The Impact of Pancreatic Beta Cell Heterogeneity on Type 1 Diabetes Pathogenesis.
To discuss advances in our understanding of beta-cell heterogeneity and the ramifications of this for type 1 diabetes (T1D) and its therapy. A number of studies have challenged the long-standing dogma that the majority of beta cells are eliminated in T1D. As many as 80% are present in some T1D subjects. Why don't these cells function properly to release insulin in response to high glucose? Other findings deploying single-cell "omics" to study both healthy and diseased cells-from patients with both T1D and type 2 diabetes (T2D)-have revealed cell subpopulations and heterogeneity at the transcriptomic/protein level between individual cells. Finally, our own and others' findings have demonstrated the importance of functional beta-cell subpopulations for insulin secretion. Heterogeneity may endow beta cells with molecular features that predispose them to failure/death during T1D.


Predictors of adherence to a physical activity counseling intervention delivered by exercise physiologists: secondary analysis of the NewCOACH trial data.
General practitioners (GPs) cite time as a barrier to physical activity counseling. An alternative for time-poor GPs in Australia is the referral of insufficiently active patients to exercise physiologists (EPs). As data on the predictors of adherence to physical activity counseling interventions are limited, this study aimed to identify the sociodemographic, medical, health, and psychological characteristics of insufficiently active primary care patients who adhered to a physical activity counseling intervention delivered by EPs. This secondary analysis of data from the NewCOACH randomized trial used logistic regression to identify predictors of adherence, defined as patient participation in at least four of the five physical activity counseling sessions. EPs provided information about the number of sessions, while other potential predictors were obtained from the self-administered baseline questionnaire and medical summary sheets provided by the GPs. Of the 132 patients referred to an EP, 102 (77%) were adherent: 91 (69%) and eleven (8.3%) participated in all, or all but one, of the sessions, respectively. Of the remainder, seven (5.3%) patients participated in three sessions, seven (5.3%) participated in two sessions, five (3.8%) participated in one session, and eleven (8.3%) did not participate in any session. The odds of being adherent were 5.84 (95% CI 1.46-23.4, P≤0.05) times higher among retired participants than in those who were not in paid employment. The odds of being adherent 1) increased as the positive outcome expectation score increased (OR 1.89, 95% CI 1.12-3.18, P≤0.05) and 2) decreased as the duration (days) between referral and the initial counseling session increased (OR 0.95, 95% CI 0.92-0.98, P<0.01). More than three quarters of the patients participated in all, or all but one, of the sessions. Being retired, positive outcome expectations, and having a shorter wait between referral and the initial appointment predicted adherence.


Myosin VIIA, important for human auditory function, is necessary for Drosophila auditory organ development.
Myosin VIIA (MyoVIIA) is an unconventional myosin necessary for vertebrate audition [1]-[5]. Human auditory transduction occurs in sensory hair cells with a staircase-like arrangement of apical protrusions called stereocilia. In these hair cells, MyoVIIA maintains stereocilia organization [6]. Severe mutations in the Drosophila MyoVIIA orthologue, crinkled (ck), are semi-lethal [7] and lead to deafness by disrupting antennal auditory organ (Johnston's Organ, JO) organization [8]. ck/MyoVIIA mutations result in apical detachment of auditory transduction units (scolopidia) from the cuticle that transmits antennal vibrations as mechanical stimuli to JO. Using flies expressing GFP-tagged NompA, a protein required for auditory organ organization in Drosophila, we examined the role of ck/MyoVIIA in JO development and maintenance through confocal microscopy and extracellular electrophysiology. Here we show that ck/MyoVIIA is necessary early in the developing antenna for initial apical attachment of the scolopidia to the articulating joint. ck/MyoVIIA is also necessary to maintain scolopidial attachment throughout adulthood. Moreover, in the adult JO, ck/MyoVIIA genetically interacts with the non-muscle myosin II (through its regulatory light chain protein and the myosin binding subunit of myosin II phosphatase). Such genetic interactions have not previously been observed in scolopidia. These factors are therefore candidates for modulating MyoVIIA activity in vertebrates. Our findings indicate that MyoVIIA plays evolutionarily conserved roles in auditory organ development and maintenance in invertebrates and vertebrates, enhancing our understanding of auditory organ development and function, as well as providing significant clues for future research.


