Toward an embodiment-disembodiment taxonomy.
Psychological, neuroscientific, and linguistic evidence suggests that a mental scene is in principle cognized with a mental gaze that can take on one of three forms: embodied physical gaze, embodied mental gaze, or disembodied mental gaze. Combinations of these forms also occur. A first sketch of the embodiment-disembodiment taxonomy that emerges from this threefold distinction is presented.


International collaborations in cancer control and the Third International Cancer Control Congress.
Over the past few decades, there has been growing support for the idea that cancer needs an interdisciplinary approach. Therefore, the international cancer community has developed several strategies as outlined in the WHO non-communicable diseases Action Plan (which includes cancer control) as the World Health Assembly and the UICC World Cancer Declaration, which both include primary prevention, early diagnosis, treatment, and palliative care. This paper highlights experiences/ideas in cancer control for international collaborations between low, middle, and high income countries, including collaborations between the European Union (EU) and African Union (AU) Member States, the Latin-American and Caribbean countries, and the Eastern Mediterranean countries. These proposals are presented within the context of the global vision on cancer control set forth by WHO in partnership with the International Union Against Cancer (UICC), in addition to issues that should be considered for collaborations at the global level: cancer survival (similar to the project CONCORD), cancer control for youth and adaptation of Clinical Practice Guidelines. Since cancer control is given lower priority on the health agenda of low and middle income countries and is less represented in global health efforts in those countries, EU and AU cancer stakeholders are working to put cancer control on the agenda of the EU-AU treaty for collaborations, and are proposing to consider palliative care, population-based cancer registration, and training and education focusing on primary prevention as core tools. A Community of Practice, such as the Third International Cancer Control Congress (ICCC-3), is an ideal place to share new proposals, learn from other experiences, and formulate new ideas. The aim of the ICCC-3 is to foster new international collaborations to promote cancer control actions in low and middle income countries. The development of supranational collaborations has been hindered by the fact that cancer control is not part of the objectives of the Millennium Development Goals (MGGs). As a consequence, less resources of development aids are allocated to control NCDs including cancer.


Malaria misdiagnosis in Uganda--implications for policy change.
In Uganda, like in many other countries traditionally viewed as harbouring very high malaria transmission, the norm has been to recommend that febrile episodes are diagnosed as malaria. In this study, the policy implications of such recommendations are revisited. A cross-sectional survey was undertaken at outpatient departments of all health facilities in four Ugandan districts. The routine diagnostic practices were assessed for all patients during exit interviews and a research slide was obtained for later reading. Primary outcome measures were the accuracy of national recommendations and routine malaria diagnosis in comparison with the study definition of malaria (any parasitaemia on expert slide examination in patient with fever) stratified by age and intensity of malaria transmission. Secondary outcome measures were the use, interpretation and accuracy of routine malaria microscopy. 1,763 consultations undertaken by 233 health workers at 188 facilities were evaluated. The prevalence of malaria was 24.2% and ranged between 13.9% in patients >or=5 years in medium-to-high transmission areas to 50.5% for children <5 years in very high transmission areas. Overall, the sensitivity and negative predictive value (NPV) of routine malaria diagnosis were high (89.7% and 91.6% respectively) while the specificity and positive predictive value (PPV) were low (35.6% and 30.8% respectively). However, malaria was under-diagnosed in 39.9% of children less than five years of age in the very high transmission area. At 48 facilities with functional microscopy, the use of malaria slide examination was low (34.5%) without significant differences between age groups, or between patients for whom microscopy is recommended or not. 96.2% of patients with a routine positive slide result were treated for malaria but also 47.6% with a negative result. Current recommendations and associated clinical practices result in massive malaria over-diagnosis across all age groups and transmission areas in Uganda. Yet, under-diagnosis is also common in children <5 years. The potential benefits of malaria microscopy are not realized. To address malaria misdiagnosis, Uganda's policy shift from presumptive to parasitological diagnosis should encompass introduction of malaria rapid diagnostic tests and substantial strengthening of malaria microscopy.


Does Real World Use of Liraglutide Match its Use in the LEADER Cardiovascular Outcome Trial? Study Protocol.
Liraglutide is an injectable therapy to treat type 2 diabetes (T2DM), belonging to the glucagon-like peptide-1 receptor agonist class of drugs. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial established that liraglutide demonstrated glucose-lowering benefits and improved cardiovascular outcomes in those individuals with T2DM at high cardiovascular risk. The aim of this study is to report the prevalence and characteristics of people treated with liraglutide compared with the LEADER trial. In addition, the remaining portion of the T2DM population will be examined to determine the prevalence of those who meet the inclusion criteria for the LEADER trial but who are not treated with this medication. This is a cross-sectional analysis of routinely collected primary care data on all people with T2DM included in the Royal College of General Practitioners (RCGP) Research and Surveillance Center (RSC) network database. People with T2DM will be identified from the dataset using a well-established ontological process. Read and other clinical codes will be used to identify people prescribed liraglutide and those at high cardiovascular risk. We will use descriptive statistics to report the characteristics of people with T2DM prescribed liraglutide compared with those of the LEADER trial and the proportion of the wider T2DM cohort that matches the LEADER inclusion criteria. In terms of ethical considerations, this study used pseudonymized data, and was classed as an "Audit of current practice". The results of the study will be submitted for publication in a peer-reviewed journal to report the applicability of the results of the LEADER trial to real-world clinical practice. Novo Nordisk Limited.


The Use of Fluorescence Angiography During Laparoscopic Sleeve Gastrectomy.
A new technology involving indocyanine green (ICG) fluorescence angiography has been introduced to assess tissue perfusion and perform vascular mapping during laparoscopic surgery. The purpose of this study was to describe the use of this technology to identify the variable blood supply patterns to the stomach and gastroesophageal (GE) junction during laparoscopic sleeve gastrectomy (LSG), which may help in preserving the blood supply and preventing ischemia-related leaks. Eighty-six patients underwent LSG and were examined intraoperatively with fluorescence angiography at an academic bariatric center from January 2016 to September 2017. Before the construction of the SG, 1 mL ICG was injected intravenously, and near infrared fluorescence imaging technology was used to identify the blood supply of the stomach. Afterward, the LSG was created with attention to preserving the identified blood supply to the GE junction and gastric tube. Finally, 3 mL ICG was injected to ensure that all the pertinent blood vessels were preserved. Eighty-six patients successfully underwent the laparoscopic procedure with no complications. The following patterns of blood supply to the GE junction were found: (1) a right-side-dominant pattern (20%), arising from the left gastric artery; (2) a right-side-accessory pattern (36%), running in the gastrohepatic ligament and comprising either an accessory hepatic artery or an accessory gastric artery; and (3) a left-side accessory pattern arising from tributaries from the left inferior phrenic artery significantly contributing to the right-side blood supply. In addition, in 10% of the cases both right and left accessory patterns were present simultaneously. ICG fluorescence angiography allows determination of the major blood supply to the proximal stomach before any dissection during sleeve gastrectomy, so that an effort can be made to avoid unnecessary injury to these vessels during the procedure.


Anti-metastatic activity of biologically synthesized gold nanoparticles on human fibrosarcoma cell line HT-1080.
Plants are exploited as a potential source for the large-scale production of noble gold nanoparticles in the recent years owing to their various potential applications in nanobiotechnology and nanomedicine. The present work describes green biosynthetic procedures for the production of gold nanoparticles for the first time by using an aqueous extract of the Dysosma pleiantha rhizome. The biosynthesized gold nanoparticles were confirmed and characterized by ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, and scanning electron microscopy equipped with energy dispersive spectroscopy. The results revealed that aqueous extract of D. pleiantha rhizome has potential to reduce chloroauric ions into gold nanoparticles and the synthesized gold nanoparticles were showed spherical in shape with an average of 127nm. Further, we investigated the anti-metastatic activity of biosynthesized gold nanoparticles against human fibrosarcoma cancer cell line HT-1080. The results showed that the biosynthesized gold nanoparticles were non-toxic to cell proliferation and, also it can inhibit the chemo-attractant cell migration of human fibrosarcoma cancer cell line HT-1080 by interfering the actin polymerization pathway. Thus, the usage of gold nanoparticles biosynthesized from D. pleiantha rhizome can be used as a potential candidate in the drug and gene delivery to metastatic cancer.


On the context-dependent nature of the contribution of the ventral premotor cortex to speech perception.
What is the nature of the interface between speech perception and production, where auditory and motor representations converge? One set of explanations suggests that during perception, the motor circuits involved in producing a perceived action are in some way enacting the action without actually causing movement (covert simulation) or sending along the motor information to be used to predict its sensory consequences (i.e., efference copy). Other accounts either reject entirely the involvement of motor representations in perception, or explain their role as being more supportive than integral, and not employing the identical circuits used in production. Using fMRI, we investigated whether there are brain regions that are conjointly active for both speech perception and production, and whether these regions are sensitive to articulatory (syllabic) complexity during both processes, which is predicted by a covert simulation account. A group of healthy young adults (1) observed a female speaker produce a set of familiar words (perception), and (2) observed and then repeated the words (production). There were two types of words, varying in articulatory complexity, as measured by the presence or absence of consonant clusters. The simple words contained no consonant cluster (e.g. "palace"), while the complex words contained one to three consonant clusters (e.g. "planet"). Results indicate that the left ventral premotor cortex (PMv) was significantly active during speech perception and speech production but that activation in this region was scaled to articulatory complexity only during speech production, revealing an incompletely specified efferent motor signal during speech perception. The right planum temporal (PT) was also active during speech perception and speech production, and activation in this region was scaled to articulatory complexity during both production and perception. These findings are discussed in the context of current theories of speech perception, with particular attention to accounts that include an explanatory role for mirror neurons.


