Conservation in South america: problems, consequences, and solutions.
Lack of solid data on rates of habitat conversion and on the basic biology of Neotropical organisms makes predictions of massive waves of extinction in South America premature. South America's problems regarding the use of natural resources are a result of historical, sociological, economic, and scientific factors. Most countries in South America have done a great deal to encourage conservation efforts, but the magnitude of the problem is well beyond their limited economic means to solve. The problems of species disappearance in South America are of global importance. A successful solution will involve a coordinated and massive effort of governments and specialists in all aspects of conservation biology from throughout the world. There is still time to resolve these problems. Unnecessarily dire predictions of species extinction may be counterproductive to the development of a long-term conservation strategy that is needed to manage Neotropical conservation problems.


Origins of eponymous instruments in spine surgery.
Every day, spine surgeons call for instruments named after surgical pioneers. Few know the designers or the histories behind their instruments. In this paper the authors provide a historical perspective on the Penfield dissector, Leksell rongeur, Hibbs retractor, Woodson elevator, Kerrison rongeur, McCulloch retractor, Caspar pin retractor system, and Cloward handheld retractor, and a biographical review of their inventors. Historical data were obtained by searching the HathiTrust Digital Library, PubMed, Google Scholar, Google Books, and Google, and personal communications with relatives, colleagues, and foundations of the surgeon-designers. The authors found that the Penfield dissectors filled a need for delicate tools for manipulating the brain and that the Leksell rongeur increased surgical efficiency during war-related laminectomies. Hibbs' retractor facilitated his spine fusion technique. Woodson was both a dentist and a physician whose instrument was adopted by spine surgeons. Kerrison rongeurs were developed in otology to decompress bone near the facial nerve. The McCulloch, Caspar, and Cloward retractors helped improve exposure during the emergence of new techniques, i.e., microdiscectomy and anterior cervical discectomy and fusion. The histories behind these eponymous instruments remind us that innovation sometimes begins in other specialties and demonstrate the role of innovation in improving patient care.


Identifying Patterns of Clinical Interest in Clinicians' Treatment Preferences: Hypothesis-free Data Science Approach to Prioritizing Prescribing Outliers for Clinical Review.
Data analysis is used to identify signals suggestive of variation in treatment choice or clinical outcome. Analyses to date have generally focused on a hypothesis-driven approach. This study aimed to develop a hypothesis-free approach to identify unusual prescribing behavior in primary care data. We aimed to apply this methodology to a national data set in a cross-sectional study to identify chemicals with significant variation in use across Clinical Commissioning Groups (CCGs) for further clinical review, thereby demonstrating proof of concept for prioritization approaches. Here we report a new data-driven approach to identify unusual prescribing behaviour in primary care data. This approach first applies a set of filtering steps to identify chemicals with prescribing rate distributions likely to contain outliers, then applies two ranking approaches to identify the most extreme outliers amongst those candidates. This methodology has been applied to three months of national prescribing data (June-August 2017). Our methodology provides rankings for all chemicals by administrative region. We provide illustrative results for 2 antipsychotic drugs of particular clinical interest: promazine hydrochloride and pericyazine, which rank highly by outlier metrics. Specifically, our method identifies that, while promazine hydrochloride and pericyazine are barely used by most clinicians (with national prescribing rates of 11.1 and 6.2 per 1000 antipsychotic prescriptions, respectively), they make up a substantial proportion of antipsychotic prescribing in 2 small geographic regions in England during the study period (with maximum regional prescribing rates of 298.7 and 241.1 per 1000 antipsychotic prescriptions, respectively). Our hypothesis-free approach is able to identify candidates for audit and review in clinical practice. To illustrate this, we provide 2 examples of 2 very unusual antipsychotics used disproportionately in 2 small geographic areas of England.


The potential impact of RV144-like vaccines in rural South Africa: a study using the STDSIM microsimulation model.
The only successful HIV vaccine trial to date is the RV144 trial of the ALVAC/AIDSVAX vaccine in Thailand, which showed an overall incidence reduction of 31%. Most cases were prevented in the first year, suggesting a rapidly waning efficacy. Here, we predict the population level impact and cost-effectiveness of practical implementation of such a vaccine in a setting of a generalised epidemic with high HIV prevalence and incidence. We used STDSIM, an established individual-based microsimulation model, tailored to a rural South African area with a well-functioning HIV treatment and care programme. We estimated the impact of a single round of mass vaccination for everybody aged 15-49, as well as 5-year and 2-year re-vaccination strategies for young adults (aged 15-29). We calculated proportion of new infections prevented, cost-effectiveness indicators, and budget impact estimates of combined ART and vaccination programmes. A single round of mass vaccination with a RV144-like vaccine will have a limited impact, preventing only 9% or 5% of new infections after 10 years at 60% and 30% coverage levels, respectively. Revaccination strategies are highly cost-effective if vaccine prices can be kept below 150 US$/vaccine for 2-year revaccination strategies, and below 200 US$/vaccine for 5-year revaccination strategies. Net cost-savings through reduced need for HIV treatment and care occur when vaccine prices are kept below 75 US$/vaccine. These results are sensitive to alternative assumptions on the underlying sexual network, background prevention interventions, and individual's propensity and consistency to participate in the vaccination campaign. A modestly effective vaccine can be a cost-effective intervention in highly endemic settings. To predict the impact of vaccination strategies in other endemic situations, sufficient knowledge of the underlying sexual network, prevention and treatment interventions, and individual propensity and consistency to participate, is key. These issues are all best addressed in an individual-based microsimulation model.


First Report of Powdery Mildew (Pseudoidium anacardii) of Mango Trees in Sinaloa, Mexico.
Powdery mildew of mango is an important disease in Mexico's northern Sinaloa state. Identification of the causal fungal agent has been hindered by the absence of information regarding its teleomorph, as well as a detailed morphometric analysis of the anamorph and molecular characterization. The first symptoms of the disease appear in mango inflorescences of early February, and it subsequently affects young fruits. The disease progresses during March and early April, causing significant fruit abortion and a scabby appearance in a high percentage of fruits that remain attached to the trees. We observed the disease on inflorescences but not in leaves during our sampling period. Powdery mildew specimens were collected during 2011 and 2012 and included Kent and Keith varieties from commercial orchards, and creole materials from backyards of private residences in the Ahome and Fuerte Counties of northern Sinaloa, Mexico. Symptomatic inflorescences were analyzed morphologically. Conidiophores and conidia were prepared by touching the whitish lesions with clear adhesive tape, which was then placed over microscope slides with a drop of distilled water and observed under a compound microscope. The anamorph structures of the pathogen were measured. The mycelium was septate and ramified on the surface of the host, forming a dense coat of branching hyphae. The mycelium had a diameter of 2.5 to 8.7 μm; conidiophores (Pseudoidium type) emerged from the superficial mycelium, were unbranched, and consisted of 1 to 3 cells with conidia forming singly from the apex. The length of the conidiophores varied from 30.0 to 77.5 μm; the foot cell of the conidiophores was straight, 10.0 to 47.5 μm long and with a diameter of 5.0 to 15.5 μm across its midpoint. Conidia without fibrosin bodies were borne singly, and were ellipsoid/ovoid, 22.5 to 46.2 μm long and 15.0 to 27.5 μm wide. Eighty percent of the germ tubes were forked (lobed); the rest were simple, emerged from the end, and were occasionally on the side of the conidia. Germ tubes ranged from 2.0 to 7.2 μm at the midpoint. The surface of the conidia appeared smooth under the scanning electron microscope, and elliptical conidia appeared constricted at their ends; this, however, was not observed in the ovoid conidia. In both cases, the terminal end of the conidia was smooth. The teleomorph was not found. Molecular and phylogenetic analysis of the ITS rDNA (2) region showed that samples are closely related to specimens of Pseudoidium anacardii (1) (teleomorph: Erysiphe quercicola [4]) collected from mango trees in diverse countries. Measurements of somatic and asexual structures are in agreement with descriptions of P. anachardii (formerly known as Oidium mangiferae) from India (3). The nucleotide sequences derived from this research were deposited in GenBank (Accession Nos. JX893951 to JX893957). To our knowledge, this is the first report of P. anacardii associated to mango inflorescences in Sinaloa, Mexico. Due to the economic importance of powdery mildew of mango trees in Sinaloa, future research directions should focus on finding the teleomorph of the fungus to support its identity. References: (1) U. Braun and R. T. A. Cook CBS Biodiversity Series No. 11, 2012. (2) S. Limkaisang et al. Mycoscience 47:327, 2006. (3) O. Prakash and K. C. Srivastava. Mango diseases and their management. A World Review Today and Tomorrow Publishers. New Delhi, India, 1987. (4) S. Takamatsu et al. Mycol. Res. 111:809, 2007.


Three-dimensional diffuse x-ray scattering from crystals of Staphylococcal nuclease.
We have developed methods for obtaining and characterizing three-dimensional maps of the reciprocal-space distribution of diffuse x-ray scattering from protein crystals, and have used the methods to study the nature of disorder in crystals of Staphylococcal nuclease. Experimentally obtained maps are 99.5% complete in the reciprocal-space resolution range of 10 A-2.5 A, show symmetry consistent with the P41 space group of the unit cell, and are highly reproducible. Quantitative comparisons of the data with three-dimensional simulations imply liquid-like motions of the protein [Caspar, D. L. D., Clarage, J., Salunke, D. M. & Clarage, M. (1988) Nature (London) 332, 659-662], with a correlation length of 10 A and a root-mean-square displacement of 0.36 A.