Effect of laser annealing on photoluminescence properties of phosphorus implanted ZnO nanorods.
The effect of the nanosecond laser annealing on the photoluminescence (PL) property of phosphorus ions (P(+)) implanted ZnOnanorods (NRs) has been investigated. The nanosecond laser annealing was performed with the third harmonic of a Q-switched Nd:YAG laser (355nm, 10ns/pulse) at a fluence of 100mJ/cm(2). It turned out that nanosecond laser annealing is more effective in the recovery of the PL property compared with the thermal annealing using an electric furnace. As the results, the I-V characteristics of the p-n homojunctions along ZnO NRs showed rectifying property with a threshold voltage of approximately 6V.


Monkey pulpal response to an MMA-based resin cement as adhesive luting for indirect restorations.
The objective of this study was to evaluate the pulpal response to a newly-developed MMA resin cement (MultiBond, Tokuyama) when used for adhesively luting composite resin inlays. Cervical cavities were prepared in monkey teeth. The teeth were randomly divided into 3 groups. In the experimental group, a self-etching primer and a resin cement were applied to the cavities, and then hybrid composite inlays (Estenia, Kuraray) were inserted using freshly mixed resin cement. In the other groups, a zinc oxide/eugenol cement (Eugedain, Showa Yakuhin Kakou) or a glass-ionomer cement (Fuji II, GC) was used to fill the cavity. The teeth were then extracted after 3, 30, and 90 days, fixed in 10% buffered formalin solution, and prepared using routine histological techniques. Five-mum-thick sections were stained with hematoxylin and eosin, or Brown & Brenn gram stain for bacterial observation. Histopathological reactions in the pulp tissue and bacterial penetration along the cavity walls were assessed using a standardized score. No serious inflammatory reactions in the pulp, such as necrosis or abscess formation, were observed in any of the experimental periods, except for 1 case after 30 days, in which a pulpal exposure was suspected. Disarrangement of the odontoblast layer and deposition of reparative dentin were the major reactions observed in this specimen. No bacterial penetration along the cavity walls was detected. The monkey pulpal response and in vivo sealing ability of the MMA resin cement in combination with the self-etching primer was considered as good as that of the glass-ionomer cement. The new MMA resin cement showed acceptable biological compatibility to the monkey pulp when used to adhesively lute composite resin inlays.


Cooperativity and proton transfer in hydrogen-bonded triads.
Ab initio MP2/6-311+G(3df,2pd) and MP2/aug-cc-pVTZ calculations have been carried out to investigate the structures and properties of AHXHYH(3) (A=F, Cl; X=F, Cl; Y=N, P) hydrogen-bonded complexes. Significant cooperative effects are observed in the XHYH3 dyads in the triads due to the presence of the polar near-neighbor AH. These effects are greater when the polar partner is HF, which is a better proton donor than HCl. Structural changes, red shifts of proton-donor stretching frequencies, nonadditive interaction energies, and electron density redistributions unambiguously demonstrate that the X--HY hydrogen bond (HB) is stronger in the triads than in the corresponding dyads, while the X--H bond of the proton donor becomes weaker. Even more pronounced cooperative effects are observed in the AHXH dyads due to the presence of the YH3 partner. These effects are weaker in complexes having PH3 rather than NH3 as the proton acceptor, since NH3 is a stronger base. Cooperativity also enhances the proton-donating ability of the YH3 moiety, with the result that all complexes except FHFHPH3 are cyclic. Cooperativity, together with the ease of breaking the Cl--H bond in ClHClHNH3 and FHClHNH3, leads to proton transfer (PT), so that these two complexes are better described as approaching hydrogen-bonded ClHCl- x +HNH3 and FHCl- x +HNH3 ion pairs.