Expression of citrulline and homocitrulline residues in the lungs of non-smokers and smokers: implications for autoimmunity in rheumatoid arthritis.
Smoking is a well-established risk factor for rheumatoid arthritis (RA), and it has been proposed that smoking-induced citrullination renders autoantigens immunogenic. To investigate this mechanism, we examined human lung tissue from 40 subjects with defined smoking status, with or without chronic obstructive pulmonary disease (COPD), and control tissues from other organs for citrullinated proteins and the deiminating enzymes peptidylarginine deiminase type-2 (PAD2) and -4 (PAD4). Lung tissue samples, dissected from lobectomy specimens from 10 never smokers, 10 smokers without airflow limitation, 13 COPD smokers and eight COPD ex-smokers, and control tissue samples (spleen, skeletal muscle, liver, ovary, lymph node, kidney and heart), were analysed for citrullinated proteins, PAD2 and PAD4 by immunoblotting. Citrulline and homocitrulline residues in enolase and vimentin were analysed by partial purification by gel electrophoresis followed by mass spectrometry in 12 of the lung samples and one from each control tissues. Band intensities were scored semi-quantitatively and analysed by two-tailed Mann-Whitney T-test. Within the lung tissue samples, citrullinated proteins, PAD2 and PAD4 were found in all samples, with an increase in citrullination in COPD (P = 0.039), but minimal difference between smokers and non-smokers (P = 0.77). Citrullination was also detected at lower levels in the tissues from other organs, principally in lymph node, kidney and skeletal muscle. Mass spectrometry of the lung samples showed that vimentin was citrullinated at positions 71, 304, 346, 410 and 450 in non-smokers and smokers both with and without COPD. A homocitrulline at position 104 was found in four out of six COPD samples and one out of six non-COPD. Citrulline-450 was also found in three of the control tissues. There were no citrulline or homocitrulline residues demonstrated in α-enolase. We have shown evidence of citrullination of vimentin, a major autoantigen in RA, in both non-smokers and smokers. The increase in citrullinated proteins in COPD suggests that citrullination in the lungs of smokers is mainly due to inflammation. The ubiquity of citrullination of vimentin in the lungs and other tissues suggests that the relationship between smoking and autoimmunity in RA may be more complex than previously thought.


Descriptive epidemiology of Cornelia de Lange syndrome in Europe.
Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. We present a population-based epidemiological study of the classical form of CdLS. The data were extracted from the database of European Surveillance of Congenital Anomalies (EUROCAT) database, a European network of birth defect registries which follow a standard methodology. Based on 23 years of epidemiologic monitoring (8,558,346 births in the 1980-2002 period), we found the prevalence of the classical form of CdLS to be 1.24/100,000 births or 1:81,000 births and estimated the overall CdLS prevalence at 1.6-2.2/100,000. Live born children accounted for 91.5% (97/106) of cases, fetal deaths 2.8% (3/106), and terminations of pregnancy following prenatal diagnosis 5.7% (6/106). The most frequent associated congenital malformations were limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (40.2%), and cleft palate (21.7%). In the last 11 years, as much as 68% of cases with major malformations were not detected by routine prenatal US. Live born infants with CdLS have a high first week survival (91.4%). All patients were sporadic. Maternal and paternal age did not seem to be risk factors for CdLS. Almost 70% of patients, born after the 37th week of gestation, weighed <or=2,500 g. Low birth weight correlated with a more severe phenotype. Severe limb anomalies were significantly more often present in males.


Identification of an enhancer-like element in the polyhedrin gene upstream region of Bombyx mori nucleopolyhedrovirus.
A series of deletions in the upstream region of the gene encoding polyhedrin (polh) of Bombyx mori nucleopolyhedrovirus (BmNPV) were generated in plasmid constructs and tested for transcription. In transient transfection assays in Bombyx mori-derived BmN cells with firefly luciferase as the reporter gene, a 293 bp fragment located 1.0 kb upstream with respect to the +1 ATG of polh showed 10-fold enhancement in expression from the minimal promoter. This increase in reporter activity was observed only when the fragment was positioned in cis with respect to the promoter and not in trans. The stimulation of reporter gene expression was independent of the orientation of the fragment and was due to increased transcription from the promoter. When placed upstream of another promoter, the viral very late gene p10 promoter, the enhancer brought about a 2-fold increase in expression. The region encompassing the enhancer was itself transcriptionally active, and transcripts corresponding to both of the encoded ORFs (N-terminal regions of ORF453 and ORF327, located in opposite orientations) were detected. Two AP1 sites (TGACTCG) in the 293 bp fragment did not appear to contribute to the enhancer function. Since repeat motifs, the hallmark of conventional enhancer sequences, were absent from this fragment, it is designated as an enhancer-like element. The influence of this region of the polh upstream sequence on expression from strong, very late viral promoters has not been reported previously.


Neural machine translation of clinical texts between long distance languages.
To analyze techniques for machine translation of electronic health records (EHRs) between long distance languages, using Basque and Spanish as a reference. We studied distinct configurations of neural machine translation systems and used different methods to overcome the lack of a bilingual corpus of clinical texts or health records in Basque and Spanish. We trained recurrent neural networks on an out-of-domain corpus with different hyperparameter values. Subsequently, we used the optimal configuration to evaluate machine translation of EHR templates between Basque and Spanish, using manual translations of the Basque templates into Spanish as a standard. We successively added to the training corpus clinical resources, including a Spanish-Basque dictionary derived from resources built for the machine translation of the Spanish edition of SNOMED CT into Basque, artificial sentences in Spanish and Basque derived from frequently occurring relationships in SNOMED CT, and Spanish monolingual EHRs. Apart from calculating bilingual evaluation understudy (BLEU) values, we tested the performance in the clinical domain by human evaluation. We achieved slight improvements from our reference system by tuning some hyperparameters using an out-of-domain bilingual corpus, obtaining 10.67 BLEU points for Basque-to-Spanish clinical domain translation. The inclusion of clinical terminology in Spanish and Basque and the application of the back-translation technique on monolingual EHRs significantly improved the performance, obtaining 21.59 BLEU points. This was confirmed by the human evaluation performed by 2 clinicians, ranking our machine translations close to the human translations. We showed that, even after optimizing the hyperparameters out-of-domain, the inclusion of available resources from the clinical domain and applied methods were beneficial for the described objective, managing to obtain adequate translations of EHR templates. We have developed a system which is able to properly translate health record templates from Basque to Spanish without making use of any bilingual corpus of clinical texts or health records.


Mitotic asynchrony induces transforming growth factor-β1 secretion from airway epithelium.
We recently proposed that mitotic asynchrony in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to proinflammatory cross-talk among asynchronously repairing adjacent tissues. Building on our previous finding that mitotic asynchrony is associated with proinflammatory/fibrotic cytokine secretion (e.g., transforming growth factor [TGF]-β1), here we provide evidence supporting cause-and-effect. Under normal conditions, primary airway epithelial basal cell populations undergo mitosis synchronously and do not secrete proinflammatory or profibrotic cytokines. However, when pairs of nonasthmatic cultures were mitotically synchronized at 12 hours off-set and then combined, the mixed cell populations secreted elevated levels of TGF-β1. This shows that mitotic asynchrony is not only associated with but is also causative of TGF-β1 secretion. The secreted cytokines and other mediators from asthmatic cells were not the cause of asynchronous regeneration; synchronously mitotic nonasthmatic epithelia exposed to conditioned media from asthmatic cells did not show changes in mitotic synchrony. We also tested if resynchronization of regenerating asthmatic airway epithelia reduces TGF-β1 secretion and found that pulse-dosed dexamethasone, simvastatin, and aphidicolin were all effective. We therefore propose a new model for chronic inflammatory and fibrotic conditions where an underlying factor is mitotic asynchrony.


Implementation of a school-based social and emotional learning intervention: understanding diffusion processes within complex systems.
Sporadic and inconsistent implementation remains a significant challenge for social and emotional learning (SEL) interventions. This may be partly explained by the dearth of flexible, causative models that capture the multifarious determinants of implementation practices within complex systems. This paper draws upon Rogers (2003) Diffusion of Innovations Theory to explain the adoption, implementation and discontinuance of a SEL intervention. A pragmatic, formative process evaluation was conducted in alignment with phase 1 of the UK Medical Research Council's framework for Developing and Evaluating Complex Interventions. Employing case-study methodology, qualitative data were generated with four socio-economically and academically contrasting secondary schools in Wales implementing the Student Assistance Programme. Semi-structured interviews were conducted with 15 programme stakeholders. Data suggested that variation in implementation activity could be largely attributed to four key intervention reinvention points, which contributed to the transformation of the programme as it interacted with contextual features and individual needs. These reinvention points comprise the following: intervention training, which captures the process through which adopters acquire knowledge about a programme and delivery expertise; intervention assessment, which reflects adopters' evaluation of an intervention in relation to contextual needs; intervention clarification, which comprises the cascading of knowledge through an organisation in order to secure support in delivery; and intervention responsibility, which refers to the process of assigning accountability for sustainable delivery. Taken together, these points identify opportunities to predict and intervene with potential implementation problems. Further research would benefit from exploring additional reinvention activity.


