Hepatic tuberculosis: a multimodality imaging review.
We aim to illustrate the multimodal imaging spectrum of hepatic involvement in tuberculosis (TB). Whilst disseminated tuberculosis on imaging typically manifests as multiple small nodular lesions scattered in the liver parenchyma, isolated hepatic tuberculosis remains a rare and intriguing entity. Indubitably, imaging is the mainstay for detection of tubercular hepatic lesions which display a broad spectrum of imaging manifestations on different modalities. While sonography and computed tomography (CT) findings have been described in some detail, there is a paucity of literature on magnetic resonance imaging (MRI) features. Due to a significant overlap with other commoner and similar appearing hepatic lesions, hepatic tuberculosis is often either misdiagnosed or labelled as indeterminate lesions. This article is a compendium of cases highlighting the spectrum of imaging patterns that can be encountered in patients with isolated primary hepatic tuberculosis as well as disseminated (secondary) disease. Rare patterns of primary disease such as tubercular cholangitis, hypervascular liver masses, and those with vascular complications are also illustrated and discussed. Imaging plays a valuable role in the detection of tubercular hepatic lesions. Also, imaging can be helpful in their characterisation and for assessing associated complications. • Hepatic TB has myriad imaging manifestations and is often confounded with neoplastic lesions. • Imaging patterns include miliary TB, macronodular TB, serohepatic TB and tubercular cholangitis. • Concurrent splenic, nodal or pulmonary involvements are helpful pointers towards the diagnosis. • Miliary calcifications along the bile ducts are characteristic of tubercular cholangitis. • Histological/microbiological confirmation is often necessary to confirm the diagnosis.


Respiratory Symptoms and Lung Function among Greek Cotton Industry Workers: A Cross-Sectional Study.
Workers in cotton industry are occupationally exposed to various dust-related hazards. The nature of these agents and the respective exposure levels depend on the cotton industry specific sector. These exposures could be associated with respiratory symptoms and changes in lung function parameters. To evaluate associations between occupational exposure and respiratory function as well as reported symptoms in several groups of workers at different stages of the cotton industry in a vertical approach that covers all the major sectors-from cotton ginning to weaving and fabric production. A questionnaire on respiratory symptoms and individual as well as workplace characteristics was completed by 256 workers at the cotton industry and 148 office workers (control group). Both groups underwent spirometry. Workers in cotton industry reported a higher prevalence of severe dyspnea (p=0.002) and wheezing (p=0.004) compared to the control group. Also they were found to have a lower predicted FEV1% (p<0.029) and lower FEV1/FVC (p<0.001) values. In addition, a higher prevalence of FEV1% <80% (p<0.001) and FEV1/FVC <70% (p=0.041) were found among textile workers. Similar results were found for non-smoker textile workers compared to non-smoker control group workers. Those working in cotton ginning mills recorded the highest decrease of spirometric values. Duration of employment in cotton industry and smoking use were found to be predictors of lung function decline for cotton industry workers. Occupational exposure to cotton dust was associated with increased prevalence of respiratory symptoms and obstructive pattern in pulmonary function test.


Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.
The numerous functions of the liver are controlled primarily at the transcriptional level by the concerted actions of a limited number of hepatocyte-enriched transcription factors (hepatocyte nuclear factor 1alpha [HNF1alpha], -1beta, -3alpha, -3beta, -3gamma, -4alpha, and -6 and members of the c/ebp family). Of these, only HNF4alpha (nuclear receptor 2A1) and HNF1alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells. HNF1alpha-null mice are viable, indicating that this factor is not an absolute requirement for the formation of an active hepatic parenchyma. In contrast, HNF4alpha-null mice die during embryogenesis. Moreover, recent in vitro experiments using tetraploid aggregation suggest that HNF4alpha is indispensable for hepatocyte differentiation. However, the function of HNF4alpha in the maintenance of hepatocyte differentiation and function is less well understood. To address the function of HNF4alpha in the mature hepatocyte, a conditional gene knockout was produced using the Cre-loxP system. Mice lacking hepatic HNF4alpha expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. The observed phenotypes may be explained by (i) a selective disruption of very-low-density lipoprotein secretion due to decreased expression of genes encoding apolipoprotein B and microsomal triglyceride transfer protein, (ii) an increase in hepatic cholesterol uptake due to increased expression of the major high-density lipoprotein receptor, scavenger receptor BI, and (iii) a decrease in bile acid uptake to the liver due to down-regulation of the major basolateral bile acid transporters sodium taurocholate cotransporter protein and organic anion transporter protein 1. These data indicate that HNF4alpha is central to the maintenance of hepatocyte differentiation and is a major in vivo regulator of genes involved in the control of lipid homeostasis.


Asp-49 is not an absolute prerequisite for the enzymic activity of low-M(r) phospholipases A2: purification, characterization and computer modelling of an enzymically active Ser-49 phospholipase A2, ecarpholin S, from the venom of Echis carinatus sochureki (saw-scaled viper).
Several studies have shown that Asp-49 is the residue that controls calcium binding in, and so plays a critical role in the calcium-mediated activation of, low-M(r) group I-III phospholipases A2 (PLA2s). The present paper provides experimental evidence that Asp-49 is not an absolute prerequisite for the enzymic activity of PLA2s, and that proteins with amino acid(s) other than Asp at position 49 can exhibit significant phospholipase activity. The purification, complete amino acid sequence and characterization of ecarpholin S, a PLA2 from Echis carinatus sochureki (saw-scaled viper) venom, is described. This single-chain, 122-amino-acid, basic (pI 7.9) protein is a group II PLA2. Although Asp-49 is replaced by Ser and Tyr-28 by Phe (both of these positions being involved in the Ca(2+)-binding site of PLA2s), the lipolysis of soybean phosphatidylcholine and egg yolk in the presence of 10 mM CaCl2 was 1.5 times and 2.9 times greater respectively with ecarpholin S than with recombinant human group II PLA2. The Ca(2+)-dependencies of the enzymic activities of ecarpholin S and rPLA2 were found to be similar. Ecarpholin S added to washed platelets induced aggregation; the presence of Ca2+ was a prerequisite for this platelet-aggregating effect. Computer modelling of the Ca(2+)-binding site of Ser-49 PLA2 compared with the Asp-49 and Lys-49 forms, for which crystallographic data exist, shows that the Ca(2+)-binding site is sterically blocked by Lys-49 but not by Ser-49; in the latter, the Ser hydroxy group may replace the Asp carboxylate in stabilization of Ca2+ binding. Sequence comparisons of ecarpholin S and other low-M(r) PLA2s predicts the presence of a Ser-49 group in the protein family of low-M(r) PLA2s that is distinct from the Asp-49 and Lys-49 groups.


Molecular cloning and characterization of the mouse and human TUSP gene, a novel member of the tubby superfamily.
We report here the cloning and characterization of a novel gene belonging to the tubby superfamily proteins (TUSP) in mouse and human. The mouse Tusp cDNA is 9120 bp in length and encodes a deduced protein of 1547 amino acids, while the human TUSP gene is 11,127 bp and encodes a deduced protein of 1544 amino acids. The human and mouse genes are 87% identical for their nucleotide sequences and 85% identical for their amino acid sequences. The protein sequences of these genes are 40-48% identical to other tubby family proteins at the C-terminal conserved 'tubby domain'. In addition, the TUSP proteins contain a tubby signature motif (FXGRVTQ), two bipartite nuclear localization signals (NLSs) at the C-terminal, two proline-rich regions, one WD40 repeat region and one suppressor of cytokines signaling domain. Transfection assay with green fluorescent protein-tagged TUSP expression constructs showed that the complete TUSP protein and the N-terminal portion of TUSP are localized in the cytoplasm but the C-terminal portion with the two NLSs produced distinct dots or spots localized in the cytoplasm. Northern blotting analysis showed that the major transcript with the complete coding sequence is expressed mainly in the brain, skeletal muscle, testis and kidney. Radiation hybrid mapping localized the mouse gene to chromosome 17q13 and the human TUSP gene to chromosome 6q25-q26 near the type 1 diabetes gene IDDM5. However, association analysis in diabetic families with a polymorphic microsatellite marker did not show any evidence for association between TUSP and type 1 diabetes. The precise biological function of the tubby superfamily genes is still unknown; the highly conserved tubby domain in different species, however, suggests that these proteins must have fundamental biological functions in a wide range of multi-cellular organisms.


p53 pathway activation by telomere attrition in X-DC primary fibroblasts occurs in the absence of ribosome biogenesis failure and as a consequence of DNA damage.
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome with high clinical heterogeneity. Various mutations have been reported in DC patients, affecting genes that code for components of H/ACA ribonucleoproteins, proteins of the telomerase complex and components of the shelterin complex. We aim to clarify the role of ribosome biogenesis failure in senescence induction in X-DC since some studies in animal models have reported a decrease in ribosome biogenesis as a major role in the disease. Dyskerin was depleted in normal human fibroblasts by expressing two DKC1 shRNAs. Common changes in gene expression profile between these dyskerin-depleted cells and X-DC fibroblasts were analyzed. Dyskerin depletion induced early activation of the p53 pathway probably secondary to ribosome biogenesis failure. However, the p53 pathway in the fibroblasts from X-DC patients was activated only after an equivalent number of passes to AD-DC fibroblasts, in which telomere attrition in each division rendered shorter telomeres than control fibroblasts. Indeed, no induction of DNA damage was observed in dyskerin-depleted fibroblasts in contrast to X-DC or AD-DC fibroblasts suggesting that DNA damage induced by telomere attrition is responsible for p53 activation in X-DC and AD-DC fibroblasts. Moreover, p53 depletion in senescent DC fibroblasts rescued their proliferative capacity and reverted the morphological changes produced after prolonged culture. Our data indicate that ribosome biogenesis do not seem to play an important role in dyskeratosis congenita, conversely increasing DNA damage and activation of p53 pathway triggered by telomere shortening is the main activator of cell senescence.


Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation.
Glioblastoma differ from many other tumors in the sense that they grow infiltratively into the brain tissue instead of forming a solid tumor mass with a defined boundary. Only the part of the tumor with high tumor cell density can be localized through imaging directly. In contrast, brain tissue infiltrated by tumor cells at low density appears normal on current imaging modalities. In current clinical practice, a uniform margin, typically two centimeters, is applied to account for microscopic spread of disease that is not directly assessable through imaging. The current treatment planning procedure can potentially be improved by accounting for the anisotropy of tumor growth, which arises from different factors: anatomical barriers such as the falx cerebri represent boundaries for migrating tumor cells. In addition, tumor cells primarily spread in white matter and infiltrate gray matter at lower rate. We investigate the use of a phenomenological tumor growth model for treatment planning. The model is based on the Fisher-Kolmogorov equation, which formalizes these growth characteristics and estimates the spatial distribution of tumor cells in normal appearing regions of the brain. The target volume for radiotherapy planning can be defined as an isoline of the simulated tumor cell density. This paper analyzes the model with respect to implications for target volume definition and identifies its most critical components. A retrospective study involving ten glioblastoma patients treated at our institution has been performed. To illustrate the main findings of the study, a detailed case study is presented for a glioblastoma located close to the falx. In this situation, the falx represents a boundary for migrating tumor cells, whereas the corpus callosum provides a route for the tumor to spread to the contralateral hemisphere. We further discuss the sensitivity of the model with respect to the input parameters. Correct segmentation of the brain appears to be the most crucial model input. We conclude that the tumor growth model provides a method to account for anisotropic growth patterns of glioma, and may therefore provide a tool to make target delineation more objective and automated.


Evolutionary trait-based approaches for predicting future global impacts of plant pathogens in the genus Phytophthora.
Plant pathogens are introduced to new geographical regions ever more frequently as global connectivity increases. Predicting the threat they pose to plant health can be difficult without in-depth knowledge of behaviour, distribution and spread. Here, we evaluate the potential for using biological traits and phylogeny to predict global threats from emerging pathogens.We use a species-level trait database and phylogeny for 179 Phytophthora species: oomycete pathogens impacting natural, agricultural, horticultural and forestry settings. We compile host and distribution reports for Phytophthora species across 178 countries and evaluate the power of traits, phylogeny and time since description (reflecting species-level knowledge) to explain and predict their international transport, maximum latitude and host breadth using Bayesian phylogenetic generalised linear mixed models.In the best-performing models, traits, phylogeny and time since description together explained up to 90%, 97% and 87% of variance in number of countries reached, latitudinal limits and host range, respectively. Traits and phylogeny together explained up to 26%, 41% and 34% of variance in the number of countries reached, maximum latitude and host plant families affected, respectively, but time since description had the strongest effect.Root-attacking species were reported in more countries, and on more host plant families than foliar-attacking species. Host generalist pathogens had thicker-walled resting structures (stress-tolerant oospores) and faster growth rates at their optima. Cold-tolerant species are reported in more countries and at higher latitudes, though more accurate interspecific empirical data are needed to confirm this finding. Policy implications. We evaluate the potential of an evolutionary trait-based framework to support horizon-scanning approaches for identifying pathogens with greater potential for global-scale impacts. Potential future threats from Phytophthora include Phytophthora x heterohybrida, P. lactucae, P. glovera, P. x incrassata, P. amnicola and P. aquimorbida, which are recently described, possibly under-reported species, with similar traits and/or phylogenetic proximity to other high-impact species. Priority traits to measure for emerging species may be thermal minima, oospore wall index and growth rate at optimum temperature. Trait-based horizon-scanning approaches would benefit from the development of international and cross-sectoral collaborations to deliver centralised databases incorporating pathogen distributions, traits and phylogeny.


Guarani Virophage, a New Sputnik-Like Isolate From a Brazilian Lake.
Virophages are critical regulators of viral population dynamics and potential actors in the stability of the microbial networks. These small biological entities predate the replicative cycle of giant viruses, such as the members of the Mimiviridae family or their distant relatives, which produce within the cytoplasm of their host cells a viral factory harboring a complex biochemistry propitious to the growth of the smaller parasites. In this paper, we describe the isolation and the characterization of a new virophage, the eighth, that we named Guarani. We observed that Guarani exhibits a late replication cycle compared to its giant virus host. In addition, like all Sputnik strains, Guarani is able to infect the three lineages A, B and C of the Mimiviridae family, and affects the replication and the infectivity of its host virus. In terms of genetic content, Guarani has a 18,967 bp long double-stranded DNA genome encoding 22 predicted genes very similar to Sputnik genes, except for ORF19 and ORF12. The former is more related to Zamilon while the latter seems to be novel. The architecture of the Guarani genome is closely related to Sputnik and Zamilon strains, suggesting a common origin for all these virophages.


Liability, insurance and medical practice.
We test for effects of tort liability on the use of certain diagnostic procedures, where the health care providers' expected cost of litigation is proxied by the risk-sharing arrangements agreed with their insurers. 2SLS and GMM estimators are adopted to test for possible endogeneity of these risk-sharing arrangements. Our findings are consistent with the exercise of liability-induced discretion by hospitals, especially regarding use of costly diagnostic imaging procedures. Hospitals facing higher expected costs per claim as a consequence of higher deductibles used these tests more frequently, after controlling for activity levels and casemix. These results are consistent with hospitals reacting to the incentives provided by a clinical negligence compensation system.


Asymmetric twins in boron rich boron carbide.
Twin boundaries (TBs) play an essential role in enhancing the mechanical, electronic and transport properties of polycrystalline materials. However, the mechanisms are not well understood. In particular, we considered that they may play an important role in boron rich boron carbide (BvrBC), which exhibits promising properties such as low density, super hardness, high abrasion resistance, and excellent neutron absorption. Here, we apply first-principles-based simulations to identify the atomic structures of TBs in BvrBC and their roles for the inelastic response to applied stresses. In addition to symmetric TBs in BvrBC, we identified a new type of asymmetric twin that constitutes the phase boundaries between boron rich boron carbide (B13C2) and BvrBC (B14C). The predicted mechanical response of these asymmetric twins indicates a significant reduction of the ideal shear strength compared to single crystals B13C2 and B14C, suggesting that the asymmetric twins facilitate the disintegration of icosahedral clusters under applied stress, which in turn leads to amorphous band formation and brittle failure. These results provide a mechanistic basis towards understating the roles of TBs in BvrBC and related superhard ceramics.


VITAMIN C IN RELATION TO EXPERIMENTAL POLIOMYELITIS : WITH INCIDENTAL OBSERVATIONS ON CERTAIN MANIFESTATIONS IN MACACUS RHESUS MONKEYS ON A SCORBUTIC DIET.
In the experiments reported in the present communication it was found that vitamin C, both natural and synthetic preparations, had no effect on the course of experimental poliomyelitis induced by nasal instillation of the virus. The objection cannot be raised that too large an amount of virus was used, since recent studies (3) on the fate of the nasally instilled virus indicated that all but an undetectable amount of it is swallowed and disappears from the nasal mucosa within 3 hours or less, and that none is demonstrable in the central nervous system before the 3rd day. Vitamin C administration was begun immediately after the instillation of virus and if it were capable of exerting any effect on the virus or the tissues it could have done so even before multiplication of virus had begun. Monkeys whose store of vitamin C was depleted reacted in the same way as those receiving an adequate diet. There is no apparent explanation for the difference between these results and those reported earlier by Jungeblut (1,2). During the present investigation it was found that monkeys on a scorbutic diet died of spontaneous acute infections, chiefly pneumonia and enterocolitis, while their mates receiving an adequate diet remained well. The surviving monkeys on the scorbutic diet developed the osseous and other changes of human scurvy, and the vitamin C used in this study was shown to produce healing and calcification in the bones as well as to check the edema and hemorrhagic diathesis.


Prophylactic radiotherapy against heterotopic ossification following internal fixation of acetabular fractures: a comparative estimate of risk.
Radiotherapy (RT) is effective in preventing heterotopic ossification (HO) around acetabular fractures requiring surgical reconstruction. We audited outcomes and estimated risks from RT prophylaxis, and alternatives of indometacin or no prophylaxis. 34 patients underwent reconstruction of acetabular fractures through a posterior approach, followed by a 8-Gy single fraction. The mean age was 44 years. The mean time from surgery to RT was 1.1 days. The major RT risk is radiation-induced fatal cancer. The International Commission on Radiological Protection (ICRP) method was used to estimate risk, and compared with a method (Trott and Kemprad) specifically for estimating RT risk for benign disease. These were compared with risks associated with indometacin and no prophylaxis. 28 patients (82%) developed no HO; 6 developed Brooker Class I; and none developed Class II-IV HO. The ICRP method suggests a risk of fatal cancer in the range of 1 in 1000 to 1 in 10,000; the Trott and Kemprad method suggests 1 in 3000. For younger patients, this may rise to 1 in 2000; and for elderly patients, it may fall to 1 in 6000. The risk of death from gastric bleeding or perforation from indometacin is 1 in 180 to 1 in 900 in older patients. Without prophylaxis risk of death from reoperation to remove HO is 1 in 4000 to 1 in 30,000. These results are encouraging, consistent with much larger series and endorse our multidisciplinary management. Risk estimates can be used in discussion with patients. The risk from RT prophylaxis is small, it is safer than indometacin and substantially overlaps with the range for no prophylaxis.


Cellular Uptake of Levocetirizine by Organic Anion Transporter 4.
The pharmacokinetics of cetirizine, a nonsedating antihistamine, is profoundly affected by transporter-mediated membrane transport in the kidney. In this study, we aimed to investigate the transport mechanism of levocetirizine, the pharmacologically active enantiomer of cetirizine, via human organic anion transporter 4 (OAT4) expressed in the apical membrane of renal proximal tubules and the basal plasma membrane of placental syncytiotrophoblasts. In cells expressing human OAT4 under the control of tetracycline, levocetirizine uptake was increased by tetracycline treatment. On the other hand, OAT4 expression did not facilitate efflux of preloaded levocetirizine from the cells, either in the presence or absence of extracellular Cl-. The OAT4-mediated levocetirizine uptake was concentration-dependent with a Km of 38 μM. The uptake rate of levocetirizine via OAT4 was approximately twice that of racemic cetirizine, indicating stereoselective uptake of levocetirizine. On the other hand, OAT4-mediated [3H]dehydroepiandrosterone sulfate uptake was inhibited by dextrocetirizine and levocetirizine. Overall, our findings indicate that OAT4 mediates levocetirizine uptake but is unlikely to mediate the efflux.


Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and β-cell differentiation in streptozocin-induced diabetic mice.
Depletion of pancreatic β-cells results in insulin insufficiency and diabetes mellitus (DM). Single transplantation of mesenchymal stem cells exhibits short-term effects in some preclinical studies. Here, we further investigated the long-term therapeutic effects of multiple intravenous MSC transplantations. In this study, multiple human MSC transplantations (4.2 × 10(7) cells/kg each time) were performed intravenously at 2-week intervals into streptozocin (STZ)-induced diabetic mice for 6 months. Blood sugar, insulin, renal function, cholesterol, and triglyceride levels were monitored. We demonstrated that compared to single intravenous transplantation, which only transiently decreased hyperglycemia, multiple MSC transplantations effectively restored blood glucose homeostasis. Systemic oxidative stress levels were reduced from the seventh week of treatment. From the 11th week, production of human insulin was markedly increased. When MSC transplantation was skipped after blood sugar level returned to normal at the end of 15th week, a sharp rebound of blood sugar occurred, and was then controlled by subsequent transplantations. At the end of 6 months, histopathology examination revealed MSCs specifically engrafted into liver tissues of the recipients. Fifty-one percent of human cells in the recipient liver coexpressed human insulin, especially those surrounding the central veins. Taken together, intravenous MSC delivery was safe and effective for blood glucose stabilization in this preclinical DM model. Multiple transplantations were essential to restore and maintain glucose homeostasis through decreasing systemic oxidative stress in the early stage and insulin production in the late stage. Liver engraftment and differentiation into insulin-producing cells account for the long-term therapeutic effects of MSCs.


Best practices and pearls in interdisciplinary mentoring from Building Interdisciplinary Research Careers in Women's Health Directors.
Increasingly, national programs and leaders are looking at interdisciplinary collaborations as essential to future research. Twelve years ago, the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) developed and implemented the Building Interdisciplinary Research Careers in Women's Health (BIRCWH) K12 program to focus on interdisciplinary mentored career development for junior faculty in women's health research. We applied a mixed-methods approach using an electronic survey and in-person presentations and discussions to understand best practices and lessons learned for interdisciplinary mentoring across BIRCWH K12 program leaders. We received responses from all 29 active BIRCWH programs. Factors associated with success included ensuring sufficient protected time for regular (weekly or biweekly) mentoring; mentors promoting the research independence of the Scholar; a team mentoring approach, including career as well as content mentors; and explicit and clear expectations outlined between the Scholar and mentor. The majority of programs conduct formal evaluations of mentorship, and 79% of programs offer training in mentorship for either Scholars, mentors, or both. This article presents program leaders' best practices, challenges, and lessons learned from mentoring junior faculty who are conducting women's health research, whether basic, clinical, behavioral, translational, or health services research, using an interdisciplinary mentoring approach.


Efficacy of Clinical Simulation-Based Training in Biomedical Engineering Education.
The need for biomedical engineering (BME) students to be trained in real-world healthcare settings, where most medical device industry emerges, is imperative. Clinical immersion helps accomplish this training goal. However, the growing student population in the field of BME and a shortage of clinical collaborators offer serious limitations to the clinical immersion experience. This paper describes the use of a clinical simulation-based training (SBT) tool in BME education as an alternative resource to the real-world clinical immersion experience. Through the inclusion of simulation labs in BME courses, we assessed their efficacy in need-finding and enhancing students' understanding of the current challenges of existing medical technology. We also explored the possibility of offering cross-disciplinary learning environments in these simulation labs, including engineers and students from other healthcare disciplines such as nursing. Simulation labs served as a helpful tool in the need-finding phase of the design process, and the immersed students reported higher adaptive and life-long learning outcomes. Students also reported the simulation lab immersion to be valuable to their future goals as engineers. Furthermore, the SBT labs offered repetitive training in a controlled learning environment, inclusion of an interdisciplinary setting, and feedback through student reflections. The inclusion of simulation lab immersion and SBT labs in the two BME courses served as an useful and alternative educational tool that helped train students to better understand the needs of the healthcare industry while working in interdisciplinary settings.


A scoping study of frameworks for adapting public health evidence-based interventions.
Evidence-based public health translation of research to practice is essential to improve the public's health. Dissemination and implementation researchers have explored what happens once practitioners adopt evidence-based interventions (EBIs) and have developed models and frameworks to describe the adaptation process. This scoping study identified and summarized adaptation frameworks in published reports and grey literature. We followed the recommended steps of a scoping study: (a) identifying the research question; (b) identifying relevant studies; (c) selecting studies; (d) charting the data; (e) collating, summarizing, and reporting the results; and (f) consulting with experts. We searched PubMed, PsycINFO, PsycNET, and CINAHL databases for articles referencing adaptation frameworks for public health interventions in the published and gray literature, and from reference lists of framework articles. Two reviewers independently coded the frameworks and their steps and identified common steps. We found 13 adaptation frameworks with 11 program adaptation steps: (a) assess community, (b) understand the EBI(s), (c) select the EBI, (d) consult with experts, (e) consult with stakeholders, (f) decide on needed adaptations, (g) adapt the original EBI, (h) train staff, (i) test the adapted materials, (j) implement the adapted EBI, and (k) evaluate. Eight of these steps were recommended by more than five frameworks: #1-3, 6-7, and 9-11. This study is the first to systematically identify, review, describe, and summarize frameworks for adapting EBIs. It contributes to the literature by consolidating key steps in program adaptation of EBIs and describing the associated tasks in each step.


Potential of a sequence-based antigenic distance measure to indicate equine influenza vaccine strain efficacy.
The calculation of p(epitope) values, a sequence-based measure of antigenic distance between strains, was developed for human influenza. The potential to apply the p(epitope) value to equine influenza vaccine strain selection was assessed. There was a negative correlation between p(epitope) value and vaccine efficacy for pairs of vaccine and challenge strains used in cross-protection studies in ponies that just reached statistical significance (p=0.046) only if one pair of viruses was excluded from the analysis. Thus the p(epitope) value has potential to provide additional data to consider in the decision-making process for updating equine influenza vaccine strains. However, further work is required to define the epitopes of the equine H3N8 haemagglutinin protein recognised by equine antibodies, which could lead to refinement of the p(epitope) value calculation. Furthermore, other factors such as vaccine potency and virulence of circulating strains may also influence vaccine efficacy.


First Report of Southern Blight of Mexican Petunia (Ruellia brittoniana) Caused by Sclerotium rolfsii in Taiwan.
Mexican petunia (Ruellia brittoniana) is an herbaceous flowering perennial with strikingly colored flowers, widely cultivated commercially as a potted plant and a popular garden plant. In July of 2010, root and stem rot that caused death was observed on Mexican petunia at the flower nursery of the Council of Agriculture & Chiayi County in Taiwan. Plants had rotted and girdled stem bases. Necrotic areas were covered with fans of white mycelium as well as abundant spherical sclerotia. A fungus was isolated from infected tissue and sclerotia, and maintained on potato dextrose agar (PDA) plates incubated at 25°C without light. Colonies were white, cottony, often forming fans; pure cultures were prepared by transferring hyphal tips to PDA. Sclerotia formed after 10 days, initially white becoming dark brown with age, and 0.5 to 0.6 mm in diameter. To confirm identity of the causal fungus, the complete internal transcribed spacer (ITS) rDNA region of the causal fungus was amplified using the primers ITS4 and ITS5 (2) and sequenced. The resulting sequence of 687 bp was uploaded in NCBI. The sequence was 98% similar to sequences of Athelia rolfsii (Sclerotium rolfsii) in NCBI (Accession No. JN543691.1). Koch's postulates were performed using two inoculation techniques. The soil near the base of healthy Mexican petunia plants (four plants per pot) were exposed to recently matured sclerotia (10 sclerotia per plant) developed from pure fungal cultures or 10-mm-diameter agar plugs of mycelium (one plug per plant). Noninoculated plants, in a separate pot, were used as a control. All plants were incubated in a growth chamber at 28 to 33°C. Disease symptoms occurred on all inoculated plants by 5 to 7 days and included yellowing of leaves, basal stem rot, and wilt. Ten days after inoculation, inoculated plants were dead whereas control plants remained healthy. The pathogenicity test was repeated twice with similar results and S. rolfsii was reisolated from infected plants in each test. The pathogen has been reported to cause substantial loss of Mexican petunia in Louisiana (1). The disease is becoming more common in Taiwan and could cause losses in Mexican petunia production. To our knowledge, this is the first report of disease on Mexican petunia caused by S. rolfsii in Taiwan. References: (1) G. E. Holcomb. Plant Dis. 88:770, 2004. (2) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, 1990.


Interactions of heparin and a covalently-linked antithrombin-heparin complex with components of the fibrinolytic system.
Unfractionated heparin (UFH) is used as an adjunct during thrombolytic therapy. However, its use is associated with limitations, such as the inability to inhibit surface bound coagulation factors. We have developed a covalent conjugate of antithrombin (AT) and heparin (ATH) with superior anticoagulant properties compared with UFH. Advantages of ATH include enhanced inhibition of surface-bound coagulation enzymes and the ability to reduce the overall size and mass of clots in vivo. The interactions of UFH or ATH with the components of the fibrinolytic pathway are not well understood. Our study utilised discontinuous second order rate constant (k₂) assays to compare the rates of inhibition of free and fibrin-associated plasmin by AT+UFH vs ATH. Additionally, we evaluated the effects of AT+UFH and ATH on plasmin generation in the presence of fibrin. The k₂ values for inhibition of plasmin were 5.74 ± 0.28 x 10⁶ M⁻¹ min⁻¹ and 6.39 ± 0.59 x 10⁶ M⁻¹ min⁻¹ for AT+UFH and ATH, respectively. In the presence of fibrin, the k₂ values decreased to 1.45 ± 0.10 x 10⁶ M⁻¹ min⁻¹ and 3.07 ± 0.19 x 10⁶ M⁻¹ min⁻¹ for AT+UFH and ATH, respectively. Therefore, protection of plasmin by fibrin was observed for both inhibitors; however, ATH demonstrated superior inhibition of fibrin-associated plasmin. Rates of plasmin generation were also decreased by both inhibitors, with ATH causing the greatest reduction (approx. 38-fold). Nonetheless, rates of plasmin inhibition were 2-3 orders of magnitude lower than for thrombin, and in a plasma-based clot lysis assay ATH significantly inhibited clot formation but had little impact on clot lysis. Cumulatively, these data may indicate that, relative to coagulant enzymes, the fibrinolytic system is spared from inhibition by both AT+UFH and ATH, limiting reduction in fibrinolytic potential during anticoagulant therapy.