A novel role for tamoxifen in the inhibition of human platelets.
Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), is widely used therapeutically for the treatment and prevention of breast cancer, but its use is associated with an increased risk of thrombosis. The mechanism of this adverse effect is still unclear. Arterial thromboses mostly consist of platelets that are adherent to ruptured endothelial surfaces. Several lines of evidence reported that tamoxifen stimulates platelet activation using different methodologies. In our preliminary study, tamoxifen exhibited potent antiplatelet activity in washed human platelets. The aim of this study was to examine the signal transduction pathways of tamoxifen in platelet activation. In this study, tamoxifen (3∼7 μmol/L) exhibited more potent activity in inhibiting platelet aggregation stimulated by collagen than other agonists (ie, thrombin). Tamoxifen inhibited collagen-stimulated platelet activation accompanied by relative Ca(+2) mobilization, thromboxane A(2) (TxA(2)) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) phosphorylation (ie, p38 MAPK and extracellular signal-regulated kinase 1/2), but not hydroxyl radical (OH(•)) formation. However, tamoxifen did not increase nitric oxide (NO) release or vasodilator-stimulated phosphoprotein (VASP) phosphorylation in washed platelets. Furthermore, neither ICI 182,780, a pure ER antagonist, nor ODQ, an inhibitor of guanylate cyclase, significantly reversed the tamoxifen-mediated inhibition of platelet aggregation. In conclusion, this study demonstrates for the first time that tamoxifen possesses potent antiplatelet activity, the mechanism of which may be involved in the inhibition of the PLCγ2-PKC-p38 MAPK-TxA(2) cascade, thereby leading to the inhibition of platelet activation. In our study, the direct inhibition of platelet activation by tamoxifen possibly may provide new insights into understanding its cardiovascular effects.


Adrenal steroids stimulate thiazide-sensitive NaCl transport by rat renal distal tubules.
The current experiments were designed to test the hypothesis that adrenal steroids increase thiazide-sensitive Na and Cl transport by the mammalian renal distal convoluted tubule (DCT). Male Sprague-Dawley rats were adrenalectomized and received steroid hormones by osmotic pumps. Six groups of animals were studied as follows: group I, no hormones; group II, replacement levels of dexamethasone only; group III, replacement levels of aldosterone only; group IV, replacement levels of both hormones; group V; replacement levels of aldosterone and high levels of dexamethasone; and group VI, replacement levels of dexamethasone and high levels of aldosterone. Circulating levels of both hormones were found to be in the high physiological range when infused at the high rate. In vivo microperfusion of distal tubules was performed to determine rates of Na and Cl transport. Chlorothiazide was used to assess the magnitude of electroneutral Na-Cl cotransport. Both aldosterone and dexamethasone stimulated thiazide-sensitive Na and Cl transport by the distal tubule by more than fivefold. [3H]metolazone binding was measured to assess the number of thiazide-sensitive Na-Cl cotransporters in renal cortex. Each steroid also increased the number of [3H]metolazone binding sites in kidney cortex more than threefold. The results are consistent with the presence of both mineralocorticoid and glucocorticoid receptors in the mammalian DCT. Physiological changes in circulating levels of adrenal steroids may affect renal NaCl excretion in part by regulating the rate of electroneutral Na-Cl absorption by the DCT.


Targeted proteomics of the secretory pathway reveals the secretome of mouse embryonic fibroblasts and human embryonic stem cells.
Proteins endogenously secreted by human embryonic stem cells (hESCs) and those present in hESC culture medium are critical regulators of hESC self-renewal and differentiation. Current MS-based approaches for identifying secreted proteins rely predominantly on MS analysis of cell culture supernatants. Here we show that targeted proteomics of secretory pathway organelles is a powerful alternate approach for interrogating the cellular secretome. We have developed procedures to obtain subcellular fractions from mouse embryonic fibroblasts (MEFs) and hESCs that are enriched in secretory pathway organelles while ensuring retention of the secretory cargo. MS analysis of these fractions from hESCs cultured in MEF conditioned medium (MEF-CM) or MEFs exposed to hESC medium revealed 99 and 129 proteins putatively secreted by hESCs and MEFs, respectively. Of these, 53 and 62 proteins have been previously identified in cell culture supernatants of MEFs and hESCs, respectively, thus establishing the validity of our approach. Furthermore, 76 and 37 putatively secreted proteins identified in this study in MEFs and hESCs, respectively, have not been reported in previous MS analyses. The identification of low abundance secreted proteins via MS analysis of cell culture supernatants typically necessitates the use of altered culture conditions such as serum-free medium. However, an altered medium formulation might directly influence the cellular secretome. Indeed, we observed significant differences between the abundances of several secreted proteins in subcellular fractions isolated from hESCs cultured in MEF-CM and those exposed to unconditioned hESC medium for 24 h. In contrast, targeted proteomics of secretory pathway organelles does not require the use of customized media. We expect that our approach will be particularly valuable in two contexts highly relevant to hESC biology: obtaining a temporal snapshot of proteins secreted in response to a differentiation trigger, and identifying proteins secreted by cells that are isolated from a heterogeneous population.


Temperature dependence of Na+-H+ exchange, Na+-HCO3- co-transport, intracellular buffering and intracellular pH in guinea-pig ventricular myocytes.
Almost all aspects of cardiac function are sensitive to modest changes of temperature. We have examined the thermal sensitivity of intracellular pH regulation in the heart. To do this we determined the temperature sensitivity of pHi, intracellular buffering capacity, and the activity of sarcolemmal acid-extrusion proteins, Na+-H+ exchange (NHE) and Na+-HCO3- co-transport (NBC) in guinea-pig isolated ventricular myocytes. pHi was recorded fluorimetrically with acetoxymethyl (AM)-loaded carboxy-SNARF-1 at either 27 or 37 degrees C. At 27 degrees C, intrinsic (non-CO2-dependent) buffering power (betai) was approximately 60% of that at 37 degrees C. Acid-extrusion (Je) through NHE was approximately 50% slower than at 37 degrees C, consistent with a Q10 of approximately 2. In 5% CO2/HCO3--buffered conditions, in the presence of 30 microM cariporide to inhibit NHE, acid extrusion via NBC was also slowed at 27 degrees C, suggestive of a comparable Q10. Resting pHi at 27 degrees C was similar in Hepes- or 5% CO2/HCO3--buffered superfusates but, in both cases, was approximately 0.1 pH units lower at 37 degrees C. The higher the starting pHi, the larger was the thermally induced fall of pHi, consistent with a mathematical model where intrinsic buffers with a low principal pKa (e.g. close to 6.0) are less temperature-sensitive than those with a higher pKa. The high temperature sensitivity of pHi regulation in mammalian cardiac cells has implications for experimental work conducted at room temperature. It also has implications for the ability of intracellular acidosis to generate intracellular Na+ and Ca2+ overload, cardiac injury and arrhythmia in the heart.


Genome-wide DNA methylation as an epigenetic consequence of Epstein-Barr virus infection of immortalized keratinocytes.
The oral cavity is a persistent reservoir for Epstein-Barr virus (EBV) with lifelong infection of resident epithelial and B cells. Infection of these cell types results in distinct EBV gene expression patterns regulated by epigenetic modifications involving DNA methylation and chromatin structure. Regulation of EBV gene expression relies on viral manipulation of the host epigenetic machinery that may result in long-lasting host epigenetic reprogramming. To identify epigenetic events following EBV infection, a transient infection model was established to map epigenetic changes in telomerase-immortalized oral keratinocytes. EBV-infected oral keratinocytes exhibited a predominantly latent viral gene expression program with some lytic or abortive replication. Calcium and methylcellulose-induced differentiation was delayed in EBV-positive clones and in clones that lost EBV compared to uninfected controls, indicating a functional consequence of EBV epigenetic modifications. Analysis of global cellular DNA methylation identified over 13,000 differentially methylated CpG residues in cells exposed to EBV compared to uninfected controls, with CpG island hypermethylation observed at several cellular genes. Although the vast majority of the DNA methylation changes were silent, 65 cellular genes that acquired CpG methylation showed altered transcript levels. Genes with increased transcript levels frequently acquired DNA methylation within the gene body while those with decreased transcript levels acquired DNA methylation near the transcription start site. Treatment with the DNA methyltransferase inhibitor, decitabine, restored expression of some hypermethylated genes in EBV-infected and EBV-negative transiently infected clones. Overall, these observations suggested that EBV infection of keratinocytes leaves a lasting epigenetic imprint that can enhance the tumorigenic phenotype of infected cells. Here, we show that EBV infection of oral keratinocytes led to CpG island hypermethylation as an epigenetic scar of prior EBV infection that was retained after loss of the virus. Such EBV-induced epigenetic modification recapitulated the hypermethylated CpG island methylator phenotype (CIMP) observed in EBV-associated carcinomas. These epigenetic alterations not only impacted gene expression but also resulted in delayed calcium and methylcellulose-induced keratinocyte differentiation. Importantly, these epigenetic changes occurred in cells that were not as genetically unstable as carcinoma cells, indicating that EBV infection induced an epigenetic mutator phenotype. The impact of this work is that we have provided a mechanistic framework for how a tumor virus using the epigenetic machinery can act in a "hit-and-run" fashion, with retention of epigenetic alterations after loss of the virus. Unlike genetic alterations, these virally induced epigenetic changes can be reversed pharmacologically, providing therapeutic interventions to EBV-associated malignancies.


Continuous infusion of beta-lactam antibiotics in severe sepsis: a multicenter double-blind, randomized controlled trial.
Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival. Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.