Multi-scale integration and predictability in resting state brain activity.
The human brain displays heterogeneous organization in both structure and function. Here we develop a method to characterize brain regions and networks in terms of information-theoretic measures. We look at how these measures scale when larger spatial regions as well as larger connectome sub-networks are considered. This framework is applied to human brain fMRI recordings of resting-state activity and DSI-inferred structural connectivity. We find that strong functional coupling across large spatial distances distinguishes functional hubs from unimodal low-level areas, and that this long-range functional coupling correlates with structural long-range efficiency on the connectome. We also find a set of connectome regions that are both internally integrated and coupled to the rest of the brain, and which resemble previously reported resting-state networks. Finally, we argue that information-theoretic measures are useful for characterizing the functional organization of the brain at multiple scales.


Transcript, protein and metabolite temporal dynamics in the CAM plant Agave.
Already a proven mechanism for drought resilience, crassulacean acid metabolism (CAM) is a specialized type of photosynthesis that maximizes water-use efficiency by means of an inverse (compared to C3 and C4 photosynthesis) day/night pattern of stomatal closure/opening to shift CO2 uptake to the night, when evapotranspiration rates are low. A systems-level understanding of temporal molecular and metabolic controls is needed to define the cellular behaviour underpinning CAM. Here, we report high-resolution temporal behaviours of transcript, protein and metabolite abundances across a CAM diel cycle and, where applicable, compare the observations to the well-established C3 model plant Arabidopsis. A mechanistic finding that emerged is that CAM operates with a diel redox poise that is shifted relative to that in Arabidopsis. Moreover, we identify widespread rescheduled expression of genes associated with signal transduction mechanisms that regulate stomatal opening/closing. Controlled production and degradation of transcripts and proteins represents a timing mechanism by which to regulate cellular function, yet knowledge of how this molecular timekeeping regulates CAM is unknown. Here, we provide new insights into complex post-transcriptional and -translational hierarchies that govern CAM in Agave. These data sets provide a resource to inform efforts to engineer more efficient CAM traits into economically valuable C3 crops.


Tissue-specific down-regulation of RIPK 2 in Mycobacterium leprae-infected nu/nu mice.
RIPK 2 is adapter molecule in the signal pathway involved in Toll-like receptors. However, there has been no reported association between receptor-interacting serine/threonine kinase 2 (RIPK 2) expression and the infectious diseases involving mycobacterial infection. This study found that its expression was down-regulated in the footpads and skin but was up-regulated in the liver of Mycobacterium leprae-infected nu/nu mice compared with those of the M. leprae non-infected nu/nu mice. It was observed that the interlukin-12p40 and interferon-gamma genes involved in the susceptibility of M. leprae were down-regulated in the skin but were up-regulated in the liver. Overall, this suggests that regulation of RIPK 2 expression is tissue-specifically associated with M. leprae infection.


Short-Term Exposure to Waterpipe/Hookah Smoke Triggers a Hyperactive Platelet Activation State and Increases the Risk of Thrombogenesis.
Cardiovascular disease is a major public health problem. Among cardiovascular disease's risk factors, tobacco smoking is considered the single most preventable cause of death, with thrombosis being the main mechanism of cardiovascular disease mortality in smokers. While tobacco smoking has been on the decline, the use of waterpipes/hookah has been rising, mainly due to the perception that they are less harmful than regular cigarettes. Strikingly, there are few studies on the negative effects of waterpipes on the cardiovascular system, and none regarding their direct contribution to thrombus formation. Approach and Results: We used a waterpipe whole-body exposure protocol that mimics real-life human exposure scenarios and investigated its effects, relative to clean air, on platelet function, hemostasis, and thrombogenesis. We found that waterpipe smoke (WPS)-exposed mice exhibited both shortened thrombus occlusion and bleeding times. Further, our results show that platelets from WPS-exposed mice are hyperactive, with enhanced agonist-induced aggregation, dense and α-granule secretion, αIIbβ3 integrin activation, phosphatidylserine expression, and platelet spreading, when compared with clean air-exposed platelets. Finally, at the molecular level, it was found that Akt (protein kinase B) and ERK (extracellular signal-regulated kinases) phosphorylation are enhanced in the WPS and in nicotine-treated platelets. Our findings demonstrate that WPS exposure directly modulates hemostasis and increases the risk of thrombosis and that this is mediated, in part, via a state of platelet hyperactivity. The negative health impact of WPS/hookah, therefore, should not be underestimated. Moreover, this study should also help in raising public awareness of the toxic effects of waterpipe/hookah.


Paired High-Content Analysis of Prostate Cancer Cells in Bone Marrow and Blood Characterizes Increased Androgen Receptor Expression in Tumor Cell Clusters.
Purpose: Recent studies demonstrate that prostate cancer clones from different metastatic sites are dynamically represented in the blood of patients over time, suggesting that the paired evaluation of tumor cells in circulation and bone marrow, the primary target for prostate cancer metastasis, may provide complementary information.Experimental Design: We adapted our single-cell high-content liquid biopsy platform to bone marrow aspirates (BMA) to concurrently identify and characterize prostate cancer cells in patients' blood and bone and thus discern features associated to tumorigenicity and dynamics of metastatic progression.Results: The incidence of tumor cells in BMAs increased as the disease advanced: 0% in biochemically recurrent (n = 52), 26% in newly diagnosed metastatic hormone-naïve (n = 26), and 39% in metastatic castration-resistant prostate cancer (mCRPC; n = 63) patients, and their number was often higher than in paired blood. Tumor cell detection in metastatic patients' BMAs was concordant but 45% more sensitive than using traditional histopathologic interpretation of core bone marrow biopsies. Tumor cell clusters were more prevalent and bigger in BMAs than in blood, expressed higher levels of the androgen receptor protein per tumor cell, and were prognostic in mCRPC. Moreover, the patterns of genomic copy number variation in single tumor cells in paired blood and BMAs showed significant inter- and intrapatient heterogeneity.Conclusions: Paired analysis of single prostate cancer cells in blood and bone shows promise for clinical application and provides complementary information. The high prevalence and prognostic significance of tumor cell clusters, particularly in BMAs, suggest that these structures are key mediators of prostate cancer's metastatic progression. Clin Cancer Res; 23(7); 1722-32. ©2016 AACR.


Identification of a novel luminal molecular subtype of breast cancer.
The molecular classification of human breast tumors has afforded insights into subtype specific biological processes, patient prognosis and response to therapies. However, using current methods roughly one quarter of breast tumors cannot be classified into one or another molecular subtype. To explore the possibility that the unclassifiable samples might comprise one or more novel subtypes we employed a collection of publically available breast tumor datasets with accompanying clinical information to assemble 1,593 transcript profiles: 25% of these samples could not be assigned to one of the current molecular subtypes of breast cancer. All of the unclassifiable samples could be grouped into a new molecular subtype, which we termed "luminal-like". We also identified the luminal-like subtype in an independent collection of tumor samples (NKI295). We found that patients harboring tumors of the luminal-like subtype have a better prognosis than those with basal-like breast cancer, a similar prognosis to those with ERBB2+, luminal B or claudin-low tumors, but a worse prognosis than patients with luminal A or normal-like breast tumors. Our findings suggest the occurrence of another molecular subtype of breast cancer that accounts for the vast majority of previously unclassifiable breast tumors.


1-year follow-up of 920 hip and knee arthroplasty patients after implementing fast-track.
Fast-track has become a well-known concept resulting in improved patient satisfaction and postoperative results. Concerns have been raised about whether increased efficiency could compromise safety, and whether early hospital discharge might result in an increased number of complications. We present 1-year follow-up results after implementing fast-track in a Norwegian university hospital. This was a register-based study of 1,069 consecutive fast-track hip and knee arthroplasty patients who were operated on between September 2010 and December 2012. Patients were followed up until 1 year after surgery. 987 primary and 82 revision hip or knee arthroplasty patients were included. 869 primary and 51 revision hip or knee patients attended 1-year follow-up. Mean patient satisfaction was 9.3 out of a maximum of 10. Mean length of stay was 3.1 days for primary patients. It was 4.2 days in the revision hip patients and 3.9 in the revision knee patients. Revision rates until 1-year follow-up were 2.9% and 3.3% for primary hip and knee patients, and 3.7% and 7.1% for revision hip and knee patients. Function scores and patient-reported outcome scores were improved in all groups. We found reduced length of stay, a high level of patient satisfaction, and low revision rates, together with improved health-related quality of life and functionality, when we introduced fast-track into an orthopedic department in a Norwegian university hospital.


Diel Migrations of Microorganisms within a Benthic, Hypersaline Mat Community.
We studied the diel migrations of several species of microorganisms in a hypersaline, layered microbial mat. The migrations were quantified by repeated coring of the mat with glass capillary tubes. The resulting minicores were microscopically analyzed by using bright-field and epifluorescence (visible and infrared) microscopy to determine depths of coherent layers and were later dissected to determine direct microscopic counts of microorganisms. Microelectrode measurements of oxygen concentration, fiber optic microprobe measurements of light penetration within the mat, and incident irradiance measurements accompanied the minicore sampling. In addition, pigment content, photosynthesis and irradiance responses, the capacity for anoxygenic photosynthesis, and gliding speeds were determined for the migrating cyanobacteria. Heavily pigmented Oscillatoria sp. and Spirulina cf. subsalsa migrated downward into the mat during the early morning and remained deep until dusk, when upward migration occurred. The mean depth of the migration (not more than 0.4 to 0.5 mm) was directly correlated with the incident irradiance over the mat surface. We estimated that light intensity at the upper boundary of the migrating cyanobacteria was attenuated to such an extent that photoinhibition was effectively avoided but that intensities which saturated photosynthesis were maintained through most of the daylight hours. Light was a cue of paramount importance in triggering and modulating the migration of the cyanobacteria, even though the migrating phenomenon could not be explained solely in terms of a light response. We failed to detect diel migration patterns for other cyanobacterial species and filamentous anoxyphotobacteria. The sulfide-oxidizing bacterium Beggiatoa sp. migrated as a band that followed low oxygen concentrations within the mat during daylight hours. During the nighttime, part of this population migrated toward the mat surface, but a significant proportion remained deep.


Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering.
Bisphosphonates (BPs) were introduced 45 years ago as anti-osteoporotic drugs and during the last decade have been utilized as bone-targeting groups in systemic treatment of bone diseases. Very recently, strategies of chemical immobilization of BPs in hydrogels and nanocomposites for bone tissue engineering emerged. These strategies opened new applications of BPs in bone tissue engineering. Conjugates of BPs to different drug molecules, imaging agents, proteins and polymers are discussed in terms of specific targeting to bone and therapeutic affect induced by the resulting prodrugs in comparison with the parent drugs. Conversion of these conjugates into hydrogel scaffolds is also presented along with the application of the resulting materials for bone tissue engineering. Calcium-binding properties of BPs can be successfully extended via different conjugation strategies not only for purposes of bone targeting, but also in supramolecular assembly affording either new nanocarriers or bulk nanocomposite scaffolds. Interaction between carrier-linked BPs and drug molecules should also be considered for the control of release of these molecules and their optimized delivery. Bone-targeting properties of BP-functionalized nanomaterials should correspond to bone adhesive properties of their bulk analogs.


Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline.
The aim was to develop clinical practice guidelines on hypertriglyceridemia. The Task Force included a chair selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), five additional experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Consensus was guided by systematic reviews of evidence, e-mail discussion, conference calls, and one in-person meeting. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. The Task Force recommends that the diagnosis of hypertriglyceridemia be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150-999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of > 1000 mg/dl) be considered a risk for pancreatitis. The Task Force also recommends that patients with hypertriglyceridemia be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease. The Task Force recommends that the treatment goal in patients with moderate hypertriglyceridemia be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate should be used as a first-line agent.


HER3 signaling and targeted therapy in cancer.
ERBB family members including epidermal growth factor receptor (EGFR) also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs). Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners' kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib) or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors.


Meniscal tears are more common than previously identified, however, less than a quarter of people with a tear undergo arthroscopy.
The management of meniscal tears is a widely researched and evolving field. Previous studies reporting the incidence of meniscal tears are outdated and not representative of current practice. The aim of this study was to report the current incidence of MRI confirmed meniscal tears in patients with a symptomatic knee and the current intervention rate in a large NHS trust. Radiology reports from 13,358 consecutive magnetic resonance imaging scans between 2015 and 2017, performed at a large UK hospital serving a population of 470,000, were assessed to identify patients with meniscal tears. The hospital database was interrogated to explore the subsequent treatment undertaken by the patient. A linear regression model was used to identify if any factors predicted subsequent arthroscopy. 1737 patients with isolated meniscal tears were identified in patients undergoing an MRI for knee pain, suggesting a rate of 222 MRI confirmed tears per 100,000 of the population aged 18 to 55 years old. 47% attended outpatient appointments and 22% underwent arthroscopy. Root tears [odds ratio (95% CI) 2.24 (1.0, 4.49); p = 0.049] and bucket handle tears were significantly associated with subsequent surgery, with no difference between the other types of tears. The presence of chondral changes did not significantly affect the rate of surgery [0.81 (0.60, 1.08); n.s]. Meniscal tears were found to be more common than previously described. However, less than half present to secondary care and only 22% undergo arthroscopy. These findings should inform future study design and recruitment strategies. In agreement with previous literature, bucket handle tears and root tears were significant predictors of subsequent surgery. III.


Salinity- and population-dependent genome regulatory response during osmotic acclimation in the killifish (Fundulus heteroclitus) gill.
The killifish Fundulus heteroclitus is abundant in osmotically dynamic estuaries and it can quickly adjust to extremes in environmental salinity. We performed a comparative osmotic challenge experiment to track the transcriptomic and physiological responses to two salinities throughout a time course of acclimation, and to explore the genome regulatory mechanisms that enable extreme osmotic acclimation. One southern and one northern coastal population, known to differ in their tolerance to hypo-osmotic exposure, were used as our comparative model. Both populations could maintain osmotic homeostasis when transferred from 32 to 0.4 p.p.t., but diverged in their compensatory abilities when challenged down to 0.1 p.p.t., in parallel with divergent transformation of gill morphology. Genes involved in cell volume regulation, nucleosome maintenance, ion transport, energetics, mitochondrion function, transcriptional regulation and apoptosis showed population- and salinity-dependent patterns of expression during acclimation. Network analysis confirmed the role of cytokine and kinase signaling pathways in coordinating the genome regulatory response to osmotic challenge, and also posited the importance of signaling coordinated through the transcription factor HNF-4α. These genome responses support hypotheses of which regulatory mechanisms are particularly relevant for enabling extreme physiological flexibility.


Testosterone and oxandrolone, a nonaromatizable androgen, specifically amplify the mass and rate of growth hormone (GH) secreted per burst without altering GH secretory burst duration or frequency or the GH half-life.
We investigated the mechanisms by which androgens increase mean circulating GH concentrations in boys. We tested two hypotheses: 1) testosterone increases serum GH concentrations at least in part via an androgen receptor-mediated mechanism, rather than exclusively by way of aromatization to estrogen; 2) androgen augments one or more specific features to GH secretion (secretory burst number, amplitude, and/or duration) and/or prolongs the half-life of GH removal. To examine these hypotheses, prepubertal boys with constitutionally delayed development and/or growth were given injections of testosterone (100 mg monthly; n = 7) or treated with oral oxandrolone, a nonaromatizable androgen (1.25 mg twice daily; n = 5). Pulsatile GH release was studied before and during androgen administration by sampling blood at 20-min intervals for 24 h. The immunoreactive GH time series were subjected to a novel deconvolution technique, which revealed that 1) testosterone and oxandrolone each increased mean (24-h) serum GH concentrations significantly; 2) both androgens augmented the daily endogenous GH secretory rate significantly; 3) increased GH production resulted from a higher mass of GH secreted per burst and a higher maximal rate of GH secretion within each burst; and 4) androgens amplified the magnitude of the nyctohemeral rhythm in the mass (but not frequency) of GH secretory pulses. The observed effects of androgen were specific, since the number and duration of GH secretory bursts and the subject-specific GH half-life were unaltered by androgen treatment. We conclude that androgen acting apart from conversion to estrogen is capable of specifically activating the somatotropic axis via distinct neuroendocrine secretory mechanisms.


Sequence analysis of the 5'-untranslated region of the human H1 histamine receptor-encoding gene.
A clone containing the H1 histamine receptor (H1HR)-encoding gene was isolated from a human genomic DNA library. The 5'-UTR of the H1HR gene reported here differs upstream from bp -142 from that reported previously [Fukui et al., Biochem. Biophys. Res. Comm. 201 (1994) 894-901]. PCR amplification utilizing primer pairs derived from the 5'-UTR reported herein amplified a DNA fragment of the expected size from human genomic DNA whereas 5'-UTR primers derived from the Fukui et al. sequence did not yield a PCR product. The 5'-UTR of H1HR contains potential TATA and CCAAT boxes, a CACCC sequence, potential GREs and other DNA-binding motifs.


Consequences of states' policies for SCHIP disenrollment.
Policymakers are concerned about disenrollment from the State Children's Health Insurance Program (SCHIP). We describe disenrollment in Florida, Kansas, New York, and Oregon and assess the links between disenrollment and States' SCHIP policies. We found that SCHIP is used on a long-term basis (at least 2 years) for a significant group of new enrollees and as temporary coverage (fewer than 12 months) for many others. Recertification generates large disenrollments (about one-half of children still enrolled at the time), but as many as 25 percent return within 2 months. The increased disenrollment rate at recertification is completely eliminated by a policy of passive re-enrollment.


Out of the consulting room and into the world: hermeneutic dialogue, phronesis, and psychoanalytic theory as practice.
One of the relics of positivism has been an underappreciation of the moral and ethical dimensions of psychoanalytic theory and practice. In a positivist metapsychology, cure and therapeutic gain were often defined instrumentally, with relatively little consideration given to aspects of human experience (e.g., moral, cultural, spiritual) that did not fit within a positivist framework. Conceptual and paradigmatic shifts in psychoanalysis have occurred, in part, because of the inability of the classical model to provide a language that adequately captures deeply felt human values and beliefs. Aided by hermeneutic and postmodern influences, many contemporary psychoanalytic theories are beginning to focus greater attention on the notion that analytic therapy is empowered by a set of ethical convictions, beliefs, and commitments, which are tied to a certain understanding of the good life. Along these lines, the author argues that developing a fresh understanding of the moral and ethical dimensions of psychoanalysis requires elaborating a new ontology of human subjectivity and social life. The author offers a sketch of how this gargantuan task might be started by integrating psychoanalysis within a hermeneutic perspective on dialogue, by suggesting that it would be helpful to view psychoanalysis as promoting Aristotelian practical wisdom or phronesis, and by rethinking psychoanalytic theory and interpretation as a form of practice.