Fundamentals of Force-Controlled Friction Riveting: Part II-Joint Global Mechanical Performance and Energy Efficiency.
The present work investigates the correlation between energy efficiency and global mechanical performance of hybrid aluminum alloy AA2024 (polyetherimide joints), produced by force-controlled friction riveting. The combinations of parameters followed a central composite design of experiments. Joint formation was correlated with mechanical performance via a volumetric ratio (0.28⁻0.66 a.u.), with a proposed improvement yielding higher accuracy. Global mechanical performance and ultimate tensile force varied considerably across the range of parameters (1096⁻9668 N). An energy efficiency threshold was established at 90 J, until which, energy input displayed good linear correlations with volumetric ratio and mechanical performance (R-sq of 0.87 and 0.86, respectively). Additional energy did not significantly contribute toward increasing mechanical performance. Friction parameters (i.e., force and time) displayed the most significant contributions to mechanical performance (32.0% and 21.4%, respectively), given their effects on heat development. For the investigated ranges, forging parameters did not have a significant contribution. A correlation between friction parameters was established to maximize mechanical response while minimizing energy usage. The knowledge from Parts I and II of this investigation allows the production of friction riveted connections in an energy efficient manner and control optimization approach, introduced for the first time in friction riveting.


Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner.
Hypoxia plays a vital role in cancer epithelial to mesenchymal transition (EMT) and invasion. However, it is not quite clear how hypoxia may contribute to these events. Here we investigate the role of Hedgehog (Hh) signaling in hypoxia induced pancreatic cancer EMT and invasion. Pancreatic cancer cells were cultured under controlled hypoxia conditions (3% O2) or normoxic conditions. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. The effect of hypoxia and Hh signaling on cancer cell EMT and invasion were evaluated by Quantitative real-time PCR analysis, Western blot analysis and invasion assay. Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in pancreatic cancer cells. Moreover, our data demonstrate hypoxia induces EMT process as well as invasion, and activates the non-canonical Hh pathway without affecting sonic hedgehog homolog (SHH) expression. Moreover, these effects are reversible upon HIF-1α siRNA interference with unchanged SHH and patched1 (PTCH1) level. Furthermore, our data demonstrate that hypoxia induced invasion and EMT process are effectively inhibited by Smoothened (SMO) antagonist cyclopamine and GLI1 siRNA. In addition, GLI1 interference inhibited EMT progress with significantly suppressed vimentin expression, whereas inhibition of SMO through cyclopamine could not reduce vimentin level. This data indicate that hypoxia could trigger other factors (such as TGF-β, KRAS or RTK) bypassing SMO to activate GLI1 directly. Our findings suggest that Hh signaling modulates hypoxia induced pancreatic cancer EMT and invasion in a ligand-independent manner. Thus, Hh signaling may represent a promising therapeutic target for preventing pancreatic cancer progression.


Diol dehydratase-reactivating factor is a reactivase--evidence for multiple turnovers and subunit swapping with diol dehydratase.
Adenosylcobalamin-dependent diol dehydratase (DD) undergoes suicide inactivation by glycerol, one of its physiological substrates, resulting in the irreversible cleavage of the coenzyme Co-C bond. The damaged cofactor remains tightly bound to the active site. The DD-reactivating factor reactivates the inactivated holoenzyme in the presence of ATP and Mg(2+) by mediating the exchange of the tightly bound damaged cofactor for free intact coenzyme. In this study, we demonstrated that this reactivating factor mediates the cobalamin exchange not stoichiometrically but catalytically in the presence of ATP and Mg(2+). Therefore, we concluded that the reactivating factor is a sort of enzyme. It can be designated DD reactivase. The reactivase showed broad specificity for nucleoside triphosphates in the activation of the enzyme·cyanocobalamin complex. This result is consistent with the lack of specific interaction with the adenine ring of ADP in the crystal structure of the reactivase. The specificities of the reactivase for divalent metal ions were also not strict. DD formed 1:1 and 1:2 complexes with the reactivase in the presence of ADP and Mg(2+). Upon complex formation, one β subunit was released from the (αβ)₂ tetramer of the reactivase. This result, together with the similarity in amino acid sequences and folds between the DD β subunit and the reactivase β subunit, suggests that subunit displacement or swapping takes place upon formation of the enzyme·reactivase complex. This would result in the dissociation of the damaged cofactor from the inactivated holoenzyme, as suggested by the crystal structures of the reactivase and DD.


DPS - a rapid method for genome sequencing of DNA-containing bacteriophages directly from a single plaque.
Bacteriophages (phages) coexist with bacteria in all environments and influence microbial diversity, evolution and industrial production processes. As a result of this major impact of phages on microbes, tools that allow rapid characterization of phages are needed. Today, one of the most powerful methods for characterization of phages is determination of the whole genome using high throughput sequencing approaches. Here a direct plaque sequencing (DPS) is described, which is a rapid method that allows easy full genome sequencing of DNA-containing phages using the Nextera XT™ kit. A combination of host-DNA removal followed by purification and concentration of the viral DNA, allowed the construction of Illumina-compatible sequencing libraries using the Nextera™ XT technology directly from single phage plaques without any whole genome amplification step. This method was tested on three Caudovirales phages; ϕ29 Podoviridae, P113g Siphoviridae and T4 Myovirdae, which are representative of >96% of all known phages, and were sequenced using the Illumina MiSeq platform. Successful de novo assembly of the viral genomes was possible.


Molecular complex composed of β-cyclodextrin-grafted Chitosan and pH-sensitive amphipathic peptide for enhancing cellular cholesterol efflux under acidic pH.
Excess of cholesterol in peripheral cells is known to lead to atherosclerosis. In this study, a molecular complex composed of β-cyclodextrin-grafted chitosan (BCC) and cellular cholesterol efflux enhancing peptide (CEEP), synthesized by modifying pH sensitive amphipathic GALA peptide, is introduced with the eventual aim of treating atherosclerosis. BCC has a markedly enhanced ability to induce cholesterol efflux from cell membranes compared to β-cyclodextrin, and the BCC-CEEP complex exhibited a 2-fold increase in cellular cholesterol efflux compared to BCC alone under weakly acidic conditions. Isothermal titration calorimetry and fluorescence spectroscopy measurements demonstrated that the random coil structure of CEEP at neutral pH converted to the α-helical structure at acidic pH, resulting in a three-order larger binding constant to BCC (K = 3.7 × 10(7) at pH 5.5) compared to that at pH 7.4 (K = 7.9 × 10(4)). Such high-affinity binding of CEEP to BCC at acidic pH leads to the formation of 100-nm-sized aggregate with positive surface charge, which would efficiently interact with cell membranes and induce cholesterol efflux. Since the cholesterol efflux ability of HDL is thought to be impaired under acidic environments in advanced atherosclerotic lesions, the BCC-CEEP complex might serve as a novel nanomaterial for treating atherosclerosis.


Noise Is Not Error: Detecting Parametric Heterogeneity Between Epidemiologic Time Series.
Mathematical models play a central role in epidemiology. For example, models unify heterogeneous data into a single framework, suggest experimental designs, and generate hypotheses. Traditional methods based on deterministic assumptions, such as ordinary differential equations (ODE), have been successful in those scenarios. However, noise caused by random variations rather than true differences is an intrinsic feature of the cellular/molecular/social world. Time series data from patients (in the case of clinical science) or number of infections (in the case of epidemics) can vary due to both intrinsic differences or incidental fluctuations. The use of traditional fitting methods for ODEs applied to noisy problems implies that deviation from some trend can only be due to error or parametric heterogeneity, that is noise can be wrongly classified as parametric heterogeneity. This leads to unstable predictions and potentially misguided policies or research programs. In this paper, we quantify the ability of ODEs under different hypotheses (fixed or random effects) to capture individual differences in the underlying data. We explore a simple (exactly solvable) example displaying an initial exponential growth by comparing state-of-the-art stochastic fitting and traditional least squares approximations. We also provide a potential approach for determining the limitations and risks of traditional fitting methodologies. Finally, we discuss the implications of our results for the interpretation of data from the 2014-2015 Ebola epidemic in Africa.


Genetic resilience to amyloid related cognitive decline.
Preclinical Alzheimer's disease (AD) is characterized by amyloid deposition in the absence of overt clinical impairment. There is substantial heterogeneity in the long-term clinical outcomes among amyloid positive individuals, yet limited work has focused on identifying molecular factors driving resilience from amyloid-related cognitive impairment. We apply a recently developed predicted gene expression analysis (PrediXcan) to identify genes that modify the association between baseline amyloid deposition and longitudinal cognitive changes. Participants free of clinical AD (n = 631) were selected from the AD Neuroimaging Initiative (ADNI) who had a baseline positron emission tomography measure of amyloid deposition (quantified as a standard uptake value ratio), longitudinal neuropsychological data, and genetic data. PrediXcan was used to impute gene expression levels across 15 heart and brain tissues. Mixed effect regression models assessed the interaction between predicted gene expression levels and amyloid deposition on longitudinal cognitive outcomes. The predicted gene expression levels for two genes in the coronary artery (CNTLN, PROK1) and two genes in the atrial appendage (PRSS50, PROK1) interacted with amyloid deposition on episodic memory performance. The predicted gene expression levels for two additional genes (TMC4 in the basal ganglia and HMBS in the aorta) interacted with amyloid deposition on executive function performance. Post-hoc analyses provide additional validation of the HMBS and PROK1 effects across two independent subsets of ADNI using two additional metrics of amyloid deposition. These results highlight a subset of unique candidate genes of resilience and provide evidence that cell-cycle regulation, angiogenesis, and heme biosynthesis likely play a role in AD progression.