Absence of buttock claudication following stent-graft coverage of the hypogastric artery without coil embolization in endovascular aneurysm repair.
To evaluate the safety and efficacy of stent-graft coverage of the hypogastric artery origin without coil embolization during endovascular treatment of aortoiliac or iliac aneurysms. A retrospective study was conducted of patients who underwent endovascular aneurysm repair with endograft coverage of the hypogastric artery between September 2001 and September 2005. Among the 88 patients who underwent EVAR during the study period, 21 patients (19 men; mean age 77+/-6 years, range 67-86) had unilateral hypogastric artery coverage without coil embolization. Aneurysmal arteries included 11 aortoiliac, 8 isolated common iliac arteries (CIA), and 2 isolated hypogastric arteries. Preoperative AAA size was a mean 57 mm (range 46-73), and mean CIA aneurysm diameter was 36 mm (range 17-50). All covered hypogastric arteries were patent prior to the procedure. The stent-grafts implanted were 10 Excluder, 10 AneuRx, and 1 Zenith. Clinical outcome focused on mortality and morbidity, including the occurrence and duration of new-onset buttock claudication, which was further correlated with superior gluteal and profunda femoris artery patency. Immediate seal was achieved in all patients. Mean follow-up was 16 months (range 1-54). No type I endoleaks developed from the aortic or external iliac artery, and no type II endoleaks were found from the origin of the hypogastric artery. New-onset buttock claudication occurred in 2 (9.5%) patients, but resolved in both within 4 months. No additional secondary procedures, aneurysm rupture, or aneurysm-related death occurred. Stent-graft coverage of the orifice of the hypogastric artery without coil embolization is a safe and effective adjunct during the treatment of aortoiliac or iliac aneurysm, with a low incidence of buttock claudication.


Effect of short-term fasting on lipolytic responsiveness in normal and obese human subjects.
In this study the rate of lipolysis (fatty acid and glycerol release into blood) has been quantified in both normal weight and obese volunteers after both 15 and 87 h of fasting. In each study, the basal rate and subsequent response to epinephrine infusion (0.015 microgram X kg-1 X min-1) were determined. The rate of appearance (Ra) of free fatty acids (FFA) and glycerol were quantified by infusion of [1-13C]palmitate and D-5-glycerol, respectively. Substrate flux rates per unit of body fat mass and lean body mass were calculated from total body water measurements using H2(18)O dilution. In normal volunteers, the basal Ra FFA and Ra glycerol rose markedly with 87 h of fasting, whereas the increases were more modest in the obese subjects. However, the rate of mobilization of fat, in relation to the lean body mass, was higher in the obese subjects than in the normal subjects after 15 h of fasting, and the values were similar in both groups after 87 h of fasting. There was an increased lipolytic response to epinephrine after fasting in both groups. This increased sensitivity may have resulted from the enhancement of fatty acid-triglyceride substrate cycling that occurred after fasting.


Spatial Multivariate Trees for Big Data Bayesian Regression.
High resolution geospatial data are challenging because standard geostatistical models based on Gaussian processes are known to not scale to large data sizes. While progress has been made towards methods that can be computed more efficiently, considerably less attention has been devoted to methods for large scale data that allow the description of complex relationships between several outcomes recorded at high resolutions by different sensors. Our Bayesian multivariate regression models based on spatial multivariate trees (SpamTrees) achieve scalability via conditional independence assumptions on latent random effects following a treed directed acyclic graph. Information-theoretic arguments and considerations on computational efficiency guide the construction of the tree and the related efficient sampling algorithms in imbalanced multivariate settings. In addition to simulated data examples, we illustrate SpamTrees using a large climate data set which combines satellite data with land-based station data. Software and source code are available on CRAN at https://CRAN.R-project.org/package=spamtree.