Genetic optimization of a bacteriophage-delivered alkaline phosphatase reporter to detect Escherichia coli.
A large fraction of foodborne illnesses are linked to (∼46%) leafy green vegetables contaminated by pathogens harbored in agricultural water. To prevent this, accurate point-of-production detection tools are required to identify and quantify bacterial contaminants in produce before consumers are impacted. In this study, a proof-of-concept model was engineered for a phage-based Escherichia coli detection system. We engineered the coliphage T7 to express alkaline phosphatase (ALP) to serve as the signal for E. coli detection. Wild type phoA (T7ALP) and a dominant-active allele, phoA D153G D330N (T7ALP*) was inserted into the T7 genome, with engineered constructs selected by CRISPR-mediated cleavage of unaltered chromosomes and confirmed by PCR. Engineered phages and E. coli target cells were co-incubated for 16 hours to produce lysates with liberated ALP correlated with input cell concentrations. A colorimetric assay used p-nitrophenyl phosphate (pNPP) to demonstrate significant ALP production by T7ALP and T7ALP* compared to the vector control (T7EV) (p≤ 0.05). Furthermore, T7ALP* produced 2.5-fold more signal than T7ALP (p≤ 0.05) at pH 10. Due to the increase in signal for the modified ALP* allele, we assessed T7ALP* sensitivity in a dose-responsive manner. We observed 3-fold higher signal for target cell populations as low as ∼2 × 10(5) CFU mL(-1) (p≤ 0.05 vs. no-phage control).


Challenges in Antimalarial Drug Treatment for Vivax Malaria Control.
Plasmodium vivax is the most widespread human malaria parasite, but has received much less attention than Plasmodium falciparum during the past 50 years of research. Plasmodium vivax was historically seen as causing only benign disease, but this view has recently changed, with increased recognition of the burden of vivax malaria, as well as numerous case reports of severe malaria or death caused by this parasite. The complexity of P. vivax biology is characteristic of specific features of the parasite, and recent years have seen major progress in our understanding of this complexity. In this review, we analyze the latest advances in the field, describing the constraints that the unique features of P. vivax place on drug treatments aimed at controlling or eliminating it.


SUMO binding by the Epstein-Barr virus protein kinase BGLF4 is crucial for BGLF4 function.
An Epstein-Barr virus (EBV) protein microarray was used to screen for proteins binding noncovalently to the small ubiquitin-like modifier SUMO2. Among the 11 SUMO binding proteins identified was the conserved protein kinase BGLF4. The mutation of potential SUMO interaction motifs (SIMs) in BGLF4 identified N- and C-terminal SIMs. The mutation of both SIMs changed the intracellular localization of BGLF4 from nuclear to cytoplasmic, while BGLF4 mutated in the N-terminal SIM remained predominantly nuclear. The mutation of the C-terminal SIM yielded an intermediate phenotype with nuclear and cytoplasmic staining. The transfer of BGLF4 amino acids 342 to 359 to a nuclear green fluorescent protein (GFP)-tagged reporter protein led to the relocalization of the reporter to the cytoplasm. Thus, the C-terminal SIM lies adjacent to a nuclear export signal, and coordinated SUMO binding by the N- and C-terminal SIMs blocks export and allows the nuclear accumulation of BGLF4. The mutation of either SIM prevented SUMO binding in vitro. The ability of BGLF4 to abolish the SUMOylation of the EBV lytic cycle transactivator ZTA was dependent on both BGLF4 SUMO binding and BGLF4 kinase activity. The global profile of SUMOylated cell proteins was also suppressed by BGLF4 but not by the SIM or kinase-dead BGLF4 mutant. The effective BGLF4-mediated dispersion of promyelocytic leukemia (PML) bodies was dependent on SUMO binding. The SUMO binding function of BGLF4 was also required to induce the cellular DNA damage response and to enhance the production of extracellular virus during EBV lytic replication. Thus, SUMO binding by BGLF4 modulates BGLF4 function and affects the efficiency of lytic EBV replication.


Interferometric polarization control.
We develop the Jones and Mueller matrices for structures that allow control of the path length difference between two linear orthogonal polarizations and consider the effect of placing multiple devices in series. Specifically, we find that full polarization modulation (measurement of Stokes Q, U, and V) can be achieved by placing two such modulators in series if the relative angles of the beam-splitting grids with respect to the analyzer orientation are appropriately chosen. Such a device has several potential advantages over a spinning wave plate modulator for measuring astronomical polarization in the far infrared through millimeter: (i) The use of small, linear motions eliminates the need for cryogenic rotational bearings; (ii) the phase flexibility allows measurement of circular as well as linear polarization; and (iii) this architecture allows for both multiwavelength and broadband modulation. We also present initial laboratory results.


Evaluating the effect of multiple sclerosis lesions on automatic brain structure segmentation.
In recent years, many automatic brain structure segmentation methods have been proposed. However, these methods are commonly tested with non-lesioned brains and the effect of lesions on their performance has not been evaluated. Here, we analyze the effect of multiple sclerosis (MS) lesions on three well-known automatic brain structure segmentation methods, namely, FreeSurfer, FIRST and multi-atlas fused by majority voting, which use learning-based, deformable and atlas-based strategies, respectively. To perform a quantitative analysis, 100 synthetic images of MS patients with a total of 2174 lesions are simulated on two public databases with available brain structure ground truth information (IBSR18 and MICCAI'12). The Dice similarity coefficient (DSC) differences and the volume differences between the healthy and the simulated images are calculated for the subcortical structures and the brainstem. We observe that the three strategies are affected when lesions are present. However, the effects of the lesions do not follow the same pattern; the lesions either make the segmentation method underperform or surprisingly augment the segmentation accuracy. The obtained results show that FreeSurfer is the method most affected by the presence of lesions, with DSC differences (generated - healthy) ranging from - 0.11 ± 0.54 to 9.65 ± 9.87, whereas FIRST tends to be the most robust method when lesions are present (- 2.40 ± 5.54 to 0.44 ± 0.94). Lesion location is not important for global strategies such as FreeSurfer or majority voting, where structure segmentation is affected wherever the lesions exist. On the other hand, FIRST is more affected when the lesions are overlaid or close to the structure of analysis. The most affected structure by the presence of lesions is the nucleus accumbens (from - 1.12 ± 2.53 to 1.32 ± 4.00 for the left hemisphere and from - 2.40 ± 5.54 to 9.65 ± 9.87 for the right hemisphere), whereas the structures that show less variation include the thalamus (from 0.03 ± 0.35 to 0.74 ± 0.89 and from - 0.48 ± 1.08 to - 0.04 ± 0.22) and the brainstem (from - 0.20 ± 0.38 to 1.03 ± 1.31). The three segmentation approaches are affected by the presence of MS lesions, which demonstrates that there exists a problem in the automatic segmentation methods of the deep gray matter (DGM) structures that has to be taken into account when using them as a tool to measure the disease progression.


Technical and conceptual considerations for performing and interpreting functional MRI studies in awake rats.
Functional neuroimaging studies in rodents have the potential to provide insight into neurodevelopmental and psychiatric conditions. The strength of the technique lies in its non-invasive nature that can permit longitudinal functional studies in the same animal over its adult life. The relatively good spatial and temporal resolution and the ever-growing database on the biological and biophysical basis of the blood oxygen level dependent (BOLD) signal make it a unique technique in preclinical neuroscience research. Our laboratory has used imaging to investigate brain activation in awake rats following cocaine administration and during the presentation of lactation-associated sensory stimuli. Factors that deserve attention when planning functional magnetic resonance imaging studies in rats include technical issues, animal physiology and interpretability of the resulting data. The present review discusses the pros and cons of animal imaging with a particular focus on the technical aspects of studies with awake rats. Overall, the benefits of the technique outweigh its limitations and the rapidly evolving methods will open the way for more laboratories to employ the technique in neuroscience research.


Positive family history of prostate cancer not associated with worse outcomes after radical prostatectomy.
To determine the clinical outcomes in men with (FH) and without (NFH) a family history of prostate cancer after radical prostatectomy. We performed a retrospective analysis of 557 men with localized prostate cancer treated by radical prostatectomy between 1989 and 2000. We defined a positive FH as having one or more first-degree relatives such as a father or brother with prostate cancer. The clinical and pathologic features, as well as biochemical disease-free survival, defined as an undetectable prostate-specific antigen level (less than 0.2 ng/mL), were compared between the FH and NFH groups. Compared with the NFH group, the FH men were younger at surgery (median 62 years versus 64 years, P = 0.01), had a lower median preoperative prostate-specific antigen level (7.2 ng/mL versus 7.8 ng/mL, P = 0.05), and were more likely to have only low-grade disease at the final pathologic evaluation (26.2% versus 17.8%, P = 0.05). At a median follow-up of 7.5 years (mean 7.6 +/- 2.9 years), 17% of the FH group had biochemical disease recurrence compared with 30% in the NFH group. The actuarial disease-free survival rate at 5 and 10 years for the two groups was 86% and 80% compared with 73% and 66%, respectively (P = 0.01). When controlled for pathologic variables in a multivariate analysis, FH was not an independent predictor of disease-free survival. The association of improved disease-free survival in the FH patients may have been driven by an earlier age at diagnosis and more favorable pathologic features.


Neutrophils promote 6-sulfo LacNAc+ dendritic cell (slanDC) survival.
There is increasing evidence supporting the notion that neutrophils and other leukocytes establish cooperative actions in regulating innate and adaptive immune responses. In such a context, we have shown recently that human neutrophils amplify NK cell/slanDC-mediated cytokine production by directly costimulating IFN-γ production by NK cells, as well as by potentiating IL-12p70 release by slanDCs via CD18/ICAM-1 interactions. To gain more insights into the molecular bases of the neutrophil-mediated cytokine potentiation by NK cells and slanDCs under coculture conditions, we now report that neutrophils efficaciously maintain slanDC survival by contact-dependent mechanisms. Such a phenomenon occurs in the absence or presence of NK cells, which, in the presence of LPS and IL-2 or the IL-15/IL-18 combination, accelerates slanDC apoptosis significantly. Noteworthy, αICAM-1- and αCD18-neutralizing antibodies, previously shown to suppress IL-12p70 production by slanDCs and consequently, IFN-γ by NK cells under similar experimental conditions, did not minimally alter the neutrophil-mediated prosurvival effect on slanDCs. Altogether, data not only expand our knowledge on the interactions between human neutrophils and slanDCs but also prove that neutrophil-mediated promotion of slanDC survival and potentiation of slanDC-derived IL-12p70 occur via different mechanisms.


Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A.
Recent reports have suggested that the incidence of inhibitors in haemophilia is the highest in those first exposed to factor VIII under 6 months of age. In this study, we investigated inhibitor development in children first exposed to FVIII as neonates and also examined the effect of other genetic and environmental variables. Three hundred and forty-eight children with severe haemophilia A were investigated. Inhibitors developed in 68 of 348 (20%), with 34 of 348 (10%) high titre inhibitors. The incidence in relation to initial FVIII exposure was: <1 month nine of 35 (26%), 1-6 months 13 of 51 (25%), 6-12 months 27 of 130 (21%), 12-18 months 13 of 66 (20%) and >18 months six of 66 (9%). While we observed a significant difference in inhibitor development and age at first exposure across all age groups (P = 0.018), no significant difference was observed in children treated at different time points during the first year of life (P = 0.44). Similar results were obtained for high titre inhibitors. There was also no difference in the incidence of inhibitors in relation to initial FVIII exposure in a subgroup of 144 children with the intron 22 mutation. Inhibitors developed more frequently in those initially treated with recombinant when compared with plasma-derived FVIII (P = 0.006) and in those with a major molecular defect (P = 0.009). In this study, exposure to FVIII during the neonatal period was not associated with a higher incidence of inhibitors than those treated later during the first year of life. Initial treatment with recombinant FVIII and the presence of a major molecular defect were the most important variables affecting inhibitor development.


Studies on the DIDS-binding site of monocarboxylate transporter 1 suggest a homology model of the open conformation and a plausible translocation cycle.
Site-directed mutagenesis of MCT1 was performed on exofacial lysines Lys(38), Lys(45), Lys(282), and Lys(413). K38Q-MCT1 and K38R-MCT1 were inactive when expressed at the plasma membrane of Xenopus laevis oocytes, whereas K45R/K282R/K413R-MCT1 and K45Q/K282Q/K413Q-MCT1 were active. The former exhibited normal reversible and irreversible inhibition by DIDS, whereas the latter showed less reversible and no irreversible inhibition. K45Q/K413Q-MCT1 retained some irreversible inhibition, whereas K45Q/K282Q-MCT1 and K282Q/K413Q-MCT1 did not. These data suggest that the two DIDS SO(3)(-) groups interact with positively charged Lys(282) together with Lys(45) and/or Lys(413). This positions one DIDS isothiocyanate group close to Lys(38), leading to its covalent modification and irreversible inhibition. Additional mutagenesis revealed that DIDS cross-links MCT1 to its ancillary protein embigin using either Lys(38) or Lys(290) of MCT1 and Lys(160) or Lys(164) of embigin. We have modeled a possible structure for the outward facing (open) conformation of MCT1 by employing modest rotations of the C-terminal domain of the inner facing conformation modeled previously. The resulting model structure has a DIDS-binding site consistent with experimental data and locates Lys(38) in a hydrophobic environment at the bottom of a substrate-binding channel. Our model suggests a translocation cycle in which Lys(38) accepts a proton before binding lactate. Both the lactate and proton are then passed through the channel via Asp(302-) and Asp(306+), an ion pair already identified as important for transport and located adjacent to Phe(360), which controls channel selectivity. The cross-linking data have also been used to model a structure of MCT1 bound to embigin that is consistent with published data.


An ultrastructural analysis of plasma membrane in the U18666A cataract.
Because the cholesterol concentration of lens fiber cell membrane in general and lens intercellular junctions in particular is comparatively high, it is likely that it plays a major role in maintaining these structures. In addition, the high concentration of cholesterol in fiber cell membrane is also likely to influence membrane fluidity. Subcutaneous injections of U18666A (3 beta-(2-diethylaminoethoxy) androst-5-en-17-one HCl) into rats effects: (1) a blockade of sterolgenesis in the lens; (2) a depletion of lens fiber cell membrane cholesterol; and (3) the development of irreversible nuclear cataracts. In the present study we have analyzed the ultrastructure of lens fiber cell membrane in adult rats, these by the freeze-etch technique. Whereas it has been previously demonstrated that intercellular junctions comprise approximately one-third of the intermediate cortical fiber cell membrane in adult rats, these junctions were completely absent between comparable fiber cells taken from opaque regions of the U18666A cataractous lenses. There was also a concomitant increase in the extracellular space between the opaque fiber cells and a substantial redistribution of intramembrane proteins in the exoplasmic and protoplasmic faces of these cells. These findings support a "hypothesis" that inhibition of endogenous lens cholesterol production leads to damage and/or degeneration of lens fiber cell membrane in general and in intercellular junctions in particular, resulting in the production of an irreversible nuclear cataract.


Aberrant activation of ubiquitin D at G2 phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats.
We have previously reported that renal carcinogens examined in rats increase tubular cell proliferation and topoisomerase (Topo) IIα(+) cells. The present study was aimed at identifying early prediction markers of carcinogens after 28-day treatment in rats. Following gene expression screening by microarrays in renal tubules with renal carcinogens, immunohistochemical analysis and TUNEL-assay were performed with carcinogens targeting different organs. All renal carcinogens tested (ferric nitrilotriacetic acid, ochratoxin A (OTA), monuron, tris(2-chloroethyl) phosphate, and potassium bromate) increased tubular cells immunoreactive for minichromosome maintenance 3 (Mcm3) or ubiquitin D (Ubd) or those showing apoptosis, compared with untreated controls or non-carcinogenic renal toxicants. Carcinogens targeting the liver (thioacetamide (TAA), fenbendazole, piperonyl butoxide (PBO) and methyleugenol), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole), glandular stomach (catechol), and colon (chenodeoxycholic acid and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) were examined for induction of Mcm3, Ubd, Topo IIα, Ki-67 and apoptosis using non-carcinogenic toxicants as negative controls. All carcinogens increased Mcm3(+), Ubd(+), Topo IIα(+), Ki-67(+) or TUNEL(+) cells, except for hepatocarcinogen PBO and both colon carcinogens, which did not increase cell proliferation. Ubd(+) cells co-expressing Topo IIα was increased without changing phospho-Histone H3-co-expressing cell population as examined with OTA and TAA. Results revealed cooperative responses of Topo IIα, Ubd and apoptosis by carcinogens inducing high proliferation activity, irrespective of target organs, examined here after a 28-day administration. Aberrant expression of Ubd at G(2) phase and increased apoptosis reflecting aberrant cell cycle regulation may be the common feature of these carcinogens.


The evaluation of interior lighting on the basis of visual criteria.
Contrast sensitivity and visual acuity data are used to derive a unified visual performance contour which describes the generalized improvement in visual performance resulting as task background luminance is increased. Factors which influence the difficulty of visual tasks are described, and examples are given of the degree of task background luminance, and hence illuminance, required to permit criterion levels of performance for sample tasks. Physical principles and devices are described which permit measurements of: (a) task object contrast, (b) the integral of ocular light scatter which reduces task image contrast, and (c) the joint effect of luminance differences in the environment which produce transitional adaptive effects on visual performance. These physical aspects of luminous environments are shown to influence visual performance in quantitative ways which may be assessed by reference to the standard performance contour. An over-all lighting performance index is derived which takes account of the ta background luminance and these three other measures of the effects physical aspects of luminous environments have upon visual performance. Lighting performance indices are presented for five sample lighting installations, which reveal the overriding importance of other aspects of luminous environments than the level of illuminance they provide. The problem of predicting the over-all visual performance to be expected from specific luminous environments in advance of construction is discussed, and empirically derived calculational methods are described.


Clinical comparison of the effectiveness of novel sonic instruments and curettes for periodontal debridement after 2 months.
The aim of this study was to evaluate in vivo the effectiveness of scaling and root planing of new oscillating instruments (Periosonic) using a sonic handpiece compared to hand curettes with a split mouth design after 2 months. 11 patients with adult periodontitis participated in this study. Plaque index (PII) (O'Leary), bleeding on probing (BOP), probing pocket depth (PPD), recession (REC) and clinical attachment level (CAL) were recorded at baseline and 2 months after treatment. After oral hygiene instruction, 2 randomly assigned quadrants per patient were scaled and root planed with curettes (control side) and the remaining 2 quadrants with the Periosonic instruments 1 and 2 (test side). The student t-test for paired data was used to test the significance of difference between test and control sides. There was no statistical difference (p>0.05) between the 2 sides for the improvement of the clinical parameters excepted for the group with initial PPD of 4-6 mm (test: 1.3+/-0.4 mm PPD reduction, control: 1.6+/-0.4 mm). For PPD > or =7 mm, the test side had better clinical improvement in attachment levels (2.2+/-0.9 mm), less recession (-0.4+/-0.5 mm) with lower PPD reduction (2.4+/-0.6 mm) than the control side (AL: 1.6+/-1.8 mm; REC: -1.3+/-0.7 mm, PPD reduction: 3.0+/-1.4 mm). This clinical study demonstrated that Periosonic(R) instruments are clinically at least as effective as curettes in PPD reduction when initial PPD is < or =6 mm and show better clinical attachment level improvement with less recession for initial PPD of > or =7 mm.