Identification and characterization of a novel outer membrane protein (OMP J) of Moraxella catarrhalis that exists in two major forms.
Moraxella catarrhalis is a common commensal of the human respiratory tract that has been associated with a number of disease states, including acute otitis media in children and exacerbations of chronic obstructive pulmonary disease in adults. During studies to investigate the outer membrane proteins of this bacterium, two novel major proteins, of approximately 19 kDa and 16 kDa (named OMP J1 and OMP J2, respectively), were identified. Further analysis indicated that these two proteins possessed almost identical gene sequences, apart from two insertion/deletion events in predicted external loops present within the putative barrel-like structure of the proteins. The development of a PCR screening strategy found a 100% (96/96) incidence for the genes encoding the OMP J1 and OMP J2 proteins within a set of geographically diverse M. catarrhalis isolates, as well as a significant association of OMP J1/OMP J2 with both the genetic lineage and the complement resistance phenotype (Fisher's exact test; P < 0.01). Experiments using two DeltaompJ2 mutants (one complement resistant and the other complement sensitive) indicated that both were less easily cleared from the lungs of mice than were their isogenic wild-type counterparts, with a significant difference in bacterial clearance being observed for the complement-resistant isolate but not for its isogenic DeltaompJ2 mutant (unpaired Student's t test; P < 0.001 and P = 0.32). In this publication, we characterize a novel outer membrane protein of Moraxella catarrhalis which exists in two variant forms associated with particular genetic lineages, and both forms are suggested to contribute to bacterial clearance from the lungs.


Omega 3 Polyunsaturated Fatty Acids Suppress the Development of Aortic Aneurysms Through the Inhibition of Macrophage-Mediated Inflammation.
Dietary intake of ω3 polyunsaturated fatty acids (ω3-PUFAs) reduces progression of atherosclerosis and prevents future cardiovascular events. Macrophages are key players in the pathogenesis of aortic aneurysm. The effects of ω3-PUFAs on abdominal aortic aneurysm (AAA) formation and macrophage-mediated inflammation remain unclear. METHODS AND RESULTS: The AAA model was developed by angiotensin II infusion in apolipoprotein E-deficient mice. Mice were supplemented with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). The development of AAA lesions and macrophage infiltration in the aorta were analyzed. Gene expression of inflammatory markers in aortic tissues and peritoneal macrophages were measured by using quantitative polymerase chain reaction. AAA formation and macrophage infiltration were significantly suppressed after EPA and DHA administration. EPA administration and DHA administration significantly decreased the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor-β, matrix metalloproteinases (MMP)-2, MMP-9, and vascular cell adhesion molecule-1 in the aortas. The expression of arginase 2, which is a marker of pro-inflammatory macrophages, was significantly lower and that of Ym1, which is a marker of anti-inflammatory macrophages, and was significantly higher after EPA and DHA administration. The same trends were observed in peritoneal macrophages after EPA and DHA administration. Dietary intake of EPA and DHA prevented AAA development through the inhibition of aortic and macrophage-mediated inflammation.


Evidence for functional binding and stable sliding of the TATA binding protein on nonspecific DNA.
The TATA binding protein (TBP) is required at RNA polymerase I, II, and III promoters that either contain or lack a TATA box. In an effort to understand how TBP might function at such a wide variety of promoters, we have investigated the specific and nonspecific DNA binding properties of human TBP. We show that TBP has less than a 10(3)-fold preference for binding a TATA box (TATAAAAG) than for an average nonspecific site. In contrast to TBP, which binds to the minor groove of DNA, major groove binding proteins typically display binding specificities in the range of 10(6). Once TBP is bound to DNA, whether it be a TATA box or nonspecific DNA, binding is quite stable with a t1/2 of dissociation in the range of 20-60 min for a 300-base pair DNA fragment. In this binding state, TBP appears to be capable of stable one-dimensional sliding along the DNA. Sequence-specific binding can be accounted for, in part, by different rates of sliding. Additional findings demonstrate that specific and nonspecific DNA impart upon TBP an enormous and equivalent degree of thermal stability, suggesting that the TBP-DNA interface on non-specific DNA is not radically different from that on TATA. Consistent with this notion, we find that nonspecifically bound TBP is competent in establishing pol II transcription complexes on DNA. Together, these finding provide a plausible mechanistic explanation for the ability of TBP to function at TATA-containing and TATA-less promoters.


A Body Shape Index (ABSI) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort.
Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI < 18.5 kg/m2) or obese (BMI ≥ 30 kg/m2) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.


Serum homocysteine levels and cognitive functioning in euthymic bipolar patients.
Studies have found elevated plasma homocysteine (Hcy) levels in bipolar disorder (BD). We investigated serum Hcy levels in euthymic BD patients, and its relationship with cognitive and psychosocial functioning. Sixty-five BD type I euthymic patients and 49 healthy controls were assessed using a neuropsychological test battery. Hcy levels were measured using an HPLC method with fluorescence detection. The mean Hcy levels were 1.37 mg/L for BD patients and 1.30 mg/L for healthy controls (P=0.342), male patients showing higher Hcy levels as compared to females (P=0.009). Older patients, those with later illness onset, and patients taking more medications showed higher Hcy levels, but no significant correlation was found with psychosocial functioning. Patients with "elevated" Hcy levels performed significantly worse on all neurocognitive tests, and in patients we found significant associations between Hcy levels and number of perseverations on the SCT (r=0.248, P=0.047), and number of moves on the ToH (r=0.265, P=0.033); however, a linear regression model revealed that Hcy was not a significant predictor of neurocognitive test performance. Our findings suggest that increased homocysteinemia may play a role in the pathophysiology of neurocognitive deficits in BD, with a higher impact among older patients, or who had a delayed onset of illness.


Tailored and Adaptive Computerized Cognitive Training in Older Adults at Risk for Dementia: A Randomized Controlled Trial.
Computerized Cognitive Training (CCT) has been shown to improve cognitive function in older adults with mild cognitive impairment (MCI) or mood-related neuropsychiatric symptoms (MrNPS), but many questions remain unresolved. To evaluate the extent to which CCT benefits older adults with both MCI and MrNPS, and its effects on meta-cognitive and non-cognitive outcomes, as well as establish whether adapting difficulty levels and tailoring to individuals' profile is superior to generic training. Older adults with MCI (n = 9), MrNPS (n = 11), or both (MCI+, n = 25) were randomized into a home-based individually-tailored and adaptive CCT (n = 21) or an active control condition (AC; n = 23) in a double-blind design. Interventions lasted 8-12 weeks and outcomes were assessed after the intervention, and at a 3-month follow-up. Participants in both conditions reported greater satisfaction with their everyday memory following intervention and at follow-up. However, participants in the CCT condition showed greater improvement on composite measures of memory, learning, and global cognition at follow-up. Participants with MrNPS in the CCT condition were also found to have improved mood at 3-month follow-up and reported using fewer memory strategies at the post-intervention and follow-up assessments. There was no evidence that participants with MCI+ were disadvantaged relative to the other diagnostic conditions. Finally, informant-rated caregiver burden declined at follow-up assessment in the CCT condition relative to the AC condition. Home-based CCT with adaptive difficulty and personal tailoring appears superior to more generic CCT in relation to both cognitive and non-cognitive outcomes. Mechanisms of treatment effect and future directions are discussed.


Results of the "endovascular treatment first" policy for infrapopliteal disease.
Even though differences between first-bypass vs. first-endovascular approach in below the knee (BTK) lesions have never been adequately compared, endovascular strategy first approach can be currently successfully used to treat BTK lesions in patients with critical limb ischemia (CLI). Success however is strongly associated with risk groups, severity of disease and degree of clinical presentation beside the method of revascularization. From available data, the best results of endovascular first approach for BTK lesions can be achieved with multivessel and tibial (more than peroneal alone) recanalization and Rutherford 4 or 5 ischemia changes, especially if the correct angiosome can be revascularized (direct flow to the feeding artery of the foot) and there is no renal failure. For patients in Rutherford class 6 and extensive gangrene/tissue loss, BTK endovascular strategy alone does not seem to provide ideal results. Outcomes of interventional therapy for BTK lesions are consistently better when applied in experienced centers with the use of more advanced technology and use of eluting materials. According to limited but randomized evidence, drug-eluting stent (DES) placement might be recommended in BTK lesions under 40 mm long since yields significantly better results than angioplasty alone or implantation of bare metal stents in this lesion subset. Nevertheless, this policy raises doubts on the efficacy of treatment due to limitations in generalizability of outcomes in common hospital settings and related costs. Furthermore, there are still no consistent numbers to provide the efficacy of this approach and long-term data are lacking. Waiting for the long-term results of ongoing trials and new researches, a more comprehensive analysis of outcomes with BTK endovascular first strategy can be provided in the next future.


Assembly of the eastern North American herpetofauna: new evidence from lizards and frogs.
Darwin first recognized the importance of episodic intercontinental dispersal in the establishment of worldwide biotic diversity. Faunal exchange across the Bering Land Bridge is a major example of such dispersal. Here, we demonstrate with mitochondrial DNA evidence that three independent dispersal events from Asia to North America are the source for almost all lizard taxa found in continental eastern North America. Two other dispersal events across Beringia account for observed diversity among North American ranid frogs, one of the most species-rich groups of frogs in eastern North America. The contribution of faunal elements from Asia via dispersal across Beringia is a dominant theme in the historical assembly of the eastern North American herpetofauna.