Evidence-based treatment of cancer-related breakthrough pain with opioids.
Opioids are considered important analgesics in the treatment armamentarium for moderate-to-severe background cancer pain. The past decade has seen clinical trials of transmucosal opioid formulations for breakthrough pain in cancer (BTPc), beginning with oral transmucosal fentanyl citrate (OTFC), followed by fentanyl buccal tablet and intranasal fentanyl spray, and most recently sublingual fentanyl tablet, fentanyl buccal soluble film, and fentanyl pectin nasal spray. During that time, enough rigorous evidence has accumulated to support the development of recommendations on treating BTPc with transmucosal formulations. This article describes the randomized controlled trials that have led to the support of the use of transmucosal fentanyl therapies for BTPc, starting in 1999 with OTFC formulations through to the end of 2011. Although oral opioids have been used for historical reasons, evidence supports the use of intravenous morphine or transmucosal fentanyl for treating BTPc, regardless of the opioid being taken to manage background pain. Furthermore, most studies have found no meaningful relationship between the effective dose of transmucosal opioid and the around-the-clock scheduled medication nor the previous rescue medication. The accumulated evidence shows that transmucosal fentanyl formulations provide a rapid effect on BTPc, with adverse events typical of opioids.


Barriers and Facilitators to Implementing Cost-Effective Evidence-Based Childhood Cancer Treatment in a Resource-Limited Setting in Egypt: A Qualitative Interview Study.
Childhood cancer treatment is complex, resource-intensive, and expensive, and resource-limited settings would benefit from providing cost-effective treatment approaches on the basis of evidence. Effective implementation of cost-effective evidence-based treatment requires knowledge about factors influencing its use. In this study, we determined the clinicians' perceptions of the barriers and facilitators to implementing cost-effective evidence-based treatment for children with cancer in a resource-limited pediatric oncology setting in Egypt. We conducted a qualitative study on the basis of semistructured interviews with senior clinicians who make high-level decisions on treatment protocols and tailored decisions for the atypically complicated group of patients. Purposive sampling was used to recruit the participants. Thematic analysis was conducted semantically to develop themes of barriers and facilitators. Fourteen participants agreed to participate in the study: nine pediatric oncologists; three surgeons; and two radiation oncologists. We identified four main themes of barriers and facilitators: awareness and orientation; knowledge, skills, and attitudes; system, resources, and context; and clinical practice. The main barriers included absence of easily available costs/cost-effectiveness data, limited resources and inability to pay for expensive novel (cost-effective) drugs, and gap between evidence and practice. The main facilitators included adopting standard treatment protocols on the basis of clinical effectiveness, leadership support, availability of patients' clinical and cost data from local context, and existing knowledge and skills in clinical research and health economic evaluation. The interview participants also provided suggestions to promote the implementation of cost-effective evidence-based treatment in priority areas. Our study findings provide an understanding of the barriers and facilitators affecting the implementation of cost-effective evidence-based treatment for childhood cancers in Egypt. We provide practical recommendations to address the implementation gaps with implications on practice, policy, and research.


Attend and Predict: Understanding Gene Regulation by Selective Attention on Chromatin.
The past decade has seen a revolution in genomic technologies that enabled a flood of genome-wide profiling of chromatin marks. Recent literature tried to understand gene regulation by predicting gene expression from large-scale chromatin measurements. Two fundamental challenges exist for such learning tasks: (1) genome-wide chromatin signals are spatially structured, high-dimensional and highly modular; and (2) the core aim is to understand what the relevant factors are and how they work together. Previous studies either failed to model complex dependencies among input signals or relied on separate feature analysis to explain the decisions. This paper presents an attention-based deep learning approach, AttentiveChrome, that uses a unified architecture to model and to interpret dependencies among chromatin factors for controlling gene regulation. AttentiveChrome uses a hierarchy of multiple Long Short-Term Memory (LSTM) modules to encode the input signals and to model how various chromatin marks cooperate automatically. AttentiveChrome trains two levels of attention jointly with the target prediction, enabling it to attend differentially to relevant marks and to locate important positions per mark. We evaluate the model across 56 different cell types (tasks) in humans. Not only is the proposed architecture more accurate, but its attention scores provide a better interpretation than state-of-the-art feature visualization methods such as saliency maps.