Farmers' stress and coping in a time of drought.
Farmers as a group have unique attitudes, sources of stress and a heightened risk of suicide. In the context of a prolonged drought and associated stress and increased risk of mental-health problems, this study provides an insight into the levels of psychological distress experienced by different demographic groups within the Australian farming community. The study also addresses a significant gap in the literature by exploring ways in which this unique cohort copes and may better cope, with the inevitable challenges of life 'on the land'. A sample of 309 drought-affected South Australian farmers and their spouses (M=51.81, SD=11.69) completed questionnaires containing measures of psychological distress (Kessler Psychological Distress Scale) and coping (situational version of the COPE) in response to a recent stressor. There was no significant difference detected between the levels of distress reported by men and women. Younger farmers (25-54 years) were experiencing significantly higher levels of distress than those in the 55-64 age group but not those aged 65-74 years. The most commonly employed coping strategies were planning, acceptance and active coping and least used were alcohol/drug use, denial, behavioural disengagement and religion. Gender, age-group and the type of stressor (ie farm related, non-farm related, combination) were found to affect farmers' choice of some coping strategies. A multiple regression analysis suggested that behavioural disengagement (&#946;=.28, p < .05), suppression of competing activities (&#946;= .20, p < .05), venting (&#946;= .18, p < .05), alcohol/drug use (&#946;= .18, p < .05), and mental disengagement (&#946;=.12, p < .05) all significantly and positively predicted distress in this population, collectively accounting for 34.6% of the variance. This study offers a rare examination of farmers' psychological distress and coping in a time of drought. The results demonstrate that in this unique context it is erroneous to assume the universality of models of coping that have been validated in other samples. The results provide for the development of tailored interventions to help farmers cope more effectively during future times of drought.


Novel fusion sarcomas including targetable NTRK and ALK.
Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. Fusion sarcomas (2020-2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.


Leaf and fine root carbon stocks and turnover are coupled across Arctic ecosystems.
Estimates of vegetation carbon pools and their turnover rates are central to understanding and modelling ecosystem responses to climate change and their feedbacks to climate. In the Arctic, a region containing globally important stores of soil carbon, and where the most rapid climate change is expected over the coming century, plant communities have on average sixfold more biomass below ground than above ground, but knowledge of the root carbon pool sizes and turnover rates is limited. Here, we show that across eight plant communities, there is a significant positive relationship between leaf and fine root turnover rates (r(2) = 0.68, P < 0.05), and that the turnover rates of both leaf (r(2) = 0.63, P < 0.05) and fine root (r(2) = 0.55, P < 0.05) pools are strongly correlated with leaf area index (LAI, leaf area per unit ground area). This coupling of root and leaf dynamics supports the theory of a whole-plant economics spectrum. We also show that the size of the fine root carbon pool initially increases linearly with increasing LAI, and then levels off at LAI = 1 m(2) m(-2), suggesting a functional balance between investment in leaves and fine roots at the whole community scale. These ecological relationships not only demonstrate close links between above and below-ground plant carbon dynamics but also allow plant carbon pool sizes and their turnover rates to be predicted from the single readily quantifiable (and remotely sensed) parameter of LAI, including the possibility of estimating root data from satellites.


Suppression of in vitro antibody response by a serum factor (SAA) in experimentally induced amyloidosis.
Serum from CBA/J mice made amyloidotic by chronic casein injections has been shown to suppress in vitro antibody response to SRBC. Similar suppression was also found with normal mouse serum but to a much lesser degree. This suppressive activity of both amyloidotic serum and normal serum was removed by absorption of the sera with antiserum to protein AA, the major constituent of casein-induced (secondary) amyloid fibrils. This antiserum to the amyloid fibril protein AA (mol wt 8,400 daltons) detects an immunologically cross-reacting serum alpha globulin (SAA) (mol wt approx. 100,000). It is postulated that the serum factor (SAA) is a regulator of antibody response and may be present in elevated amounts as the result of chronic antigenic stimulation.


Acquisition, retention, and generalization of rhotics with and without ultrasound visual feedback.
The purpose was to provide a preliminary within-participant comparison of speech therapy with and without exposure to ultrasound visual feedback for postvocalic rhotics (/r/- colored vowels). Effects of the two treatments on acquisition, retention, and generalization were explored. It was hypothesized that treatment with ultrasound would facilitate acquisition but hinder retention and generalization. A single subject randomized block design was replicated across four American English-speaking participants ages 7-9 years. Each participant was trained on postvocalic /r/. Each week for seven weeks, one session with ultrasound visual feedback and one session with no ultrasound were randomly ordered. A Training Probe and Generalization Probe were used to measure acquisition within each session as well as retention and generalization between two consecutive sessions. Graphical displays of the data, effect size calculation, and statistical results from a randomization test were used to analyze the results. Two participants showed essentially no evidence of acquisition, retention or generalization of rhotics (<5%). Of the two who showed evidence of acquisition, one participant showed a significant advantage and large effect size for ultrasound sessions over no ultrasound sessions in acquisition of rhotics. However, no participants showed differences between treatment conditions in generalization or retention of rhotics. For some children, acquisition may be facilitated by ultrasound visual feedback. Ultrasound visual feedback neither inhibited nor facilitated retention or generalization of rhotics. As a whole, the 14 treatment sessions (7 with ultrasound and 7 without) were effective for 2 of the 4 participants when comparing pre/post generalization scores. Future studies should evaluate the effectiveness of ultrasound visual feedback given a larger dose and differing age groups.


A seamless three-dimensional carbon nanotube graphene hybrid material.
Graphene and single-walled carbon nanotubes are carbon materials that exhibit excellent electrical conductivities and large specific surface areas. Theoretical work suggested that a covalently bonded graphene/single-walled carbon nanotube hybrid material would extend those properties to three dimensions, and be useful in energy storage and nanoelectronic technologies. Here we disclose a method to bond graphene and single-walled carbon nanotubes seamlessly during the growth stage. The hybrid material exhibits a surface area >2,000 m(2) g(-1) with ohmic contact from the vertically aligned single-walled carbon nanotubes to the graphene. Using aberration-corrected scanning transmission electron microscopy, we observed the covalent transformation of sp(2) carbon between the planar graphene and the single-walled carbon nanotubes at the atomic resolution level. These findings provide a new benchmark for understanding the three-dimensional graphene/single-walled carbon nanotube-conjoined materials.


Anti-inflammatory effect of acetylharpagide demonstrated by its influence on leukocyte adhesion and transmigration in endothelial cells under controlled shear stress.
This research was aimed to investigate the anti-inflammatory mechanism of acetylharpagide extracted from Ajuga decumbens Thunb. Human umbilical vein endothelial cells (HUVECs) and human monocytic leukemia cell line THP-1 were employed as experimental materials. The MTT assay (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) was used to determine the safe dose range of acetylharpagide. TNF-α (20 ng/ml) was used to model THP-HUVECs adhesion/transmigration and trypsin was used to model wounding of HUVECs under controlled shear stress of 0.1 Pa and 0.2 Pa (5 h) by Bioflux1000 assays accordingly. Effects of acetylharpagide were dynamically monitored by microscopic time-lapse photography. Acetylharpagide within the concentration of 0-200 μM showed no sign of toxicity to HUVECs and THP-1. Acetylharpagide dose-dependently inhibited THP-1 adhesion to TNF-α activated HUVECs monolayer with an IC50 of 171 μM under static conditions. Acetylharpagide at 200 μM inhibited leukocyte adhesion and transmigration to HUVECs monolayer activated by TNF-α under 0.1 Pa shear stress (P < 0.05). The compound at 200 μM also inhibited HUVECs migration under 0.2 Pa in the wound healing model compared with the control group (P < 0.05). In conclusion, the anti-inflammatory effects of acetylharpagide are possibly related to inhibiting leukocytes adhesion and transmigration. Moreover, acetylharpagide also inhibits the endothelial cells migration notably, which might be the additional action responsible for its effect in reliving-chronic inflammatory progress.


Treatment-independent, treatment-associated, and pregnancies after additional therapy in a program of in vitro fertilization and embryo transfer.
Although the technique of in vitro fertilization and embryo transfer (IVF-ET) was developed for couples with untreatable tubal factor infertility, IVF-ET is now being applied to women with other causes of infertility and normal pelvic anatomy. In an effort to determine the treatment-independent pregnancy rate, we retrospectively reviewed the first 245 couples enrolled in the IVF-ET program at Duke University Medical Center. There were 19 treatment-independent pregnancies in 18 women and 3 treatment-associated pregnancies in cycles in which the oocyte retrieval was canceled (in 2 women washed intrauterine insemination was substituted for oocyte retrieval). Six pregnancies were established after an unsuccessful attempt at IVF-ET with additional non-IVF-ET therapy, including washed intrauterine insemination in three couples, and donor insemination in two couples. These observations suggest that a significant number of treatment-independent pregnancies will occur in couples clinically deemed appropriate for IVF-ET, pregnancies can be established in cycles of controlled hyperstimulation without oocyte retrieval, and additional non-IVF-ET therapy can result in pregnancy despite failure of IVF-ET in selected couples.