Accuracy of pleural biopsy using thoracoscopy for the diagnosis of histologic subtype in patients with malignant pleural mesothelioma.
Promising results with trimodality therapy combining surgery, chemotherapy, and radiotherapy have been obtained in the management of patients with malignant pleural mesothelioma (MPM). However, the histologic subtype has to be taken into account because of its influence on prognosis. The aim of the current study was to analyze retrospectively the accuracy, sensitivity, and specificity of preoperative thoracoscopy for diagnosis of the histologic subtype of MPM. The histologic reports from all consecutive patients undergoing 'intent-to-treat' surgery from 3 institutions as well as the initial pathologic diagnosis obtained using thoracoscopy were reviewed and compared after institutional review board approval. All cases of MPM were confirmed by a panel of pathologists. Ninety-five patients were included in the current study. Of these 95 patients, 75 underwent extrapleural pneumonectomy, 9 patients underwent pleurectomy/decortication, and 11 patients underwent pleurectomy. Of the 95 patients with a final diagnosis of MPM, 80 (84.2%) were classified as having epithelial and 15 (15.8%) as having biphasic subtype. Among the 87 patients classified as having MPM of epithelial subtype after the initial thoracoscopy, 75 cases (86.2%) were confirmed to be a true histologic diagnosis and 12 cases (13.8%) were found to be of biphasic subtype at final diagnosis. One patient with a biphasic subtype at initial thoracoscopy was found to have MPM of epithelial subtype after surgery. The sensitivity and specificity values of an epithelial subtype diagnosis after thoracoscopy were 94% and 20%, respectively, with a positive predictive value of 86% and a negative predictive value of 37%. Conversely, the sensitivity and specificity values of a biphasic subtype diagnosis after thoracoscopy were 20% and 98%, respectively, with a positive predictive value of 75% and a negative predictive value of 87%. Pleural biopsy performed using thoracoscopy is considered to be the cornerstone of the diagnosis and pleural staging of MPM. However, this procedure appears to be less efficient in diagnosing the histologic subtype as either epithelial or biphasic.


Is Rotation a Concern with Anatomical Breast Implants? A Statistical Analysis of Factors Predisposing to Rotation.
Since their introduction in 1993, anatomical implants have provided a more natural appearance in breast augmentation, and many surgeons advocate their use and promote the good aesthetic results. However, the risk of implant rotation makes some of them reluctant to use these devices. The rotation rate varies among authors. The authors present a 6.5-year series of 531 patients who underwent primary breast augmentation with macrotextured anatomical implants in a Swedish facility performed by one consultant surgeon (P.M.). The authors examined the rotation rate and the correlation with possible predisposing factors such as preoperative breast cup size, childbirth, and body mass index. A total of 20 implants (1.88 percent; 95 percent CI, 1.15 to 2.89 percent) in 19 patients (3.58 percent; 95 percent CI, 2.17 to 5.53 percent) were rotated. In one patient (0.22 percent), both implants rotated, whereas in the remaining patients, the rotation was unilateral. The authors were unable to establish a statistically significant correlation between implant rotation and previous childbirth or increased body mass index. However, there was a relation between rotation rate and preoperative breast cup size that showed an upward trend as the cup size increased from A to C. The authors believe that if the implant is correctly selected and the operation is performed meticulously with proper pocket dissection, the rotation rate is minimal and it should not be considered a disadvantage for the use of anatomical implants. Risk, III.


Evaluation of two new commercial tests for the diagnosis of acute dengue virus infection using NS1 antigen detection in human serum.
We compared the performance of two new commercial tests for the detection of dengue NS1 protein during the clinical phase of dengue virus (DENV) infection-an immunochromatographic test allowing rapid detection of the NS1 antigen, Dengue NS1 Ag STRIP (Bio-Rad Laboratories - Marnes La Coquette, France), and a two-step sandwich-format microplate enzyme-linked immunosorbent assay (ELISA), pan-E Dengue Early ELISA (Panbio - Brisbane, Australia)-with a one-step sandwich-format microplate ELISA, the Platelia Dengue NS1 Ag test (Bio-Rad). We tested 272 serum samples from patients with dengue disease. Of these, 222 were from patients with acute infection of one of the four dengue serotypes, detected by RT-PCR and/or virus isolation. Forty-eight acute-phase serum samples from patients not infected with dengue virus were also included. The sensitivity of the Platelia Dengue NS1 Ag test on acute serum samples (n = 222) was 87.4% (95% confidence interval: 82.3% to 91.5%); that of Dengue NS1 Ag STRIP was 81.5% (95% CI: 75.8% to 86.4%) after 15 minutes and 82.4% (95% CI: 76.8% to 87.2%) after 30 minutes. Both tests had a specificity of 100% (97.5% CI, one-sided test: 92.6% to 100.0%). The pan-E Dengue Early ELISA had a sensitivity of 60.4% (95% CI: 53.4% to 66.8%) and a specificity of 97.9% (95% CI: 88.9% to 99.9%). Our findings support the use of diagnostic tools based on the NS1 antigen detection for the diagnosis of acute DENV infection. The immunochromatographic test, Dengue NS1 Ag STRIP-the first rapid diagnostic test for DENV infection-was highly sensitive and specific, and would therefore be a suitable first-line test in the field. The pan-E Dengue Early ELISA was less sensitive than the Platelia test; this two-step ELISA should be combined with DENV IgM antibody detection for the diagnosis of DENV infection.


Management of antibiotic-resistant Streptococcus pneumoniae infections and the use of pneumococcal conjugate vaccines.
The epidemiology of Streptococcus pneumoniae, a major cause of meningitis, pneumonia, bacteraemia and acute otitis media in both children and adults, has been altered by the availability of the seven-valent pneumococcal conjugate vaccine (PCV7) and selection pressure from broad-spectrum antibiotics. In Spain, the rates of antimicrobial consumption and resistance are high; of all S. pneumoniae isolates collected between 2001 and 2003, 9.2% were penicillin-resistant and 26.4% were penicillin-intermediate. These rates were even higher in children aged < or =4 years; 52.3% of isolates were penicillin-resistant or penicillin-intermediate. Serogroup 14 comprises nearly 9% of pneumococcal strains and exhibits the highest resistance to penicillin (69%). Since the introduction of PCV7 in Madrid, the isolates collected from hospitalized children aged <15 years from 21 hospitals revealed that only 8% of cases involving S. pneumoniae isolates were due to PCV7 serotypes, and no PCV7 vaccination failures were identified. These isolates demonstrated low rates of penicillin-non-susceptible and erythromycin-non-susceptible strains. Among multiresistant strains, serotype 19A was identified as most important. Although the recent WHO position paper on childhood immunizations speaks to the growing resistance of pneumococci, antibiotic resistance in Spain is noted to be decreasing and must be evaluated in conjunction with global studies.


Robot-assisted thoracic surgery in Colombia: a multi-institutional initial experience.
Robotic assisted videothoracoscopic surgery (RVATS) adoption has increased worldwide from 3.4% in 2010 to 17.5% in 2015. However, in Latin America, the literature is limited to a report of a series of 10 patients who underwent RVATS lobectomy and one case report of an RVATS thymectomy from Brazil. This is a retrospective review of all RVATS performed in Bogotá Colombia since 2012. A single thoracic surgeon (RB) performed all the operations at three institutions: Clínica de Marly, Fundación Clínica Shaio and Instituto Nacional de Cancerología. Preoperative, intraoperative, postoperative and pathology report variables were included. Patients were analyzed in three groups: robotic RVATS pulmonary resections, RVATS mediastinal surgeries and other RVATS procedures. Descriptive statistics were used to report the median and interquartile range (IQR) of the continuous variables, and number and percentage were used to describe categorical variables. The association between total operative time and the year the surgery was analyzed using a linear regression model. Forty-seven patients underwent RVATS pulmonary resections; 72.3% (n=34) of these patients underwent a RVATS lobectomy. The median total operative time was 220 (IQR: 200 to 250) minutes, 6.4% (n=3) had intraoperative complications, and the most frequent histologic diagnosis was adenocarcinoma (n=24, 51.1%). Of 18 patients who underwent RVATS mediastinal surgeries, 50.0% (n=9) had RVATS thymectomy, the median total operative time was 195.5 (IQR: 131 to 221) minutes and two patients (11.1%) had intraoperative complications. The linear regression model of the association between total operative time and the year the surgery showed a 10.3 minute reduction per year (P=0.006). This is the second series of RVATS published in Latin America and the first published in Colombia, with comparable perioperative results to other reports.


Allantois and placenta as developmental sources of hematopoietic stem cells.
While the aortic region, the para-aortic splanchnopleura/aorta-gonads-mesonephros (P-Sp/AGM) is currently considered as the source of definitive hematopoietic stem cells during development, the mouse placenta has been found to generate large numbers of these cells and to remain functional in this respect for a longer period than the P-Sp/AGM. The fetal component, which derives from the fused allantois and chorion, is responsible for this activity. We and others have shown that the pre-fusion allantois (before the stage of 6 pairs of somites) is able to yield clonogenic progenitors, provided that it is pre-cultured in toto before it is dissociated into single cells and seeded in semi-solid medium. Thus placental hematopoiesis can be concluded to derive from intrinsic precursors. It is similar in this regard to the yolk sac which both produces hematopoietic progenitors and supports their multiplication and differentiation. Hematopoietic activity, detected by in vitro colony assays, has also been recently uncovered in the human placenta. According to the data available, this newly identified source probably provides a large number of HSC during development and must play a foremost role in founding the definitive hematopoietic system.


Structure-activity studies of the binding of the flavonoid scaffold to DNA.
Flavonoids have been shown to have a wide variety of biological activities and proven to be good scaffolds for the design of DNA-binding agents as anticancer therapeutics. In structure-activity relationship studies, flavonoid derivatives were designed and synthesised through various organic synthesis protocols, resulting in novel or previously described molecules. These were studied by UV-Vis absorbance and fluorescence spectroscopy as well as competition dialysis for their binding to DNA isoforms. Their cytotoxic potential was assessed using MTS assays on MCF-7 breast cancer and CCRFCEM leukaemia cell lines. Introduction of moieties such as chloride, nitrogen, acetoxy and methoxy groups did not help to improve binding affinity, but introduction of tertiary amines improved the binding 1,000-fold due to an improved interaction of the compound with the nucleic acid; replacement of oxygen by sulphur increased the binding 7-fold, possibly because sulphur being less electronegative than oxygen would allow the electrons of the molecule to interact more strongly with the nucleic acid. Inhibition of growth by 50% (IG(50)) values were moderate in breast and leukaemia cancer cell lines possibly due to the flavonoids interacting with other cellular components besides the nucleic acids.