Improving the organization and interactivity of metabolic pathfinding with precomputed pathways.
The rapid growth of available knowledge on metabolic processes across thousands of species continues to expand the possibilities of producing chemicals by combining pathways found in different species. Several computational search algorithms have been developed for automating the identification of possible heterologous pathways; however, these searches may return thousands of pathway results. Although the large number of results are in part due to the large number of possible compounds and reactions, a subset of core reaction modules is repeatedly observed in pathway results across multiple searches, suggesting that some subpaths between common compounds were more consistently explored than others.To reduce the resources spent on searching the same metabolic space, a new meta-algorithm for metabolic pathfinding, Hub Pathway search with Atom Tracking (HPAT), was developed to take advantage of a precomputed network of subpath modules. To investigate the efficacy of this method, we created a table describing a network of common hub metabolites and how they are biochemically connected and only offloaded searches to and from this hub network onto an interactive webserver capable of visualizing the resulting pathways. A test set of nineteen known pathways taken from literature and metabolic databases were used to evaluate if HPAT was capable of identifying known pathways. HPAT found the exact pathway for eleven of the nineteen test cases using a diverse set of precomputed subpaths, whereas a comparable pathfinding search algorithm that does not use precomputed subpaths found only seven of the nineteen test cases. The capability of HPAT to find novel pathways was demonstrated by its ability to identify novel 3-hydroxypropanoate (3-HP) synthesis pathways. As for pathway visualization, the new interactive pathway filters enable a reduction of the number of displayed pathways from hundreds down to less than ten pathways in several test cases, illustrating their utility in reducing the amount of presented information while retaining pathways of interest. This work presents the first step in incorporating a precomputed subpath network into metabolic pathfinding and demonstrates how this leads to a concise, interactive visualization of pathway results. The modular nature of metabolic pathways is exploited to facilitate efficient discovery of alternate pathways.


The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to counteract Polycomb group repression in Drosophila.
Members of the Polycomb group of repressors and trithorax group of activators maintain heritable states of transcription by modifying nucleosomal histones or remodeling chromatin. Although tremendous progress has been made toward defining the biochemical activities of Polycomb and trithorax group proteins, much remains to be learned about how they interact with each other and the general transcription machinery to maintain on or off states of gene expression. The trithorax group protein Kismet (KIS) is related to the SWI/SNF and CHD families of chromatin remodeling factors. KIS promotes transcription elongation, facilitates the binding of the trithorax group histone methyltransferases ASH1 and TRX to active genes, and counteracts repressive methylation of histone H3 on lysine 27 (H3K27) by Polycomb group proteins. Here, we sought to clarify the mechanism of action of KIS and how it interacts with ASH1 to antagonize H3K27 methylation in Drosophila. We present evidence that KIS promotes transcription elongation and counteracts Polycomb group repression via distinct mechanisms. A chemical inhibitor of transcription elongation, DRB, had no effect on ASH1 recruitment or H3K27 methylation. Conversely, loss of ASH1 function had no effect on transcription elongation. Mutations in kis cause a global reduction in the di- and tri-methylation of histone H3 on lysine 36 (H3K36) - modifications that antagonize H3K27 methylation in vitro. Furthermore, loss of ASH1 significantly decreases H3K36 dimethylation, providing further evidence that ASH1 is an H3K36 dimethylase in vivo. These and other findings suggest that KIS antagonizes Polycomb group repression by facilitating ASH1-dependent H3K36 dimethylation.