Clinical Relevance of Collagen Protein Degradation Markers C3M and C4M in the Serum of Breast Cancer Patients Treated with Neoadjuvant Therapy in the GeparQuinto Trial.
Background: Remodeling of extracellular matrix through collagen degradation is a crucial step in the metastatic cascade. The aim of this study was to evaluate the potential clinical relevance of the serum collagen degradation markers (CDM) C3M and C4M during neoadjuvant chemotherapy for breast cancer. Methods: Patients from the GeparQuinto phase 3 trial with untreated HER2-positive operable or locally advanced breast cancer were enrolled between 7 November 2007, and 9 July 2010, and randomly assigned to receive neoadjuvant treatment with EC/docetaxel with either trastuzumab or lapatinib. Blood samples were collected at baseline, after four cycles of chemotherapy and at surgery. Cutoff values were determined using validated cutoff finder software (C3M: Low ≤9.00 ng/mL, high >9.00 ng/mL, C4M: Low ≤40.91 ng/mL, high >40.91 ng/mL). Results: 157 patients were included in this analysis. At baseline, 11.7% and 14.8% of patients had high C3M and C4M serum levels, respectively. No correlation was observed between CDM and classical clinical-pathological factors. Patients with high levels of CDM were significantly more likely to achieve a pathological complete response (pCR, defined as ypT0 ypN0) than patients with low levels (C3M: 66.7% vs. 25.7%, p = 0.002; C4M: 52.7% vs. 26.6%, p = 0.031). Median levels of both markers were lower at the time of surgery than at baseline. In the multivariate analysis including clinical-pathological factors and C3M levels at baseline and changes in C3M levels between baseline and after four cycles of therapy, only C3M levels at baseline (p = 0.035, OR 4.469, 95%-CI 1.115-17.919) independently predicted pCR. In a similar model including clinical-pathological factors and C4M, only C4M levels at baseline (p = 0.028, OR 6.203, 95%-CI 1.220-31.546) and tumor size (p = 0.035, OR 4.900, 95%-CI 1.122-21.393) were independent predictors of pCR. High C3M levels at baseline did not correlate with survival in the entire cohort but were associated with worse disease-free survival (DFS; p = 0.029, 5-year DFS 40.0% vs. 74.9%) and overall survival (OS; p = 0.020, 5-year OS 60.0% vs. 88.3%) in the subgroup of patients randomized to lapatinib. In the trastuzumab arm, C3M did not correlate with survival. In the entire patient cohort, high levels of C4M at baseline were significantly associated with shorter DFS (p = 0.001, 5-year DFS 53.1% vs. 81.6%) but not with OS. When treatment arms were considered separately, the association with DFS was still significant (p = 0.014, 5-year DFS 44.4% vs. 77.0% in the lapatinib arm; p = 0.023, 5-year DFS 62.5% vs. 86.2% in the trastuzumab arm). Conclusions: Collagen degradation markers are associated with response to neoadjuvant therapy and seem to play a role in breast cancer.


Xenopus Cdc14 alpha/beta are localized to the nucleolus and centrosome and are required for embryonic cell division.
The dual specificity phosphatase Cdc14 has been shown to be a critical regulator of late mitotic events in several eukaryotes, including S. cerevisiae, S. pombe. C. elegans and H. sapiens. However, Cdc14 homologs have clearly evolved to regulate distinct cellular processes and to respond to regulatory signals important for these processes. The human paralogs hCdc14A and B are the only vertebrate Cdc14 homologues studied to date, but their functions are not well understood. Therefore, it is of great interest to examine the function Cdc14 homologs in other vertebrate species. We identified two open reading frames from Xenopus laevis closely related to human Cdc14A, called XCdc14alpha and XCdc14beta, although no obvious paralog of the hCdc14B was found. To begin a functional characterization of Xcdc14alpha and XCdc14beta, we raised polyclonal antibodies against a conserved region. These antibodies stained both the nucleolus and centrosome in interphase Xenopus tissue culture cells, and the mitotic centrosomes. GFP-tagged version of XCdc14alpha localized to the nucleulus and GFP-XCdc14beta localized to the centrosome, although not exclusively. XCdc14alpha was also both meiotically and mitotically phosphorylated. Injection of antibodies raised against a conserved region of XCdc14/beta into Xenopus embryos at the two-cell stage blocked division of the injected blastomeres, suggesting that activities of XCdc14alpha/beta are required for normal cell division. These results provide evidence that XCdc14alpha/beta are required for normal cellular division and are regulated by at least two mechanisms, subcellular localization and possibly phosphorylation. Due to the high sequence conservation between Xcdc14alpha and hCdc14A, it seems likely that both mechanisms will contribute to regulation of Cdc14 homologs in vertebrates.


The University of Wisconsin Breast Cancer Epidemiology Simulation Model: An Update.
The University of Wisconsin Breast Cancer Epidemiology Simulation Model (UWBCS), also referred to as Model W, is a discrete-event microsimulation model that uses a systems engineering approach to replicate breast cancer epidemiology in the US over time. This population-based model simulates the lifetimes of individual women through 4 main model components: breast cancer natural history, detection, treatment, and mortality. A key feature of the UWBCS is that, in addition to specifying a population distribution in tumor growth rates, the model allows for heterogeneity in tumor behavior, with some tumors having limited malignant potential (i.e., would never become fatal in a woman's lifetime if left untreated) and some tumors being very aggressive based on metastatic spread early in their onset. The model is calibrated to Surveillance, Epidemiology, and End Results (SEER) breast cancer incidence and mortality data from 1975 to 2010, and cross-validated against data from the Wisconsin cancer reporting system. The UWBCS model generates detailed outputs including underlying disease states and observed clinical outcomes by age and calendar year, as well as costs, resource usage, and quality of life associated with screening and treatment. The UWBCS has been recently updated to account for differences in breast cancer detection, treatment, and survival by molecular subtypes (defined by ER/HER2 status), to reflect the recent advances in screening and treatment, and to consider a range of breast cancer risk factors, including breast density, race, body-mass-index, and the use of postmenopausal hormone therapy. Therefore, the model can evaluate novel screening strategies, such as risk-based screening, and can assess breast cancer outcomes by breast cancer molecular subtype. In this article, we describe the most up-to-date version of the UWBCS.


Microbial ecosystem and methanogenesis in ruminants.
Ruminant production is under increased public scrutiny in terms of the importance of cattle and other ruminants as major producers of the greenhouse gas methane. Methanogenesis is performed by methanogenic archaea, a specialised group of microbes present in several anaerobic environments including the rumen. In the rumen, methanogens utilise predominantly H2 and CO2 as substrates to produce methane, filling an important functional niche in the ecosystem. However, in addition to methanogens, other microbes also have an influence on methane production either because they are involved in hydrogen (H2) metabolism or because they affect the numbers of methanogens or other members of the microbiota. This study explores the relationship between some of these microbes and methanogenesis and highlights some functional groups that could play a role in decreasing methane emissions. Dihydrogen ('H2' from this point on) is the key element that drives methane production in the rumen. Among H2 producers, protozoa have a prominent position, which is strengthened by their close physical association with methanogens, which favours H2 transfer from one to the other. A strong positive interaction was found between protozoal numbers and methane emissions, and because this group is possibly not essential for rumen function, protozoa might be a target for methane mitigation. An important function that is associated with production of H2 is the degradation of fibrous plant material. However, not all members of the rumen fibrolytic community produce H2. Increasing the proportion of non-H2 producing fibrolytic microorganisms might decrease methane production without affecting forage degradability. Alternative pathways that use electron acceptors other than CO2 to oxidise H2 also exist in the rumen. Bacteria with this type of metabolism normally occupy a distinct ecological niche and are not dominant members of the microbiota; however, their numbers can increase if the right potential electron acceptor is present in the diet. Nitrate is an alternative electron sinks that can promote the growth of particular bacteria able to compete with methanogens. Because of the toxicity of the intermediate product, nitrite, the use of nitrate has not been fully explored, but in adapted animals, nitrite does not accumulate and nitrate supplementation may be an alternative under some dietary conditions that deserves to be further studied. In conclusion, methanogens in the rumen co-exist with other microbes, which have contrasting activities. A better understanding of these populations and the pathways that compete with methanogenesis may provide novel targets for emissions abatement in ruminant production.


Reformulation of the covering and quantizer problems as ground states of interacting particles.
It is known that the sphere-packing problem and the number-variance problem (closely related to an optimization problem in number theory) can be posed as energy minimizations associated with an infinite number of point particles in d-dimensional Euclidean space R(d) interacting via certain repulsive pair potentials. We reformulate the covering and quantizer problems as the determination of the ground states of interacting particles in R(d) that generally involve single-body, two-body, three-body, and higher-body interactions. This is done by linking the covering and quantizer problems to certain optimization problems involving the "void" nearest-neighbor functions that arise in the theory of random media and statistical mechanics. These reformulations, which again exemplify the deep interplay between geometry and physics, allow one now to employ theoretical and numerical optimization techniques to analyze and solve these energy minimization problems. The covering and quantizer problems have relevance in numerous applications, including wireless communication network layouts, the search of high-dimensional data parameter spaces, stereotactic radiation therapy, data compression, digital communications, meshing of space for numerical analysis, and coding and cryptography, among other examples. In the first three space dimensions, the best known solutions of the sphere-packing and number-variance problems (or their "dual" solutions) are directly related to those of the covering and quantizer problems, but such relationships may or may not exist for d≥4 , depending on the peculiarities of the dimensions involved. Our reformulation sheds light on the reasons for these similarities and differences. We also show that disordered saturated sphere packings provide relatively thin (economical) coverings and may yield thinner coverings than the best known lattice coverings in sufficiently large dimensions. In the case of the quantizer problem, we derive improved upper bounds on the quantizer error using sphere-packing solutions, which are generally substantially sharper than an existing upper bound in low to moderately large dimensions. We also demonstrate that disordered saturated sphere packings yield relatively good quantizers. Finally, we remark on possible applications of our results for the detection of gravitational waves.


Recurrent failings of medical humanitarianism: intractable, ignored, or just exaggerated?
Humanitarian health workers operate in dangerous and uncertain contexts, in which mistakes and failures are common, often have severe consequences, and are regularly repeated, despite being documented by many reviews. This Series paper aims to discuss the failures of medical humanitarianism. We describe why some of these recurrent failings, which are often not identified until much later, seem intractable: they are so entrenched in humanitarian action that they cannot be addressed by simple technical fixes. We argue that relief health-care interventions should be contextualised. Perhaps medical humanitarianism deserves a better reputation than the one at times tarnished by unfair criticism, resulting from inapplicable guiding principles and unrealistic expectations. The present situation is not conducive to radical reforms of humanitarian medicine; complex crises multiply and no political, diplomatic, or military solutions are in sight. Relief agencies have to compete for financial resources that do not increase at the same pace as health needs. Avoiding the repetition of failures requires recognising previous mistakes and addressing them through different policies by donors, stronger documentation and analysis of humanitarian programmes and interventions, increased professionalisation, improved, opportunistic relationships with the media, and better ways of working together with local health stakeholders and through indigenous institutions.


