male skeleton. In men aged > 65 years, there is a positive association between bone mineral density (BMD) and greater serum estradiol levels at all skeletal sites and a negative association between BMD and testosterone at some sites. It is crucial to exclude pathological causes of osteoporosis, because 30 to 60% of men with vertebral fractures have another illness contributing to bone disease. Glucocorticoid excess (predominantly exogenous) is common. Gastrointestinal disease predisposes patients to bone disease as a result of intestinal malabsorption of calcium and colecalciferol (vitamin D). Hypercalciuria and nephrolithiasis, anticonvulsant drug use, thyrotoxicosis, immobilisation, liver and renal disease, multiple myeloma and systemic mastocytosis have all been associated with osteoporosis in men. It is possible that low-dose estrogen therapy or specific estrogen receptor-modulating drugs might increase BMD in men as well as in women. In the future, parathyroid hormone peptides may be an effective treatment for osteoporosis, particularly in patients in whom other treatments, such as bisphosphonates, have failed. Men with idiopathic osteoporosis have low circulating insulin-like growth factor-1 (IGF-1; somatomedin-1) concentrations, and IGF-1 administration to these men increases bone formation markers more than resorption markers. Studies of changes in BMD with IGF-1 treatment in osteoporotic men and women are underway. Osteoporosis in men will become an increasing worldwide public health problem over the next 20 years, so it is vital that safe and effective therapies for this disabling condition become available. Effective public health measures also need to be established and targeted to men at risk of developing the disease.


DNA methylation and cis-regulation of gene expression by prostate cancer risk SNPs.
Genome-wide association studies have identified more than 100 SNPs that increase the risk of prostate cancer (PrCa). We identify and compare expression quantitative trait loci (eQTLs) and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The role of DNA methylation in eQTL regulation of gene expression was investigated by data triangulation using several causal inference approaches, including a proposed adaptation of the Causal Inference Test (CIT) for causal direction. Comparing eQTLs between tumors and benign samples, we show that 98 of the 147 risk SNPs were identified as eQTLs in the tumor-adjacent benign samples, and almost all 34 eQTL identified in tumor sets were also eQTLs in the benign samples. Three lines of results support the causal role of DNA methylation. First, nearly 100 of the 147 risk SNPs were identified as meQTLs in one tumor set, and almost all eQTLs in tumors were meQTLs. Second, the loss of eQTLs in tumors relative to benign samples was associated with altered DNA methylation. Third, among risk SNPs identified as both eQTLs and meQTLs, mediation analyses suggest that over two-thirds have evidence of a causal role for DNA methylation, mostly mediating genetic influence on gene expression. In summary, we provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in tumor genome. Finally, our mediation analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression.


Creating a coherent set of indicators to monitor health across Europe: the Euro-REVES 2 project.
The Euro-REVES 2 project, 'Setting up of a coherent set of health expectancies for the European Union', was begun in 1998 under the European Health Monitoring Programme with the aim of selecting a concise set of instruments to simultaneously monitor mortality and the different facets of health. An in-depth analysis of the current health survey instruments in Europe together with a review of past research, found that, although harmonization in instruments appeared to exist superficially, major differences existed. Four instruments have been recommended (where necessary using existing instruments with modifications suggested by the research literature) covering physical and sensory functional limitations, activity restriction, self-perceived health and mental health. Additionally a new global activity limitation indicator (GALI) has been developed. These instruments are firmly anchored to past research and the health concepts behind the indicators and their relevance to policy and guidelines for implementation are explicitly made. The second phase of the project will recommend further instruments, leading to health expectancies that cover all the conceptual framework of population health measurement. This will allow assessment of health inequalities between the European Union countries, an appreciation of the causes and the production of profiles for each country in terms of the various facets of health.


Cardiovascular disease risk of abdominal obesity vs. metabolic abnormalities.
It remains unclear whether abdominal obesity increases cardiovascular disease (CVD) risk independent of the metabolic abnormalities that often accompany it. Therefore, the objective of this study was to evaluate the independent effects of abdominal obesity vs. metabolic syndrome and diabetes on the risk for incident coronary heart disease (CHD) and stroke. The Framingham Offspring, Atherosclerosis Risk in Communities, and Cardiovascular Health studies were pooled to assess the independent effects of abdominal obesity (waist circumference >102 cm for men and >88 cm for women) vs. metabolic syndrome (excluding the waist circumference criterion) and diabetes on risk for incident CHD and stroke in 20,298 men and women aged ≥45 years. The average follow-up was 8.3 (s.d. 1.9) years. There were 1,766 CVD events. After adjustment for demographic factors, smoking, alcohol intake, number of metabolic syndrome components, and diabetes, abdominal obesity was not significantly associated with an increased risk of CVD (hazard ratio (HR) (95% confidence interval): 1.09 (0.98, 1.20)). However, after adjustment for demographics, smoking, alcohol intake, and abdominal obesity, having 1-2 metabolic syndrome components, the metabolic syndrome and diabetes were each associated with a significantly increased risk of CVD (2.12 (1.80, 2.50), 2.82 (1.92, 4.12), and 5.33 (3.37, 8.41), respectively). Although abdominal obesity is an important clinical tool for identification of individuals likely to possess metabolic abnormalities, these data suggest that the metabolic syndrome and diabetes are considerably more important prognostic indicators of CVD risk.


Face-selective electrostatic control of hydrothermal zinc oxide nanowire synthesis.
Rational control over the morphology and the functional properties of inorganic nanostructures has been a long-standing goal in the development of bottom-up device fabrication processes. We report that the geometry of hydrothermally grown zinc oxide nanowires can be tuned from platelets to needles, covering more than three orders of magnitude in aspect ratio (~0.1-100). We introduce a classical thermodynamics-based model to explain the underlying growth inhibition mechanism by means of the competitive and face-selective electrostatic adsorption of non-zinc complex ions at alkaline conditions. The performance of these nanowires rivals that of vapour-phase-grown nanostructures, and their low-temperature synthesis (<60 °C) is favourable to the integration and in situ fabrication of complex and polymer-supported devices. We illustrate this capability by fabricating an all-inorganic light-emitting diode in a polymeric microfluidic manifold. Our findings indicate that electrostatic interactions in aqueous crystal growth may be systematically manipulated to synthesize nanostructures and devices with enhanced structural control.


Characterization of optical coatings using a multisource table-top scatterometer.
Light scattering measurement and analysis is a powerful tool for the characterization of optical and nonoptical surfaces. To enable a more comprehensive postmeasurement characterization, three visible laser sources were recently implemented in a highly sensitive table-top scatterometer with 3D spherical detection capability. Based on wavelength scaling, the instrument is utilized to characterize thin-film coatings and their substrates with respect to surface roughness, roughness growth, and contamination. Topographic measurement techniques are used to verify the results. The spectral sensitivity to contamination (scatter loss) is demonstrated to be significantly different for single surfaces and interference coatings. In addition, power losses of a highly reflective coating are analyzed.