Virological diagnosis of central nervous system infections by use of PCR coupled with mass spectrometry analysis of cerebrospinal fluid samples.
Viruses are the leading cause of central nervous system (CNS) infections, ahead of bacteria, parasites, and fungal agents. A rapid and comprehensive virologic diagnostic testing method is needed to improve the therapeutic management of hospitalized pediatric or adult patients. In this study, we assessed the clinical performance of PCR amplification coupled with electrospray ionization-time of flight mass spectrometry analysis (PCR-MS) for the diagnosis of viral CNS infections. Three hundred twenty-seven cerebrospinal fluid (CSF) samples prospectively tested by routine PCR assays between 2004 and 2012 in two university hospital centers (Toulouse and Reims, France) were retrospectively analyzed by PCR-MS analysis using primers targeted to adenovirus, human herpesviruses 1 to 8 (HHV-1 to -8), polyomaviruses BK and JC, parvovirus B19, and enteroviruses (EV). PCR-MS detected single or multiple virus infections in 190 (83%) of the 229 samples that tested positive by routine PCR analysis and in 10 (10.2%) of the 98 samples that tested negative. The PCR-MS results correlated well with herpes simplex virus 1 (HSV-1), varicella-zoster virus (VZV), and EV detection by routine PCR assays (kappa values [95% confidence intervals], 0.80 [0.69 to 0.92], 0.85 [0.71 to 0.98], and 0.84 [0.78 to 0.90], respectively), whereas a weak correlation was observed with Epstein-Barr virus (EBV) (0.34 [0.10 to 0.58]). Twenty-six coinfections and 16 instances of uncommon neurotropic viruses (HHV-7 [n = 13], parvovirus B19 [n = 2], and adenovirus [n = 1]) were identified by the PCR-MS analysis, whereas only 4 coinfections had been prospectively evidenced using routine PCR assays (P < 0.01). In conclusion, our results demonstrated that PCR-MS analysis is a valuable tool to identify common neurotropic viruses in CSF (with, however, limitations that were identified regarding EBV and EV detection) and may be of major interest in better understanding the clinical impact of multiple or neglected viral neurological infections.


Enhancement of neutrophil infiltration in the corpus after failure of Helicobacter pylori eradication.
Neutrophil accumulation plays an important role in Helicobacter pylori-associated gastric mucosal injury. In this study, the mucosal content of myeloperoxidase (MPO), which is a measure of neutrophil accumulation and interleukin-8 (IL-8) was assayed and changes in MPO and IL-8 content were determined before and after H. pylori eradication therapy. Thirty-seven H. pylori-positive patients (11DU/26GU) underwent H. pylori eradication therapy with lansoprazole (30 mg/day, 6 weeks) and amoxicillin (2 g/day, 2 weeks), followed by famotidine (20 mg/day, 8 weeks). H. pylori-infection status was evaluated by routine endoscopic examinations (culture, CLO, histology). Immediately and 8 weeks after cessation of the anti-H. pylori therapy, these tests were repeated. Intragastric urease activity was estimated by delta 13CO2, which was obtained by the [13C]urea breath test (UBT). Mucosal samples were taken and tissue MPO and IL-8 contents were assayed by EIA and ELISA, respectively. Histologic examination was also performed. Among the 37 patients, 21 cases of H. pylori infection were eradicated (56.8%). Intragastric urease activity was dramatically reduced immediately after the anti-H. pylori therapy, whereas, it was re-elevated 8 weeks later in the relapsed cases. Antral MPO content was decreased in the eradicated and relapsed cases. MPO in the corpus was also decreased in the eradicated cases. Nevertheless, it was enhanced (3.5-fold) in the relapsed cases at 8 weeks after therapy. Changes in mucosal IL-8 content were similar to those of MPO. In eradicated cases, neutrophil infiltration is improved in both the antrum and corpus. However failure of eradication therapy results in the enhancement of neutrophil accumulation in the corpus. Further study is necessary to clarify the mechanism of neutrophil accumulation after therapy for H. pylori.