Effects of antioxidant supplementation on exercise performance in acute normobaric hypoxia.
To compare the effects of a 3-week supplementation between two different mixtures of antioxidants and placebo on aerobic exercise performance in acute normobaric hypoxia. Seventeen subjects were randomly assigned in a double-blind fashion to receive a broad-based antioxidants supplement containing beta-carotene, ascorbic acid, d-alpha-tocopherol-succinate, N-acetylcysteine, riboflavin, zinc, and selenium (antioxidant capsule group [AO group]), or a combination of alpha-ketoglutaric acid (α-KG) and 5-hydroxymethylfurfural (5-HMF; CYL concentrate supplementation group [CS group]), or placebo (PL group). Before and after supplementation, subjects performed two incremental cycle-exercise tests until exhaustion. The first test was conducted under normoxic conditions (LA, FiO2 of 20.9%, ~547 m) and the second after the 3-week supplementation period under normobaric hypoxic conditions (AHA, FiO2 of 12.9%, ~4300m). In CS peak cycling performance (peak power) declined from LA to AHA 7.3% (90% CI: 2.2-12.4) less compared with PL (p = .04) and 6.7% (90%CI: 3.2-10.2) less compared with AO (p = .03). Better maintenance of aerobic exercise capacity in CS was associated with an attenuated reduction in maximal heart rate in hypoxia. Aerobic exercise performance was less impaired in acute normobaric hypoxia after 3 weeks with supplementation of α-KG and 5-HMF compared with a broad-based antioxidants supplement or PL.


Explaining and understanding in psychopathology.
Psychoanalytical methodology has been described as causal explanation or hermeneutic understanding. This methodological dichotomy has been introduced into psychopathology by Karl Jaspers. Contemporary authors' contributions in the area are discussed. Although these authors accept a role for both methods, they agree with Jaspers that psychoanalysis should be subjected to the logical limitations of hermeneutic analysis. A logical framework for the interaction of explaining with understanding is presented and discussed in relation to psychiatric research.


Regional grassland productivity responses to precipitation during multiyear above- and below-average rainfall periods.
There is considerable uncertainty in the magnitude and direction of changes in precipitation associated with climate change, and ecosystem responses are also uncertain. Multiyear periods of above- and below-average rainfall may foretell consequences of changes in rainfall regime. We compiled long-term aboveground net primary productivity (ANPP) and precipitation (PPT) data for eight North American grasslands, and quantified relationships between ANPP and PPT at each site, and in 1-3 year periods of above- and below-average rainfall for mesic, semiarid cool, and semiarid warm grassland types. Our objective was to improve understanding of ANPP dynamics associated with changing climatic conditions by contrasting PPT-ANPP relationships in above- and below-average PPT years to those that occurred during sequences of multiple above- and below-average years. We found differences in PPT-ANPP relationships in above- and below-average years compared to long-term site averages, and variation in ANPP not explained by PPT totals that likely are attributed to legacy effects. The correlation between ANPP and current- and prior-year conditions changed from year to year throughout multiyear periods, with some legacy effects declining, and new responses emerging. Thus, ANPP in a given year was influenced by sequences of conditions that varied across grassland types and climates. Most importantly, the influence of prior-year ANPP often increased with the length of multiyear periods, whereas the influence of the amount of current-year PPT declined. Although the mechanisms by which a directional change in the frequency of above- and below-average years imposes a persistent change in grassland ANPP require further investigation, our results emphasize the importance of legacy effects on productivity for sequences of above- vs. below-average years, and illustrate the utility of long-term data to examine these patterns.


Nest parasitism, productivity, and clutch size in purple martins.
Mean maximum nestling weight of purple martins decreased with increase in brood size from three to five. Martins in the absence of acarine nest parasites produced young heavier than parasitized young of the same brood size; in addition, unparasitized nestlings tended to reach a maximum weight equivalent to that of young in parasitized broods of one less member. Modal brood size for parasitized and unparasitized martins was four, but there was a significant trend toward production of broods of five by mite-free birds, and of broods of three by parasitized parents. This suggests a potentially important role for nest parasitism in the determination of clutch size in martins and other birds.


Control of I-V hysteresis in CH3NH3PbI3 perovskite solar cell.
Mismatch of current (I)-voltage (V) curves with respect to the scan direction, so-called I-V hysteresis, raises critical issue in MAPbI3 (MA = CH3NH3) perovskite solar cell. Although ferroelectric and ion migration have been proposed as a basis for the hysteresis, origin of hysteresis has not been apparently unraveled. We report here on the origin of I-V hysteresis of perovskite solar cell that was systematically evaluated by the interface-dependent electrode polarizations. Frequency (f)-dependent capacitance (C) revealed that the normal planar structure with the TiO2/MAPbI3/spiro-MeOTAD configuration showed most significant I-V hysteresis along with highest capacitance (10(-2) F/cm(2)) among the studied cell configurations. Substantial reduction in capacitance to 10(-3) F/cm(2) was observed upon replacing TiO2 with PCBM, indicative of the TiO2 layer being mainly responsible for the hysteresis. The capacitance was intensively reduced to 10(-5) F/cm(2) and C-f feature shifted to higher frequency for the hysteresis-free planar structures with combination of PSS, NiO, and PCBM, which underlines the spiro-MeOTAD in part contributes to the hysteresis. This work is expected to provide a key to the solution of the problem on I-V hysteresis in perovskite solar cell.


Progress in the treatment of adolescents with acute lymphoblastic leukemia.
BACKGROUND AND METHODS. The authors studied the clinical and biologic features and treatment response of 358 children with acute lymphoblastic leukemia (ALL), including 90 adolescents, treated on a single multiagent protocol (St. Jude Total Study XI, 1984-1988). This was done to clarify whether the disease differed in adolescents and to determine the degree of improvement in treatment outcome produced by this modern intense chemotherapy. Compared with the younger children (1-9 years of age; infants 1 year old or younger excluded; n = 257), adolescents (10-18 years of age; n = 90) were significantly more likely to have adverse prognostic features, including T-cell phenotype, L2 blast cell morphologic characteristics, blasts with negative findings for common ALL antigen, and ploidy other than hyperdiploidy greater than 50. Eighty-six of the 90 (96%) adolescents achieved a complete remission, a rate similar to that of the children (97%). Although the event-free survival (EFS) of adolescents was shorter than that of younger children (5-year EFS of 66 +/- 8% versus 75 +/- 5%, respectively; P = 0.04), in this analysis of consecutively treated patients with ALL it showed a significant statistical and clinical improvement as compared with that in our previous study (St. Jude Total Study X, 1979-1983; 5-year EFS rate of 66 +/- 8% versus 37 +/- 5%, respectively; P < 0.001). Within the adolescent group treated on Total Study XI, the EFS was worse for those older than 15 years of age than for those 10-14 years old (46 +/- 15% versus 75 +/- 8%, respectively; P = 0.007). Toxic effects primarily included myelosuppression without severe sequelae. Approximately 96% of the therapy was administered in the outpatient setting. The increased frequency of unfavorable clinical and biologic features undoubtedly accounts for the poorer prognosis of adolescents with ALL, a conclusion supported by the lack of independent prognostic importance of age in this study. The authors conclude that approximately two-thirds of adolescents can be cured when treated with this intensive but tolerable therapy, showing that this form of treatment significantly has changed the prognosis of adolescents with ALL.


Electromechanical actuator with controllable motion, fast response rate, and high-frequency resonance based on graphene and polydiacetylene.
Although widely investigated, novel electromechanical actuators with high overall actuation performance are still in urgent need for various practical and scientific applications, such as robots, prosthetic devices, sensor switches, and sonar projectors. In this work, combining the properties of unique environmental perturbations-actuated deformational isomerization of polydiacetylene (PDA) and the outstanding intrinsic features of graphene together for the first time, we design and fabricate an electromechanical bimorph actuator composed of a layer of PDA crystal and a layer of flexible graphene paper through a simple yet versatile solution approach. Under low applied direct current (dc), the graphene-PDA bimorph actuator with strong mechanical strength can generate large actuation motion (curvature is about 0.37 cm(-1) under a current density of 0.74 A/mm(2)) and produce high actuation stress (more than 160 MPa/g under an applied dc of only 0.29 A/mm(2)). When applying alternating current (ac), this actuator can display reversible swing behavior with long cycle life under high frequencies even up to 200 Hz; significantly, while the frequency and the value of applied ac and the state of the actuators reach an appropriate value, the graphene-PDA actuator can produce a strong resonance and the swing amplitude will jump to a peak value. Moreover, this stable graphene-PDA actuator also demonstrates rapidly and partially reversible electrochromatic phenomenon when applying an ac. Two mechanisms-the dominant one, electric-induced deformation, and a secondary one, thermal-induced expansion of PDA-are proposed to contribute to these interesting actuation performances of the graphene-PDA actuators. On the basis of these results, a mini-robot with controllable direction of motion based on the graphene-PDA actuator is designed to illustrate the great potential of our discoveries for practical use. Combining the unique actuation mechanism and many outstanding properties of graphene and PDA, this novel kind of graphene-PDA actuator exhibits compelling advantages to traditional electromechanical actuation technology and may provide a new avenue for actuation applications.


Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression analysis suggests induction of DNA double-strand breaks and cell cycle progression.
Ochratoxin A (OTA) is a renal carcinogen primarily affecting the S3 segment of proximal tubules in rodents. In our previous study, we reported that OTA induces reporter gene mutations, primarily deletion mutations, in the renal outer medulla (OM), specifically in the S3 segment. In the present study, to identify genes involved in OTA-induced genotoxicity, we conducted a comparative analysis of global gene expression in the renal cortex (COR) and OM of kidneys from gpt delta rats administered OTA at a carcinogenic dose for 4 weeks. Genes associated with DNA damage and DNA damage repair, and cell cycle regulation were site-specifically changed in the OM. Interestingly, genes that were deregulated in the OM possessed molecular functions such as DNA double-strand break (DSB) repair (Rad18, Brip1, and Brcc3), cell cycle progression (Cyce1, Ccna2, and Ccnb1), G(2)/M arrest in response to DNA damage (Chek1 and Wee1), and p53-associated factors (Phlda3 and Ccng1). Significant increases in the mRNA levels of many of these genes were observed in the OM using real-time RT-PCR. However, genes related to oxidative stress exhibited no differences in either the number or function of altered genes in both the OM and COR. These results suggested that OTA induced DSB and cell cycle progression at the target site. These events other than oxidative stress could trigger genotoxicity leading to OTA-induced renal tumorigenicity.


Proteomic analysis identifies in vivo candidate matrix metalloproteinase-9 substrates in the left ventricle post-myocardial infarction.
Matrix metalloproteinase-9 (MMP-9) deletion has been shown to improve remodeling of the left ventricle post-myocardial infarction (MI), but the mechanisms to explain this improvement have not been fully elucidated. MMP-9 has a broad range of in vitro substrates, but relevant in vivo substrates are incompletely defined. Accordingly, we evaluated the infarct regions of wild-type (wt) and MMP-9 null (null) mice using a proteomic strategy. Wt and null groups showed similar infarct sizes (48+/-3 in wt and 45+/-3% in null), indicating that both groups received an equal injury stimulus. Left ventricle infarct tissue was homogenized and analyzed by 2-DE and MS. Of 31 spot intensity differences, the intensities of 9 spots were higher and 22 spots were lower in null mice compared to wt (all p<0.05). Several extracellular matrix proteins were identified in these spots by MS, including fibronectin, tenascin-C, thrombospondin-1, and laminin. Fibronectin was observed on the gels at a lower than expected molecular weight in the wt group, which suggested substrate cleavage, and the lower molecular weight spot was observed at lower intensity in the MMP-9 null group, which suggested cleavage by MMP-9. Immunoblotting confirmed the presence of fibronectin cleavage products in the wt samples and lower levels in the absence of MMP-9. In conclusion, examining infarct tissue from wt and MMP-9 null mice by proteomic analysis provides a powerful and unique method to identify in vivo candidate MMP substrates.


An unusual complication of pigtail catheter insertion.
Thoracostomy tubes are indicated for management of air or fluid in the pleural cavity. Pigtail catheters have emerged as an effective and less morbid alternative to traditional large bore chest tubes for evacuation of pleural air or fluid. However, they do not come without complications which commonly include pneumothorax and hemothorax. Rare complications in the literature such as left ventricular penetration, subclavian artery laceration and cerebral air embolism have been reported. We report a case of a 72-year-old male who presented with dyspnea and was found to have a right-sided pleural effusion requiring thoracentesis and subsequent pigtail catheter placement because of re-accumulation of the fluid. After accidental dislodgement of the catheter, it was replaced and the following day a chest X-ray (CXR) demonstrated diffuse subcutaneous emphysema. Computed tomography (CT) scan of the chest demonstrated the pigtail catheter tracking through the right middle and lower lobes reaching the posterior pleural space. We discuss the implications of this occurrence and recommended management based on our experience.


Keratin mutation predisposes to mouse liver fibrosis and unmasks differential effects of the carbon tetrachloride and thioacetamide models.
Keratins 8 and 18 (K8/K18) are important hepatoprotective proteins. Animals expressing K8/K18 mutants show a marked susceptibility to acute/subacute liver injury. K8/K18 variants predispose to human end-stage liver disease and associate with fibrosis progression during chronic hepatitis C infection. We sought direct evidence for a keratin mutation-related predisposition to liver fibrosis using transgenic mouse models because the relationship between keratin mutations and cirrhosis is based primarily on human association studies. Mouse hepatofibrosis was induced by carbon tetrachloride (CCl(4)) or thioacetamide. Nontransgenic mice, or mice that over express either human Arg89-to-Cys (R89C mice) or wild-type K18 (WT mice) were used. The extent of fibrosis was evaluated by quantitative real-time reverse-transcription polymerase chain reaction of fibrosis-related genes, liver hydroxyproline measurement, and Picro-Sirius red staining and collagen immunofluorescence staining. Compared with control animals, CCl(4) led to similar liver fibrosis but increased injury in K18 R89C mice. In contrast, thioacetamide caused more severe liver injury and fibrosis in K18 R89C as compared with WT and nontransgenic mice and resulted in increased messenger RNA levels of collagen, tissue inhibitor of metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 13. Analysis in nontransgenic mice showed that thioacetamide and CCl(4) have dramatically different molecular expression responses involving cytoskeletal and chaperone proteins. Over expression of K18 R89C predisposes transgenic mice to thioacetamide- but not CCl(4)-induced liver fibrosis. Differences in the keratin mutation-associated fibrosis response among the 2 models raise the hypothesis that keratin variants may preferentially predispose to fibrosis in unique human liver diseases. Findings herein highlight distinct differences in the 2 widely used fibrosis models.


Three-dimensional analysis of acetabular cup orientation and an evaluation of the relationship with pelvic sagittal parameters.
This study aimed to evaluate the effect of total hip arthroplasty (THA) on sagittal pelvic parameters and to evaluate the effect of sagittal pelvic parameters on acetabular cup orientation. The study included 86 patients who underwent THA for a diagnosis of unilateral coxarthrosis between 2011 and 2015. Measurements were taken of the preoperative and postoperative acetabular cup inclination (ACI), anteversion, and sagittal pelvic parameters. The effect of THA on sagittal pelvic parameters and the effects of the sagittal pelvic parameters on acetabular cup orientation were investigated. The sagittal pelvic tilt values calculated were mean 9.7° ± 6.3° (2°; 23°) preoperatively and 11.0° ± 6.1° (2°; 25°) postoperatively. The increase in postoperative pelvic incidence (PI) values was determined to be statistically significant (p < 0.05). The preoperative PI values had no significant effect on ACI, but in cases with high preoperative PI values, a tendency to high anteversion values was determined. The mean inclination values were found to be 40.2° ± 11.0° in the low PI group, 41.7° ± 7.4° in the normal PI group, and 44.1° ± 8.3° in the high PI group. As no increase in inclination values was observed with an increase in PI values, no statistical correlation was determined (p = 0.343). Average of anteversion values in the low PI group was 9.2° ± 13.7°, in the normal PI group 19.3° ± 10.5°, and in the high PI group 21.1° ± 12.5°. The difference between the groups was statistically significant (p = 0.001). Evaluating the results of this study, it can be concluded that varying PI values do affect the acetabular cup anterversion in THA. So, preoperative assessment of PI values is important in preventing postoperative acetabular cup malposition.


Health-related quality of life differs between adolescent athletes and adolescent nonathletes.
Patient-oriented outcome measures such as the Medical Outcomes Short Form (SF-36) and the Pediatric Outcomes Data Collection Instrument (PODCI) are important tools for determining the impact of events like sport-related injury on health-related quality of life (HRQoL). Unfortunately, there are no published studies using these instruments that compare adolescent athletes with their nonathlete peers, making interpretations of these measures in this population difficult. To compare HRQoL in adolescent athletes and nonathletes using 2 common instruments. Cross-sectional. 7 high schools. 219 athletes and 106 nonathletes. None. The SF-36 and the PODCI were completed in a counterbalanced manner during 1 session. Dependent variables included the 8 subscale and 2 composite scores of the SF-36 and the 5 subscale scores and 1 global score of the PODCI. On the SF-36, athletes reported higher scores on the physical function, general health, social functioning, and mental health subscales and the mental composite score and lower scores on the bodily pain subscale than nonathletes. On the PODCI, athletes reported higher scores on the sport and physical function and happiness subscales and lower scores on the pain/comfort subscale. Athletes reported higher scores on a number of SF-36 and PODCI subscales related to mental, emotional, and physical well-being than nonathletes. Our findings suggest that athletic involvement may be a benefit to the overall health status of adolescents and imply that athletes may be a distinct adolescent group requiring their own normative values when using the SF-36 and PODCI.


Promoting smoking cessation at the workplace. Results of a randomized controlled intervention study.
This paper presents results from a preliminary short-term work-site intervention study aimed at smoking cessation. The 3-month intervention included consultation for employers on the adoption of a nonsmoking policy, training for nonsmokers to provide assistance to smokers attempting to quit, and cessation classes for smokers. Eight work sites from Bloomington, Minnesota were recruited to the study and randomly assigned to an intervention or comparison condition after a baseline survey of all employees. To assess the effect of the intervention, smokers were surveyed 1 and 6 months after the intervention was completed. At the 1-month follow-up, the overall quit rate in the intervention group was 12% compared to 5% in the control group (P < .05). At the 6-month follow-up, 12% of smokers in the intervention group reported quitting, compared to 9% in the control group (P < .05). Co-worker support for quitting was higher in the intervention group compared to the comparison group. Cessation was highest overall among smokers whose co-workers frequently asked them not to smoke and among those who worked with a high proportion of nonsmokers. These results indicate that a short-term, multifaceted smoking cessation program implemented in work sites can affect smoking cessation rates as well as the work-site norms about smoking.