A Population-Based Study of 30-day Incidence of Ischemic Stroke Following Surgical Neck Dissection.
The objective of this study was to determine the 30-day incidence of ischemic stroke following neck dissection compared to matched patients undergoing non-head and neck surgeries.A surgical dissection of the neck is a common procedure performed for many types of cancer. Whether such dissections increase the risk of ischemic stroke is uncertain.A retrospective cohort study using data from linked administrative and registry databases (1995-2012) in the province of Ontario, Canada was performed. Patients were matched 1-to-1 on age, sex, date of surgery, and comorbidities to patients undergoing non-head and neck surgeries. The primary outcome was ischemic stroke assessed in hospitalized patients using validated database codes.A total of 14,837 patients underwent surgical neck dissection. The 30-day incidence of ischemic stroke following the dissection was 0.7%. This incidence decreased in recent years (1.1% in 1995 to 2000; 0.8% in 2001 to 2006; 0.3% in 2007 to 2012; P for trend <0.0001). The 30-day incidence of ischemic stroke in patients undergoing neck dissection is similar to matched patients undergoing thoracic surgery (0.5%, P = 0.26) and colectomy (0.5%, P = 0.1). Factors independently associated with a higher risk of stroke in 30 days following neck dissection surgery were of age ≥75 years (odds ratio (OR) 1.63, 95% confidence interval (CI) 1.05-2.53), and a history of diabetes (OR 1.60, 95% CI 1.02-2.49), hypertension (OR 2.64, 95% CI 1.64-4.25), or prior stroke (OR 4.06, 95% CI 2.29-7.18).Less than 1% of patients undergoing surgical neck dissection will experience an ischemic stroke in the following 30 days. This incidence of stroke is similar to thoracic surgery and colectomy.


Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype.
To define in patients affected by familial Mediterranean fever (FMF) whether or not interleukin (IL)-1β secretion (1) is enhanced, (2) correlates with the type of MEFV mutation and (3) is mediated by NLRP3. Freshly isolated monocytes from 21 patients with FMF (12 homozygous and 9 heterozygous), 14 MEFV healthy carriers and 30 healthy donors (HDs), unstimulated or after lipopolysaccharide (LPS)-induced activation, were analysed for redox state (production of reactive oxygen species (ROS) and antioxidant responses) and IL-1β and IL-1 receptor antagonist (IL-1Ra) secretion. NLRP3 down-modulation was induced by in vitro silencing of the NLRP3 gene. LPS-stimulated monocytes from patients with FMF displayed enhanced IL-1β secretion, which correlated with number and penetrance of MEFV mutations. Silencing of NLRP3 consistently inhibited IL-1β secretion. As in other autoinflammatory diseases, FMF monocytes produced more ROS than genetically negative cells from HDs. Unlike in cryopyrin-associated periodic fever syndromes (CAPS), however, they were characterised by a conserved and sustained antioxidant response. Consistent with this finding, activated MEFV-mutated monocytes did not exhibit the functional indicators of oxidative stress observed in CAPS, including accelerated IL-1β secretion and deficient production of IL-1Ra. MEFV-mutated monocytes display enhanced IL-1β secretion, which correlates with number of high-penetrance mutations and level of endogenous ROS. Unlike NLRP3-mutated cells, monocytes carrying MEFV mutations withstand oxidative stress and preserve IL-1Ra production, thereby limiting inflammation. Finally, in contrast with that found in the animal model, the increased secretion of IL-1β by LPS-stimulated FMF monocytes is NLRP3-dependent.


Changes in prandial glucagon levels after a 2-year treatment with vildagliptin or glimepiride in patients with type 2 diabetes inadequately controlled with metformin monotherapy.
To determine if the dipeptidyl peptidase-4 inhibitor vildagliptin more effectively inhibits glucagon levels than the sulfonylurea glimepiride during a meal. Glucagon responses to a standard meal were measured at baseline and study end point (mean 1.8 years) in a trial evaluating add-on therapy to metformin with 50 mg vildagliptin b.i.d. compared with glimepiride up to 6 mg q.d. in type 2 diabetes (baseline A1C 7.3 +/- 0.6%). A1C and prandial glucose area under the curve (AUC)(0-2 h) were reduced similarly in both groups, whereas prandial insulin AUC(0-2 h) increased to a greater extent by glimepiride. Prandial glucagon AUC(0-2 h) (baseline 66.6 +/- 2.3 pmol . h(-1) . l(-1)) decreased by 3.4 +/- 1.6 pmol . h(-1) . l(-1) by vildagliptin (n = 137) and increased by 3.8 +/- 1.7 pmol . h(-1) . l(-1) by glimepiride (n = 121). The between-group difference was 7.3 +/- 2.1 pmol . h(-1) . l(-1) (P < 0.001). Vildagliptin therapy but not glimepiride improves postprandial alpha-cell function, which persists for at least 2 years.


Routine data sources challenge international diabetes Federation extrapolations of national diabetes prevalence in Switzerland.
Information on diabetes prevalence in the general population is scarce and often based on extrapolations. We evaluated whether prevalence could be estimated from routine data sources. The sources were 1) hospital discharges (2008, n = 828,171), 2) death registry (2007/2008, n = 118,659), and 3) Swiss Health Survey (SHS; 2007, n = 18,665). Persons without diabetes as underlying cause of death (death registry) or principal diagnosis (hospital discharges) were regarded as surrogate for a general population random sample. In those aged 20-84 years, 4.5% of men and 3% of women were expected to have diabetes. By source, estimations were 4.4 and 2.8% (hospital discharges), 3.8 and 3.1% (death registry), and 4.9 and 3.7% (SHS) for men and women, respectively. Among sources, age-sex patterns were similar. In countries with adequate data quality, combination of routine data may provide valid and reliable estimations of diabetes prevalence. Our figures suggest that International Diabetes Federation extrapolations substantially overestimate diabetes prevalence in Switzerland.


An immunohistochemical study of pro-somatostatin-derived peptides in the human brain.
The distribution of pro-somatostatin-derived-peptide-positive profiles was examined by indirect immunohistofluorescence in nine post-mortem human brains (age 58-73 years). Three specific antisera were used for this study which recognize, respectively, somatostatin-28, somatostatin-28 (1-12) and somatostatin (1-14). Pro-somatostatin-derived-peptide-positive immunoreactive profiles were observed throughout the neuraxis. Cell bodies were found within archeo-, paleo- and neocortical areas, the subcortical white matter, in the nucleus accumbens, caudate nucleus and putamen, as well as in the hypothalamus, the reticular thalamic nucleus and the reticular formation of the brainstem. Fibers and terminals were seen in the same areas as well as in various thalamic nuclei, in the brainstem and spinal cord. Pro-somatostatin-derived-peptide-positive fibre tracts include the bed nucleus of the stria terminalis, the diagonal band of Broca, the stria medullaris, the inter-thalamic adhesion, the posterior commissure and the spinothalamic tract. Furthermore, differences between human and animal brains were noted and some somatostatin systems reported which may be implicated in certain human neuropathological states.


The effect and optimal dose of sufentanil in reducing injection pain of microemulsion propofol.
Propofol is used as an induction and maintenance agent for general anesthesia but it can cause adverse reactions like hyperlipidemia, growth of microorganisms, and pulmonary embolisms. Microemulsion propofol was developed to avoid these side effects but incidence and severity of pain on injection is higher than with lipid emulsion propofol. We aimed to compare the effects of sufentanil in analgesic doses for reducing the injection pain of microemulsion propofol. The candidates included eighty patients, 19-60 years old and ASA I-II. They were randomly classified into four groups and pretreated with normal saline, sufentanil 0.1 µg/kg, 0.2 µg/kg or 0.3 µg/kg before injection of microemulsion propofol. Five minutes after receiving pretreatment drug, 2 mg/kg of microemulsion propofol was injected and VAS was recorded. There were no significant differences in the incidence of injection pain among the groups. Severity of injection pain was significantly lower in the sufentanil 0.3 µg/kg group than normal saline and sufentanil 0.1 µg/kg group. Significant differences in blood pressure and heart rate were observed in sufentanil groups only after endotracheal intubation. One patient each in sufentanil 0.1 µg/kg and 0.3 µg/kg group experienced mild cough, one from sufentanil 0.3 µg/kg group experienced dizziness and another showed signs of hypoxia. One patient each in normal saline and sufentanil 0.1 µg/kg group showed clinical symptoms of phlebitis in the injection area. Pretreatment with sufentanil 0.3 µg/kg reduced the severity of microemulsion propofol injection pain without increasing arterial blood pressure and heart rate after endotracheal intubation.


Predictors of 4-year outcome of community residential treatment for patients with substance use disorders.
This study examined systematically how predictors of substance use disorder (SUD) treatment outcome worked together over time and identified mediators and moderators of outcome. The MacArthur model was applied in this naturalistic study to identify how baseline, discharge and 1-year follow-up factors worked together to predict 4-year improvement in substance-related problems. Eighty-eight community residential facilities were selected based on geographic representativeness, number of patient referrals and type of treatment orientation. Of 2796 male patients who completed intake assessments, 2324 were assessed at the 1-year follow-up and 2023 at the 4-year follow-up. Self-report measures of symptom severity, functioning, social resources and coping, treatment and involvement in Alcoholics Anonymous (AA) were collected at baseline and at 1- and 4-year follow-ups. Provider-rated treatment participation measures were obtained at discharge. Greater substance use severity, more psychiatric symptoms, more prior arrests and stronger belief in AA-related philosophy at treatment entry predicted improvement significantly in substance-related problems 4 years later. At the 1-year follow-up, being employed and greater use of AA-related coping predicted outcome significantly. AA-related coping at 1 year mediated the relationship partially between belief in AA philosophy at treatment entry and 4-year outcome. The findings highlight the unique and positive impact of AA involvement on long-term SUD treatment outcome and extend understanding of why AA is beneficial for patients.


Knowing when to respond and the efficiency of the cortical motor command: a Laplacian ERP study.
The objective was to test whether motor preparation can modulate the efficiency of the cortical motor command. The electroencephalogram (EEG) was recorded from electrodes located over the primary sensorimotor cortices during the performance of a between-hand choice reaction time task in which foreperiod duration (the interval between the warning and the imperative signals, 800 vs. 2800 ms) was varied across blocks of trials. In order to increase the spatial resolution of the EEG traces, surface Laplacian was estimated. The amplitude of the negative wave developing over the hemisphere contralateral to the response was smaller for the short foreperiod associated with the best performance level. These results indicate that the activation of the primary sensorimotor cortex involved in the response is less pronounced for the short foreperiod, suggesting that temporal advance information increases the efficiency of the cortical motor command.