Protein phosphorylation analysis based on proton release detection: potential tools for drug discovery.
Phosphorylation is the most important post-translational modification of proteins in eukaryotic cells and it is catalysed by enzymes called kinases. The balance between protein phosphorylation and dephosphorylation is critical for the regulation of physiological processes and its unbalance is the cause of several diseases. Conventional assays used to analyse the kinase activity are limited as they rely heavily on phospho-specific antibodies and radioactive tags. This makes their use impractical for high throughput drug discovery platforms. We have developed two versatile methods to detect the release of protons (H(+)) associated with the protein phosphorylation catalysed by kinases. The first approach is based on the pH-sensitive response of oxide-semiconductor interfaces and the second method detects the pH changes in phosphorylation reaction using a commercial micro-pH electrode. The proposed methods successfully detected phosphorylation of myelin basic protein by PKC-α kinase. These techniques can be readily adopted for multiplexed arrays and high throughput analysis of kinase activity, which will represent an important innovation in biomedical research and drug discovery.


Demineralization effects of phosphoric acid on surface and subsurface bovine enamel bleached with in-office hydrogen peroxide.
To measure the demineralization capacity of 37% phosphoric acid on surface and subsurface bovine enamel after bleaching with hydrogen peroxide (H2O2). Three equally-sized sections with 16 mm2 of exposed enamel surface were obtained from the enamel of 10 bovine incisors. One specimen sample from each crown was assigned to one of three groups (n = 10): group I, no bleaching agent; group II, bleached with 38% H202 for 20 min; or group III, 30% H202 for 60 min. After 24 h, the thickness of specimens was measured and they were immersed in 37% phosphoric acid solution, of which 5-ml aliquots were collected at 30 s and 60 s. Specimens were then ground to a depth of 25 μm and again immersed in 37% phosphoric acid solution. This procedure was repeated for enamel depths of 50 and 100 μm. Ca2+ concentrations in the phosphoric acid aliquots were measured by atomic absorption spectroscopy. No significant differences were found in the total amounts of extracted Ca2+ between bleached and unbleached specimens (F = 0.142; p = 0.869). The amount of Ca2+ extracted was similar among the four depth levels in the unbleached and in the 30% H202 bleached specimens. A significantly larger amount of Ca2+ was obtained at 25 μm depth (subsurface) from specimens treated with 38% H202. Pre-bleaching with 38% H202 significantly increased the decalcifying effect of phosphoric acid on subsurface enamel at a depth of 25 μm compared to 100 μm, whereas pre-bleaching with 30% H202 did not modify this effect at any level.


Combatting the Increasing Threat of Vector-Borne Disease in the United States with a National Vector-Borne Disease Prevention and Control System.
Reported cases of vector-borne diseases in the United States have more than tripled since 2004, characterized by steadily increasing incidence of tick-borne diseases and sporadic outbreaks of domestic and invasive mosquito-borne diseases. An effective public health response to these trends relies on public health surveillance and laboratory systems, proven prevention and mitigation measures, scalable capacity to implement these measures, sensitive and specific diagnostics, and effective therapeutics. However, significant obstacles hinder successful implementation of these public health strategies. The recent emergence of Haemaphysalis longicornis, the first invasive tick to emerge in the United States in approximately 80 years, serves as the most recent example of the need for a coordinated public health response. Addressing the dual needs for innovation and discovery and for building state and local capacities may overcome current challenges in vector-borne disease prevention and control, but will require coordination across a national network of collaborators operating under a national strategy. Such an effort should reduce the impact of emerging vectors and could reverse the increasing trend of vector-borne disease incidence and associated morbidity and mortality.


2D, 3D and 4D active compound delivery in tissue engineering and regenerative medicine.
Recent advances in tissue engineering and regenerative medicine have shown that controlling cells microenvironment during growth is a key element to the development of successful therapeutic system. To achieve such control, researchers have first proposed the use of polymeric scaffolds that were able to support cellular growth and, to a certain extent, favor cell organization and tissue structure. With nowadays availability of a large pool of stem cell lines, such approach has appeared to be rather limited since it does not offer the fine control of the cell micro-environment in space and time (4D). Therefore, researchers are currently focusing their efforts on developing strategies that include active compound delivery systems in order to add a fourth dimension to the design of 3D scaffolds. This review will focus on recent concepts and applications of 2D and 3D techniques that have been used to control the load and release of active compounds used to promote cell differentiation and proliferation in or out of a scaffold. We will first present recent advances in the design of 2D polymeric scaffolds and the different techniques that have been used to deposit molecular cues and cells in a controlled fashion. We will continue presenting the recent advances made in the design of 3D scaffolds based on hydrogels as well as polymeric fibers and we will finish by presenting some of the research avenues that are still to be explored.


Automatic extraction of mandibular nerve and bone from cone-beam CT data.
The exact localization of the mandibular nerve with respect to the bone is important for applications in dental implantology and maxillofacial surgery. Cone beam computed tomography (CBCT), often also called digital volume tomography (DVT), is increasingly utilized in maxillofacial or dental imaging. Compared to conventional CT, however, soft tissue discrimination is worse due to a reduced dose. Thus, small structures like the alveolar nerves are even harder recognizable within the image data. We show that it is nonetheless possible to accurately reconstruct the 3D bone surface and the course of the nerve in a fully automatic fashion, with a method that is based on a combined statistical shape model of the nerve and the bone and a Dijkstra-based optimization procedure. Our method has been validated on 106 clinical datasets: the average reconstruction error for the bone is 0.5 +/- 0.1 mm, and the nerve can be detected with an average error of 1.0 +/- 0.6 mm.


Primary localized orbital amyloidosis composed of the immunoglobulin gamma heavy chain CH3 domain.
1. Primary orbital amyloidosis is a rare form of localized amyloidosis in which the precursor protein has not previously been identified. We report here the first extraction of amyloid fibrils from a tissue biopsy containing orbital amyloid, and characterization of the fibril protein. 2. The N-terminal nine residues were identical with residues 278-286 and 275-283 of the third constant (CH3) domains of IgG1 and IgG4 gamma heavy chains, respectively. The mass of the fibril subunit protein was 6125Da by time-of-flight mass spectrometry, compared with the expected masses of 6169.9Da and 6214.9Da for the CH3 domains of gamma 1 from residue 278 and gamma 4 from residue 275, respectively. The fibril protein thus appeared to consist exclusively of an immunoglobulin heavy chain constant domain. 3. Only two examples of immunoglobulin heavy chain derived amyloid have been reported previously and both of these, as well as all published cases of the usual immunoglobulin light chain derived amyloid, contained variable domain sequence. The present case therefore represents a form of local, presumably clonal, B-cell/plasma-cell disorder characterized uniquely by deposition of an amyloidogenic immunoglobulin heavy chain constant domain fragment.


Complex adaptive systems: a new approach for understanding health practices.
This article explores the potential of complex adaptive systems (CAS) theory to inform behaviour change research. A CAS describes a collection of heterogeneous agents interacting within a particular context, adapting to each other's actions. In practical terms, this implies that behaviour change is (1) socially and culturally situated; (2) highly sensitive to small baseline differences in individuals, groups, and intervention components; and (3) determined by multiple components interacting 'chaotically'. Two approaches to studying CAS are briefly reviewed. Agent-based modelling is a computer simulation technique that allows researchers to investigate 'what if' questions in a virtual environment. Applied qualitative research techniques, on the other hand, offer a way to examine what happens when an intervention is pursued in real-time, and to identify the sorts of rules and assumptions governing social action. Although these represent very different approaches to complexity, there may be scope for mixing these methods - for example, by grounding models in insights derived from qualitative fieldwork. Finally, I will argue that the concept of CAS offers one opportunity to gain a deepened understanding of health-related practices, and to examine the social psychological processes that produce health-promoting or damaging actions.


Rh-catalyzed Reagent-Free Ring Expansion of Cyclobutenones and Benzocyclobutenones.
Here we report a reagent-free rhodium-catalyzed ring-expansion reaction via C-C cleavage of cyclobutenones. A variety of poly-substituted cyclopentenones and 1-indanones can be synthesized from simple cyclobutenones and benzocyclobutenones. The reaction condition is near pH neutral without additional oxidants or reductants. The potential for developing a dynamic kinetic asymmetric transformation of this reaction has also been demonstrated. Further study supports the proposed pathway involving Rh-insertion into the cyclobutenone C-C bond, followed by β-hydrogen elimination, olefin insertion and reductive elimination.


Interventions to achieve ongoing exercise adherence for adults with chronic health conditions who have completed a supervised exercise program: systematic review and meta-analysis.
To determine which exercise adherence interventions are most effective for achieving ongoing exercise adherence in adults with chronic health conditions who had already completed a supervised short-term program. Search of MEDLINE (Ovid Medline 1946 to April 8th, 2016), EMBASE (1980 to April 8th, 2016), CINAHL (1982-April 8th 2016) and the Cochrane Central Register of Controlled Trials was conducted. The chronic health conditions search terms as per the Chronic Disease and Participation in Work AIHW Report, 2008. Included were randomised (or quasi-randomised) trials and observational studies evaluating interventions that aimed to improve exercise adherence in adults with chronic health conditions that had completed a supervised exercise program. Random-effects meta-analyses and random-effects logistic meta-regression were used to examine relationships between exercise adherence strategy and adherence. Eleven studies were included with a total of 1231 participants with Chronic Obstructive Pulmonary Disease, Diabetes, Cardiovascular disease or Osteoarthritis. Methods used for maintaining adherence were categorized post hoc as: centre based programs; home exercise programs with telephone follow-up; home exercise programs with no follow-up; and weaning programs that transitioned patients to an independent, off-site exercise program. There was no difference in the proportion of participants who were fully adherent to an exercise program 12 months between the centre-based follow-up (pooled proportion fully adherent=0.34) and telephone follow-up (pooled proportion fully adherent=0.30, difference p-value=0.75). Interventions such as centre-based exercise programs or home exercise programs (with or without telephone follow-up) do not differentially impact exercise adherence for people who have completed a short-term supervised program.