A novel stepwise analysis procedure of genome-wide expression profiles identifies transcript signatures of thiamine genes as classifiers of mitochondrial mutants.
To extract functional information on genes and processes from large expression datasets, analysis methods are required that can computationally deal with these amounts of data, are tunable to specific research questions, and construct classifiers that are not overspecific to the dataset at hand. To satisfy these requirements, a stepwise procedure that combines elements from principal component analysis and discriminant analysis, was developed to specifically retrieve genes involved in processes of interest and classify samples based upon those genes. In a global expression dataset of 300 gene knock-outs in Saccharomyces cerevisiae, the procedure successfully classified samples with similar 'cellular component' Gene Ontology annotations of the knock-out gene by expression signatures of limited numbers of genes. The genes discriminating 'mitochondrion' from the other subgroups were evaluated in more detail. The thiamine pathway turned out to be one of the processes involved and was successfully evaluated in a logistic model to predict whether yeast knock-outs were mitochondrial or not. Further, this pathway is biologically related to the mitochondrial system. Hence, this strongly indicates that our approach is effective and efficient in extracting meaningful information from large microarray experiments and assigning functions to yet uncharacterized genes.


Antibiotic prophylaxis for children with sickle cell disease: a survey of pediatric dentistry residency program directors and pediatric hematologists.
The purposes of this study were to: (1) investigate the current clinical practice regarding the use of antibiotic prophylaxis by pediatric dentistry residency program directors and pediatric hematologists for children with sickle cell disease (SCD) requiring dental treatment; and (2) evaluate the perceived relative risk of bacteremia following specific dental procedures, as defined by pediatric dentistry residency program directors and pediatric hematologists. A written survey depicting various clinical scenarios of SCD children requiring common dental procedures was mailed to directors of pediatric dental advanced education programs and distributed to pediatric hematologists attending the 2003 Annual Sickle Cell Disease Association of America conference in Washington, DC. Surveys were returned by 60% (N=34/57) of the pediatric dentistry residency program directors. The surveys were obtained from 51% of pediatric hematologists at the meeting (N=72/140). At least 50% of all respondents recommended prophylaxis for the following clinical situations: dental extractions, treatment under general anesthesia, and status post splenectomy. The perceived risk of infectious complication was highest for extractions, followed by restorative treatment and tooth polishing. Dental residency program directors were more likely (71%, N=24/34) to recommend additional antibiotic therapy for patients taking penicillin prophylaxis if they required an invasive oral surgical procedure. Conversely, only 38% (N=25/66) of pediatric hematologists recommended additional antibiotic therapy (P=.001). Eighty-six percent of dental residency program directors (N=25/29) chose amoxicillin for prophylaxis whereas only 62% of pediatric hematologists (N=36/58) recommended amoxicillin. (P<.05). There is a lack of consensus on the appropriate use of antibiotic prophylaxis in SCD children undergoing dental treatments. Further research and risk/benefit assessment is needed to create a unified approach.


Kawasaki disease: a comprehensive review of treatment options.
Kawasaki disease (KD) is an acute self-limiting systemic vasculitis with specific predilection for the coronary arteries that affects previously healthy young infants and children. It is the leading cause of childhood-acquired heart disease in the developed world. Although the stimulus for the cascade of inflammation in KD is unknown, prompt treatment within 10 days of symptom onset has been shown to improve clinical outcomes and reduce the risk of coronary artery complications. Standard initial therapy is intravenous immunoglobulin (IVIG) and aspirin. Non-responders to initial therapy remain a challenge. This present review summarizes the treatment options for initial and refractory KD, including the role of steroids and other immunosuppressive therapies. Literature search using PubMed database to identify pharmacologic studies in KD using the terms Kawasaki disease, intravenous immunoglobulin, refractory, corticosteroids, infliximab, cyclosporine, methotrexate, high risk from January 1988-May 2015 was performed. Bibliographies of selected references were also evaluated for relevant articles. Results were limited to those published in English. All articles identified from the PubMed searches were evaluated. Initial IVIG therapy results in rapid resolution of clinical symptoms in 80-90% of patients and has been shown to reduce the risk of coronary disease. Although concomitant aspirin remains the standard of care for the initial management of KD, the evidence to support its efficacy in improving coronary artery outcomes are lacking. Initial therapy with corticosteroids in addition to intravenous immunoglobulin and aspirin improves outcomes in patients in Japan. However, identifying patients at high risk who may benefit from additional corticosteroids in heterogeneous populations has been challenging. Therapeutic options for non-responders to initial therapy are also challenging given the paucity of data. Patients who fail to respond to the first dose of IVIG will most often receive a second dose. Patients who fail to respond to two doses of IVIG present a unique challenge as the appropriate treatment remains uncertain. Although their effectiveness remains unproven, treatment with infliximab, cyclosporine or methotrexate may be considered in those patients who fail multiple doses of IVIG and steroids. The role of steroids in high-risk non-Japanese patients is unclear, with the biggest challenge being early identification of patients at high risk of developing adverse coronary artery outcomes. Limited data evaluating other immunosuppressive agents are available and should be reserved for patients failing two doses of IVIG. Although recent advances in research have broadened our understanding of the epidemiology, genetic susceptibility and pathogenesis of KD, the aetiology of KD remains unclear. Ongoing research will help determine more precise pathogenesis and may assist in developing a diagnostic test as well as identifying new targets for more precise treatment interventions.


Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus.
Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia.


Visible and infrared extinction of atmospheric aerosol in the marine and coastal environment.
The microphysical model Marine Aerosol Extinction Profiles (MaexPro) for surface layer marine and coastal atmospheric aerosols, which is based on long-term observations of size distributions for 0.01-100 μm particles, is presented. The fundamental feature of the model is a parameterization of amplitudes and widths for aerosol modes of the aerosol size distribution function (ASDF) as functions of fetch and wind speed. The shape of the ASDF and its dependence on meteorological parameters, altitudes above the sea level (H), fetch (X), wind speed (U), and relative humidity is investigated. The model is primarily to characterize aerosols for the near-surface layer (within 25 m). The model is also applicable to higher altitudes within the atmospheric boundary layer, where the change in the vertical profile of aerosol is not very large. In this case, it is only valid for "clean" marine environments, in the absence of air pollution or any other major sources of continental aerosols, such desert dust or smoke from biomass burning. The spectral profiles of the aerosol extinction coefficients calculated by MaexPro are in good agreement with observational data and the numerical results obtained by the well-known Navy Aerosol Model and Advanced Navy Aerosol Model codes. Moreover, MaexPro was found to be an accurate and reliable instrument for investigation of the optical properties of atmospheric aerosols.


Twelve tips for developing and sustaining a programme of student selected components.
Student selected components (SSCs) represent a significant component of medical curricula in the UK and a new approach in medical education. Despite the prominence given to SSCs by the General Medical Council in each of its seminal papers regarding undergraduate medical education, there remains a diverse view of the purpose, outcomes, structure and assessment of SSCs. Many Schools have adopted their own perspective of SSCs and created different but often innovative courses. This article brings together the Scottish Medical Schools and their experience in organising SSCs, highlights some of the challenges and offers possible solutions to some of the difficulties encountered. The SSC Director from each of the Scottish medical schools each contributed their own '12 Tips'. From these a consensus was achieved. Even though the Scottish medical schools have a wide range of curriculum and timetable formats, there was a great deal of agreement in the challenges and problems encountered in their SSC programmes, as expressed through these 12 Tips. There is much diversity in SSC programmes at different medical schools, although there is also much commonality in the challenges that arise. We hope that this paper will promote thought and discussion amongst those involved, and be useful to those involved in curriculum and programme development and also to those new to medical education.


Global host molecular perturbations upon in situ loss of bacterial endosymbionts in the deep-sea mussel Bathymodiolus azoricus assessed using proteomics and transcriptomics.
Colonization of deep-sea hydrothermal vents by most invertebrates was made efficient through their adaptation to a symbiotic lifestyle with chemosynthetic bacteria, the primary producers in these ecosystems. Anatomical adaptations such as the establishment of specialized cells or organs have been evidenced in numerous deep-sea invertebrates. However, very few studies detailed global inter-dependencies between host and symbionts in these ecosystems. In this study, we proposed to describe, using a proteo-transcriptomic approach, the effects of symbionts loss on the deep-sea mussel Bathymodiolus azoricus' molecular biology. We induced an in situ depletion of symbionts and compared the proteo-transcriptome of the gills of mussels in three conditions: symbiotic mussels (natural population), symbiont-depleted mussels and aposymbiotic mussels. Global proteomic and transcriptomic results evidenced a global disruption of host machinery in aposymbiotic organisms. We observed that the total number of proteins identified decreased from 1118 in symbiotic mussels to 790 in partially depleted mussels and 761 in aposymbiotic mussels. Using microarrays we identified 4300 transcripts differentially expressed between symbiont-depleted and symbiotic mussels. Among these transcripts, 799 were found differentially expressed in aposymbiotic mussels and almost twice as many in symbiont-depleted mussels as compared to symbiotic mussels. Regarding apoptotic and immune system processes - known to be largely involved in symbiotic interactions - an overall up-regulation of associated proteins and transcripts was observed in symbiont-depleted mussels. Overall, our study showed a global impairment of host machinery and an activation of both the immune and apoptotic system following symbiont-depletion. One of the main assumptions is the involvement of symbiotic bacteria in the inhibition and regulation of immune and apoptotic systems. As such, symbiotic bacteria may increase their lifespan in gill cells while managing the defense of the holobiont against putative pathogens.