Silk fibroin scaffolds promote formation of the ex vivo niche for salivary gland epithelial cell growth, matrix formation, and retention of differentiated function.
Salivary gland hypofunction often results from a number of causes, including the use of various medications, radiation for head and neck tumors, autoimmune diseases, diabetes, and aging. Since treatments for this condition are lacking and adult salivary glands have little regenerative capacity, there is a need for cell-based therapies to restore salivary gland function. Development of these treatment strategies requires the establishment of a system that is capable of replicating the salivary gland cell "niche" to support the proliferation and differentiation of salivary gland progenitor cells. In this study, a culture system using three-dimensional silk fibroin scaffolds (SFS) and primary salivary gland epithelial cells (pSGECs) from rat submandibular (SM) gland and parotid gland (PG) was established and characterized. pSGECs grown on SFS, but not tissue culture plastic (TCP), formed aggregates of cells with morphological features resembling secretory acini. High levels of amylase were released into the media by both cell types after extended periods in culture on SFS. Remarkably, cultures of PG-derived cells on SFS, but not SM cells, responded to isoproterenol, a β-adrenergic receptor agonist, with increased enzyme release. This behavior mimics that of the salivary glands in vivo. Decellularized extracellular matrix (ECM) formed by pSGECs in culture on SFS contained type IV collagen, a major component of the basement membrane. These results demonstrate that pSGECs grown on SFS, but not TCP, retain important functional and structural features of differentiated salivary glands and produce an ECM that mimics the native salivary gland cell niche. These results demonstrate that SFS has potential as a scaffold for creating the salivary gland cell niche in vitro and may provide an approach for inducing multipotent stem cells to provide therapeutically meaningful numbers of salivary gland progenitor cells for regenerating these tissues in patients.


Discovery of phosphotyrosine-binding oligopeptides with supramolecular target selectivity.
We demonstrate phage-display screening on self-assembled ligands that enables the identification of oligopeptides that selectively bind dynamic supramolecular targets over their unassembled counterparts. The concept is demonstrated through panning of a phage-display oligopeptide library against supramolecular tyrosine-phosphate ligands using 9-fluorenylmethoxycarbonyl-phenylalanine-tyrosine-phosphate (Fmoc-FpY) micellar aggregates as targets. The 14 selected peptides showed no sequence consensus but were enriched in cationic and proline residues. The lead peptide, KVYFSIPWRVPM-NH2 (P7) was found to bind to the Fmoc-FpY ligand exclusively in its self-assembled state with K D = 74 ± 3 μM. Circular dichroism, NMR and molecular dynamics simulations revealed that the peptide interacts with Fmoc-FpY through the KVYF terminus and this binding event disrupts the assembled structure. In absence of the target micellar aggregate, P7 was further found to dynamically alternate between multiple conformations, with a preferred hairpin-like conformation that was shown to contribute to supramolecular ligand binding. Three identified phages presented appreciable binding, and two showed to catalyze the hydrolysis of a model para-nitro phenol phosphate substrate, with P7 demonstrating conformation-dependent activity with a modest k cat/K M = 4 ± 0.3 × 10-4 M-1 s-1.


Creating a Framework for Medical Professionalism: An Initial Consensus Statement From an Arab Nation.
Background Medical professionalism has received increased worldwide attention, yet there is limited information on the applicability and utility of established Western professionalism frameworks in non-Western nations. Objective We developed a locally derived consensus definition of medical professionalism for the United Arab Emirates (UAE), which reflects the cultural and social constructs of the UAE and the Middle East. Methods We used a purposive sample of 14 physicians working in the UAE as clinical and education leaders. This expert panel used qualitative methods, including the world café, nominal group technique, the Delphi method, and an interpretive thematic analysis to develop the consensus statement. Results The expert panel defined 9 attributes of medical professionalism. There was considerable overlap with accepted Western definitions, along with important differences in 3 aspects: (1) the primacy of social justice and societal rights; (2) the role of the physician's personal faith and spirituality in guiding professional practices; and (3) societal expectations for professional attributes of physicians that extend beyond the practice of medicine. Conclusions Professionalism is a social construct influenced by cultural and religious contexts. It is imperative that definitions of professionalism used in the education of physicians in training and in the assessment of practicing physicians be formulated locally and encompass specific competencies relevant to the local, social, and cultural context for medical practice. Our goal was to develop a secular consensus statement that encompasses culture and values relevant to professionalism for the UAE and the Arab region.


Epidemiology of NSAID induced gastrointestinal complications.
Nonsteroidal antiinflammatory drugs (NSAID) are one of the most commonly used classes of medications worldwide. It is estimated that more than 30 million people take NSAID daily. Gastrointestinal (GI) complications related to NSAID therapy are the most prevalent category of adverse drug reactions. Patients with arthritis are among the most frequent users of NSAID and are therefore particularly at risk for these side effects. To evaluate the nature of NSAID-related GI complications and to determine how their frequency can be reduced, a series of studies of such complications in patients with rheumatic disease have been carried out based on data from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS). This report briefly reviews the literature and presents recent findings from the ARAMIS studies, which provide an update on published information. It addresses whether GI side effects such as dyspepsia can serve as warning symptoms for life-threatening GI complications and describes the risk factors for these events. It also summarizes a study that investigated whether H2-receptor antagonists and antacids affect the development of serious GI complications. In addition, ongoing research and topics to be addressed in future studies are described.


Eradication of invasive mammals on islands inhabited by humans and domestic animals.
Non-native invasive mammal species have caused major ecological change on many islands. To conserve native species diversity, invasive mammals have been eradicated from several islands not inhabited by humans. We reviewed the challenges associated with campaigns to eradicate invasive mammals from islands inhabited by humans and domestic animals. On these islands, detailed analyses of the social, cultural, and economic costs and benefits of eradication are required to increase the probability of local communities supporting the eradication campaign. The ecological benefits of eradication (e.g., improvement of endemic species' probability of survival) are difficult to trade-off against social and economic costs due to the lack of a common currency. Local communities may oppose an eradication campaign because of perceived health hazards, inconvenience, financial burdens, religious beliefs, or other cultural reasons. Besides these social challenges, the presence of humans and domestic animals also complicates eradication and biosecurity procedures (measures taken to reduce the probability of unwanted organisms colonizing an island to near zero). For example, houses, garbage-disposal areas, and livestock-feeding areas can provide refuges for certain mammals and therefore can decrease the probability of a successful eradication. Transport of humans and goods to an island increases the probability of inadvertent reintroduction of invasive mammals, and the establishment of permanent quarantine measures is required to minimize the probability of unwanted recolonization after eradication. We recommend a close collaboration between island communities, managers, and social scientists from the inception of an eradication campaign to increase the probability of achieving and maintaining an island permanently free of invasive mammals.


Determination of Factors Affecting Physical Activity Status of University Students on a Health Sciences Campus.
Upon graduation, students studying in departments related to health will work in the health sector and will guide and enlighten people with their knowledge and behavior. The purpose of this study was to determine the factors affecting the physical activity (PA) conditions of university students on a health sciences campus. A cross-sectional study was carried out on 706 students in a Turkish university. The data was obtained from a survey prepared by the researchers. The 26-question survey aimed to discover the students' socio-demographic characteristics and their awareness and practices concerning PA. We found that 30% of the students engage in some type of PA during their university education. A relationship was observed concerning their current PA and their family inactivity levels, as well as between inactivity before entering the university and inactivity during their education. The presence of a chronic disease in family members does not affect student PA. A majority of the students believe PA is beneficial (98.7%), 93.9% believe it relieves stress, and 94.5% believe it helps control body weight. Although students of medicine and related disciplines are aware of the importance of proper diet and adequate levels of PA in health, they did not implement theory into practice. Thus, it is questionable how young health professionals will promote the positive effects and necessity of regular physical activity if they do not apply these activities to their own lifestyle.


Clinical significance of circulating galectins as colorectal cancer markers.
The utility of CEA and CA19-9 as colorectal carcinoma (CRC) markers is limited and development of additional reliable markers is under investigation. We previously showed that galectin-1 is overexpressed in CRC tissues. If such a protein leaks into the peripheral circulation, it might constitute a tumor marker candidate. Here, we test the hypothesis that the levels of circulating galectins could reflect the presence of CRC and/or its progression state. We constructed sandwich ELISAs for galectin-1/-2/-3/-4/-7 and determined their plasma concentrations in 105 CRC patients and 100 healthy volunteers (control). Matched pair samples of 56 patients pre- and post-surgery were also subjected to ELISA analysis. Circulating levels of galectin-1/-3/-4 in CRC patients were significantly higher compared to those in controls. Galectin-1 and galectin-4 levels significantly decreased after surgery (P<0.01), and the level of galectin-4 in most patients fell below the cut-off value. The levels of circulating galectin-4 significantly increased as the tumor stage progressed (P<0.001), whereas those for galectin-1 were relatively high from an early stage. Combined use of galectin-4 with CEA and/or CA19-9 markedly increased the proportion of CRC patients who were positive for tumor markers (from 33.3 to 59.0% for CEA and from 17.1 to 51.4% for CA19-9). Our data show that galectin-4 may be a tumor marker for use in patient follow-up, while galectin-1 could be used for tumor screening. In particular, galectin-4 can be useful as a complementary marker when combined with CEA/CA19-9 to improve CRC follow-up.


SLE--systemic lupus erythematosus: a BLySful, yet BAFFling, disorder.
BLyS/BAFF (B-lymphocyte stimulator/B-cell activating factor) is a vital B-cell survival factor. Overexpression of BLyS in mice may lead to systemic-lupus-erythematosus-like (SLE-like) disease, and BLyS overexpression is common in human SLE. Treatment of SLE-prone mice with a BLyS antagonist ameliorates disease progression and enhances survival, making BLyS an attractive therapeutic target in human disease. However, several unresolved issues remain, including what is the contributory role of APRIL (a tumor-necrosis-factor superfamily member related to BLyS) in the 'autoimmunogenic' effects of BLyS, identification of the 'optimal' BLyS antagonist, and identification of those SLE patients most likely to benefit from BLyS antagonist therapy.