Differences in Medicare Expenditures Between Appalachian and Nationally Representative Cohorts of Elderly Women With Breast Cancer: An Application of Decomposition Technique.
Background: Differences in Medicare expenditures during the initial phase of cancer care among rural and medically underserved elderly women with breast cancer (BC) and those from a nationally representative cohort have not been reported. The objective of this study was to determine Medicare expenditures during the initial phase of care among women in West Virginia (WV) who were Medicare beneficiaries with BC and compare them with national estimates. The magnitude of differences in these expenditures was also determined by using a linear decomposition technique. Methods: A retrospective observational study was conducted using the WV Cancer Registry-Medicare database and the SEER-Medicare database. Our study cohorts consisted of elderly women aged ≥66 years diagnosed with incident BC in 2003 to 2006. Medicare expenditures during the initial year after BC diagnosis were derived from all of the Medicare files. Generalized linear regressions were performed to model expenditures, after controlling for predisposing factors, enabling resources, need, healthcare use, and external healthcare environmental factors. Blinder-Oaxaca decomposition was conducted to examine the proportion of the differences in the average expenditures explained by independent variables included in the model. Results: Average Medicare expenditures for the WV Medicare cohort during the initial phase of BC care were $25,626 compared with $29,502 for the SEER-Medicare cohort; a difference of $3,876. In the multivariate regression, this difference decreased to $708 and remained significant. Only 16% of the differences in the average expenditures between the cohorts were explained by the independent variables included in the model. Enabling resources (6.86%), healthcare use (7.55%), and external healthcare environmental factors (3.33%) constituted most of the explained portion of the differences in the average expenditures. Conclusions: The difference in average Medicare expenditures between the elderly beneficiaries with BC from a rural state (WV) and their national counterparts narrowed but remained significantly lower after multivariate adjustment. The explained portion of this difference was mainly driven by enabling and healthcare use factors, whereas 84% of this difference remained unexplained.


Protein phosphatase-2A is a target of epigallocatechin-3-gallate and modulates p53-Bak apoptotic pathway.
(-)-Epigallocatechin-3-gallate (EGCG) is a well-known chemoprevention factor. Recent studies have revealed that EGCG triggers cancer cells undergoing apoptosis through p53-dependent pathway. How EGCG activates p53-dependent apoptosis is not fully understood. In the present study using JB6 cell as a model system, we have shown that EGCG can negatively regulate protein serine/threonine phosphatase-2A (PP-2A) to positively regulate p53-dependent apoptosis. First, EGCG at physiologic levels down-regulates PP-2A at the protein and enzyme activity levels. Second, EGCG induces apoptosis of JB6 cells, which is associated with hyperphosphorylation of p53 and up-regulation of the proapoptotic gene, Bak. DNA sequence analysis, gel mobility shifting, chromatin immunoprecipitation, and reporter gene activity assays revealed that p53 directly controls Bak in JB6 cells. Knockdown of p53 and Bak expression with RNAi substantially inhibits EGCG-induced apoptosis. Third, PP-2A directly interacts with p53 and dephosphorylates p53 at Ser-15 in vitro and in vivo. Fourth, overexpression of the catalytic subunit for PP-2A down-regulates p53 phosphorylation at Ser15, attenuates expression of the downstream proapoptotic gene, Bak, and antagonizes EGCG-induced apoptosis. Inhibition of PP-2A activity enhances p53 phosphorylation at Ser-15 and up-regulates Bak expression to promote EGCG-induced apoptosis. Finally, in the p53(-/-) H1299 and p53(+/+) H1080 cells, EGCG down-regulates PP-2A similarly but induces differential apoptosis. In summary, our results show that (a) PP-2A directly dephosphorylates p53 at Ser-15; (b) P53 directly controls Bak expression; and (c) EGCG negatively regulates PP-2A. Together, our results show that EGCG-mediated negative regulation of PP-2A is an important molecular event for the activation of p53-dependent apoptosis during its chemoprevention.


Impact of electronic nicotine delivery systems and other respondent characteristics on tobacco use transitions among a U.S. national sample of women of reproductive age.
Identifying predictors of tobacco use patterns that differ in harm among reproductive-aged women may inform efforts to protect women and children against adverse health impacts of tobacco use. Changes in tobacco use patterns were examined among women (18-49 years) who completed Wave 1 (W1) and Wave 2 (W2), or W2 and Wave 3 (W3) of the U.S. Population Assessment of Tobacco and Health (PATH, 2013-2016) study, and were using cigarettes, filtered cigars and/or cigarillos in the first wave over which data were included for that respondent (Time 1; T1). We examined the proportion of respondents whose tobacco use transitions from T1 to Time 2 (T2) were harm-maintaining (continued using combusted tobacco), harm-reducing (transitioned to electronic nicotine delivery systems (ENDS), or harm-eliminating (quit tobacco). Multinomial logistic regressions (with harm-maintaining as the baseline category) were conducted to examine associations between ENDS use, demographic, and psychosocial characteristics with each transition. A majority of women (83 %) exhibited harm-maintaining transitions, followed by harm-eliminating (14.7 %) and harm-reducing (2.3 %) transitions. Use of ENDS at T1 was associated with increased odds of harm reduction and decreased odds of harm elimination. Younger women were more likely to make both harm-reducing and harm-eliminating transitions. Increased educational attainment, identifying as Black or Hispanic, increased psychiatric symptoms, and pregnancy were associated with harm elimination, whereas living at or above poverty was associated with harm reduction. Study results contribute new information on the impact of ENDS, sociodemographic characteristics, psychiatric symptoms, and pregnancy on tobacco use transitions among reproductive-aged women.


Few-cycle solitons and supercontinuum generation with cascaded quadratic nonlinearities in unpoled lithium niobate ridge waveguides.
Formation and interaction of few-cycle solitons in a lithium niobate ridge waveguide are numerically investigated. The solitons are created through a cascaded phase-mismatched second-harmonic generation process, which induces a dominant self-defocusing Kerr-like nonlinearity on the pump pulse. The inherent material self-focusing Kerr nonlinearity is overcome over a wide wavelength range, and self-defocusing solitons are supported from 1100 to 1900 nm, covering the whole communication band. Single cycle self-compressed solitons and supercontinuum generation spanning 1.3 octaves are observed when pumped with femtosecond nanojoule pulses at 1550 nm. The waveguide is not periodically poled, as quasi-phase-matching would lead to detrimental nonlinear effects impeding few-cycle soliton formation.


Aberrant activation of bone marrow Ly6C high monocytes in diabetic mice contributes to impaired glucose tolerance.
Accumulating evidence indicates that diabetes and obesity are associated with chronic low-grade inflammation and multiple organ failure. Tissue-infiltrated inflammatory M1 macrophages are aberrantly activated in these conditions and contribute to hyperglycemia and insulin resistance. However, it is unclear at which stage these cells become aberrantly activated: as precursor monocytes in the bone marrow or as differentiated macrophages in tissues. We examined the abundance, activation state, and function of bone marrow-derived Ly6Chigh monocytes in mice with diabetes and/or obesity. Ly6Chigh monocytes were FACS-purified from six groups of male mice consisting of type 2 diabetes model db/db mice, streptozotocin (STZ) induced insulin depletion mice, high fat diet (HFD) induced obesity mice and each control mice. Ly6Chigh monocytes were then analyzed for the expression of inflammation markers by qRT-PCR. In addition, bone marrow-derived Ly6Chigh monocytes from db/+ and db/db mice were fluorescently labeled and injected into groups of db/db recipient mice. Cell trafficking to tissues and levels of markers were examined in the recipient mice. The expression of many inflammation-related genes was significantly increased in Ly6Chigh monocytes from db/db mice, compared with the control. Bone marrow-derived Ly6Chigh monocytes isolated from db/db mice, but not from db/+ mice, displayed prominent infiltration into peripheral tissues at 1 week after transfer into db/db mice. The recipients of db/db Ly6Chigh monocytes also exhibited significantly increased serum glucose levels and worsening tolerance compared with mice receiving db/+ Ly6Chigh monocytes. These novel observations suggest that activated Ly6Chigh monocytes may contribute to the glucose intolerance observed in diabetes.


Migration, neighborhoods, and networks: approaches to understanding how urban environmental conditions affect syndemic adverse health outcomes among gay, bisexual and other men who have sex with men.
Adopting socioecological, intersectionality, and lifecourse theoretical frameworks may enhance our understanding of the production of syndemic adverse health outcomes among gay, bisexual and other men who have sex with men (MSM). From this perspective, we present preliminary data from three related studies that suggest ways in which social contexts may influence the health of MSM. The first study, using cross-sectional data, looked at migration of MSM to the gay resort area of South Florida, and found that amount of time lived in the area was associated with risk behaviors and HIV infection. The second study, using qualitative interviews, observed complex interactions between neighborhood-level social environments and individual-level racial and sexual identity among MSM in New York City. The third study, using egocentric network analysis with a sample of African American MSM in Baltimore, found that sexual partners were more likely to be found through face-to-face means than the Internet. They also observed that those who co-resided with a sex partner had larger networks of people to depend on for social and financial support, but had the same size sexual networks as those who did not live with a partner. Overall, these findings suggest the need for further investigation into the role of macro-level social forces on the emotional, behavioral, and physical health of urban MSM.


Sorting it out: Eliciting consumer priorities for recovery in supportive housing.
This study aims to understand participant priorities in their personal recovery journey and their perspectives of recovery domains. A card sort data gathering technique was employed to elicit priorities in recovery from consumers in supportive housing programs serving formerly homeless adults with severe mental illnesses in New York City. Participants (N=38) were asked to sort 12 cards printed with recovery domains in order of importance and describe the meaning attached to each domain. Mental health (95%), physical health (89%), and housing (92%) were the domains most frequently included and prioritized in the top three rankings. Family (76%) and partner (74%) were also frequently included and endorsed as most important second only to mental health. Housing was prioritized yet rated most important less often (58%). Work, school, hobbies, program, friends and neighborhood were less frequently endorsed. 'Card sort talk' revealed critical understanding of participants' priorities and their reasons for endorsing other domains less frequently. Most important to participants was regaining functional independence through improved mental and physical health and access to housing. With underlying principles of efficiency and empowerment, card sort is a promising engagement technique for providers to elicit consumer priorities in their own recovery.


Baseline entomological data for a pilot malaria control program in Equatorial Guinea.
Entomological studies conducted on the island of Bioko and the mainland province, Río Muni, in Equatorial Guinea provided baseline data for a pilot malaria control program. The main species collected resting in houses at low density were Anopheles gambiae s.l. Giles and Anopheles funestus Giles. An. gambiae s.l. density increased during the rainy season, whereas An. funestus populations remained stable during both dry and wet seasons. Both species tended to be endophilic and were not collected resting or biting outdoors. Overall, delayed sporozoite rates were about 10% for both species and were highest in the dry season. An. gambiae s.l. from the mainland showed resistance to 4% DDT, but the island population was still susceptible. All populations were completely susceptible to 5% malathion and 0.025% deltamethrin.


Parasitoid wasp venom SERCA regulates Drosophila calcium levels and inhibits cellular immunity.
Because parasite virulence factors target host immune responses, identification and functional characterization of these factors can provide insight into poorly understood host immune mechanisms. The fruit fly Drosophila melanogaster is a model system for understanding humoral innate immunity, but Drosophila cellular innate immune responses remain incompletely characterized. Fruit flies are regularly infected by parasitoid wasps in nature and, following infection, flies mount a cellular immune response culminating in the cellular encapsulation of the wasp egg. The mechanistic basis of this response is largely unknown, but wasps use a mixture of virulence proteins derived from the venom gland to suppress cellular encapsulation. To gain insight into the mechanisms underlying wasp virulence and fly cellular immunity, we used a joint transcriptomic/proteomic approach to identify venom genes from Ganaspis sp.1 (G1), a previously uncharacterized Drosophila parasitoid species, and found that G1 venom contains a highly abundant sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. Accordingly, we found that fly immune cells termed plasmatocytes normally undergo a cytoplasmic calcium burst following infection, and that this calcium burst is required for activation of the cellular immune response. We further found that the plasmatocyte calcium burst is suppressed by G1 venom in a SERCA-dependent manner, leading to the failure of plasmatocytes to become activated and migrate toward G1 eggs. Finally, by genetically manipulating plasmatocyte calcium levels, we were able to alter fly immune success against G1 and other parasitoid species. Our characterization of parasitoid wasp venom proteins led us to identify plasmatocyte cytoplasmic calcium bursts as an important aspect of fly cellular immunity.


The (over)use of SMART goals for physical activity promotion: A narrative review and critique.
The SMART acronym (e.g., Specific, Measurable, Achievable, Realistic, Timebound) is a highly prominent strategy for setting physical activity goals. While it is intuitive, and its practical value has been recognised, the scientific underpinnings of the SMART acronym are less clear. Therefore, we aimed to narratively review and critically examine the scientific underpinnings of the SMART acronym and its application in physical activity promotion. Specifically, our review suggests that the SMART acronym: is not based on scientific theory; is not consistent with empirical evidence; does not consider what type of goal is set; is not applied consistently; is lacking detailed guidance; has redundancy in its criteria; is not being used as originally intended; and has a risk of potentially harmful effects. These issues are likely leading to sub-optimal outcomes, confusion, and inconsistency. Recommendations are provided to guide the field towards better practice and, ultimately, more effective goal setting interventions to help individuals become physically active.


Homelessness and gender in out-of-treatment drug users.
This study examines 5225 out-of-treatment crack users and drug injectors drawn from five different geographic areas to examine selected factors associated with homelessness. Of these crack users, 27% considered themselves undomiciled, and 60% had previously entered some type of drug treatment. Logistic regression found that substance abusers who were married, female, and persons of color were less likely to be without a home when other variables were controlled. Trading sex for money and perceived chance of getting acquired immunodeficiency syndrome (AIDS) were associated positively with homelessness, while participating in methadone detoxification and methadone maintenance programs seemed to offer some protection from homelessness.


Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in vivo.
Expression of lipoprotein lipase (LPL) by the macrophage has been proposed to promote foam cell formation and atherosclerosis, primarily on the basis of in vitro studies. LPL-deficient mice might provide a model for testing the role of LPL secretion by the macrophage in an in vivo system. Unfortunately, homozygous deficiency of LPL in the mouse is lethal shortly after birth. Because the fetal liver is the major site of hematopoiesis in the developing fetus, transplantation of C57BL/6 mice with LPL-/- fetal liver cells (FLCs) was used to investigate the physiologic role of macrophage LPL expression in vivo. Thirty-four female C57BL/6 mice were lethally irradiated and reconstituted with FLCs from day 14 LPL+/+, LPL+/-, and LPL-/- donors. No significant differences were detected in plasma levels of post-heparin LPL activity or in serum cholesterol or triglyceride levels between the 3 groups on either a chow diet or an atherogenic diet. After 19 weeks on the atherogenic diet, aortae were collected for quantitative analysis of the extent of aortic atherosclerosis. LPL expression was detected by immunocytochemistry and in situ hybridization in macrophages of aortic atherosclerotic lesions of LPL+/+-->C57BL/6 and LPL+/--->C57BL/6 mice, but not in LPL-/--->C57BL/6 mice, whereas myocardial cells expressed LPL in all groups. The mean aortic lesion area was reduced by 55% in LPL-/--->C57BL/6 mice compared with LPL+/+-->C57BL/6 mice and by 45% compared with LPL+/--->C57BL/6 mice, respectively. These data demonstrate in vivo that LPL expression by macrophages in the artery wall promotes foam cell formation and atherosclerosis. off


Null lens design techniques.
There are a surprising number of discrete, well-corrected null lens designs with just two elements for testing a large, fast-speed parabolic mirror from its center of curvature. Some design techniques are discussed for generating these solutions, which may be applicable to the design of null lenses for other mirror shapes. Without examining these multiple solutions, which differ greatly in performance, there is no way to know if the optimum configuration has been found.


Individual and situational factors that influence the efficacy of personalized feedback substance use interventions for mandated college students.
Little is known about individual and situational factors that moderate the efficacy of personalized feedback interventions (PFIs). Mandated college students (N = 348) were randomly assigned either to a PFI delivered in the context of a brief motivational interview (BMI; n = 180) or to a written PFI only (WF) condition and were followed up at 4 months and 15 months postintervention. The authors empirically identified heterogeneous subgroups utilizing mixture modeling analysis based on heavy episodic drinking and alcohol-related problems. The 4 identified groups were dichotomized into an improved group (53.4%) and a nonimproved group (46.6%). Logistic regression results indicated that the BMI was no more efficacious than the WF across all mandated students. However, mandated students who experienced a serious incident requiring medical or police attention and those with higher levels of alcohol-related problems at baseline benefited more from the BMI than from the WF. It may be an efficacious and cost-effective approach to provide a written PFI for low-risk mandated students and an enhanced PFI with a BMI for those students who experience a serious incident or have higher baseline alcohol-related problems.


Add-on LABA in a separate inhaler as asthma step-up therapy versus increased dose of ICS or ICS/LABA combination inhaler.
Asthma management guidelines recommend adding a long-acting β2-agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12-80 years) prescribed step-up therapy as a ≥50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point in comparisons of cohorts matched for asthma severity and control during the baseline year. After 1:2 cohort matching, the increased extrafine ICS versus separate ICS+LABA cohorts included 3232 and 6464 patients, respectively, and the fine-particle ICS/LABA FDC versus separate ICS+LABA cohorts included 7529 and 15 058 patients, respectively (overall mean age 42 years; 61-62% females). Over one outcome year, adjusted OR (95% CI) for achieving asthma control were 1.25 (1.13-1.38) for increased ICS versus separate ICS+LABA and 1.06 (1.05-1.09) for ICS/LABA FDC versus separate ICS+LABA. For patients with asthma, increased dose of extrafine-particle ICS, or add-on LABA via ICS/LABA combination inhaler, is associated with significantly better outcomes than ICS+LABA via separate inhalers.


Antenatal coffee and tea consumption and the effect on birth outcome and hypertensive pregnancy disorders.
Coffee and tea are commonly consumed during pregnancy. While several of their components, like caffeine, have strong pharmacological effects, the effect on the unborn fetus remains unclear. Caffeine intake has been associated with abortion, preterm birth and fetal growth restriction, but a general consensus on caffeine restriction is still lacking. We aimed to investigate antenatal coffee, tea and caffeine consumption and the effect on birth weight and length, gestational age at birth and hypertensive disorders in pregnancy. A total of 936 healthy pregnancies from the WHISTLER birth cohort with data on coffee and tea consumption were included. Maternal and child characteristics as well as antenatal coffee and tea consumption were obtained through postpartum questionnaires. Reported consumption was validated using available preconceptional data. Caffeine intake was calculated from coffee and tea consumption. Linear and logistic regression was used to assess the association with birth outcome and hypertensive disorders. After adjustment for smoking and maternal age, a daily consumption of more than 300mg of caffeine compared to less than 100mg of caffeine was significantly associated with an increased gestational age (linear regression coefficient = 2.00 days, 95%CI = 0.12-4.21, P = 0.03). Tea consumption was significantly related to a higher risk of pregnancy induced hypertension (OR = 1.13, 95%CI = 1.04-1.23, P = 0.004). No associations concerning coffee consumption or birth weight and birth length were observed. Daily caffeine consumption of more than 300mg is possibly associated with an increase in gestational age at birth. A possible relation between high tea consumption and increased risk for pregnancy induced hypertension warrants further research. For most outcomes, we found no significant associations with coffee or tea intake.


Nucleophilic or electrophilic interactions of C₂ with HX systems (X = F, Cl, Br).
Highly correlated ab initio wave functions within the MRCI approach are used in a comparative study of the interactions between C2 and the three hydrogen halides HX (X = F, Cl, Br). Test calculations are also presented using the UCCSD(T)-F12 approach. The asymptotic regions are investigated for different relative orientations of the two moieties. It is shown that the three systems C2 + HX are bound, for intermolecular distances close to 3 Å, through nucleophilic interactions between C2 and HX for approaches perpendicular to the C-C axis, with decreasing interaction energies from HF to HBr. For HX approaching C2 along its axis, the interactions, governed by the electrophilic character of C2 are decreasing from HBr to HF. Even though the reactions toward the molecular systems HCCX or CCHX are exothermic, activation barriers (0.58 eV and more) are calculated at short distances, preventing the direct reactions toward the corresponding tetra-atomic systems.