Mapping two measures to the International Classification Of Functioning, Disability and Health and the brief ICF core set for spinal cord injury in the post-acute context.
To evaluate the extent to which the rehabilitation outcome levels (ROL) and the spinal cord independence measure (SCIM) III could be mapped to the International Classification of Functioning, Disability and Health (ICF) and the brief core set for spinal cord injury (SCI) in the post-acute context. Two professionals used the published protocol to map the concepts derived from both measures to the ICF categories. Further, the endorsed categories at the second level of the ICF were used to determine the coverage of the Brief ICF Core Set for SCI. Three items of the ROL could not be conceptualised within the ICF, while the rest were mapped to 42 second-level categories, mainly to the activity and participation domain. All the items of the SCIM III were mapped, yielding 52 ICF categories, mostly at the third level (32). For the mapping to the Core Set for SCI, the ROL covered five and the SCIM III all nine categories of 'activities and participation' included as the candidate categories of the brief version. In terms of content, the ROL appears to be a more global measure of functioning, compared with the SCIM III that covers specific 'activity' aspects as proposed in the Brief Core Set for SCI. It is thus recommended that standardised measures, such as the SCIM III, be used due to its conceptual underpinnings and coverage of important aspects. Implications for Rehabilitation Rehabilitation professionals should select appropriately validated outcome measures specific to the health condition in order to evaluate the effectiveness of rehabilitation. Rehabilitation professional working with outcome measures should be aware of the limitations of measures, in terms of content, and supplement the evaluation with appropriate standardised measures or the use of the Core Sets. To enhance evidence-based practise in routine clinical practise, standardised outcome measures should be used.


Comparative study of material loss at the taper interface in retrieved metal-on-polyethylene and metal-on-metal femoral components from a single manufacturer.
There have been a number of reports on the occurrence of taper corrosion and/or fretting and some have speculated on a link to the occurrence of adverse local tissue reaction specifically in relation to total hip replacement which have a metal-on-metal bearing. As such a study was carried out to compare the magnitude of material loss at the taper in a series of retrieved femoral heads used in metal-on-polyethylene bearings with that in a series of retrieved heads used in metal-on-metal bearings. A total of 36 metal-on-polyethylene and 21 metal-on-metal femoral components were included in the study all of which were received from a customer complaint database. Furthermore, a total of nine as-manufactured femoral components were included to provide a baseline for characterisation. All taper surfaces were assessed using an established corrosion scoring method and measurements were taken of the female taper surface using a contact profilometry. In the case of metal-on-metal components, the bearing wear was also assessed using coordinate metrology to determine whether or not there was a relationship between bearing and taper material loss in these cases. The study found that in this cohort the median value of metal-on-polyethylene taper loss was 1.25 mm3 with the consequent median value for metal-on-metal taper loss being 1.75 mm3. This study also suggests that manufacturing form can result in an apparent loss of material from the taper surface determined to have a median value of 0.59 mm3. Therefore, it is clear that form variability is a significant confounding factor in the measurement of material loss from the tapers of femoral heads retrieved following revision surgery.


Changes in anatomy and terpene chemistry in roots of Douglas-fir seedlings following treatment with methyl jasmonate.
Replicated trials were conducted on two full-sibling families of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) seedlings. In response to the application of a 0.01% solution of methyl jasmonate (MeJA) to the soil of potted seedlings, numerous anatomical and chemical changes were observed in the roots, stem and foliage. These changes were, for the most part, similar for both sib groups. Methyl jasmonate induced traumatic resin duct formation in roots and stems. Chemical differences between MeJA-treated and control seedlings were mainly limited to the roots and stem, though some changes also occurred in the foliage. A total of 35 terpenoids were observed in the P. menziesii seedlings. In response to MeJA treatment, several of the 22 detected monoterpenoids (linalool, bornyl acetate, camphene, myrcene, alpha- and beta-pinene, tricyclene and beta-phellandrene) increased significantly in roots and stems, whereas (E)-beta-ocimene decreased significantly in the foliage. Four of the five detected sesquiterpenoids (alpha-humulene, germacrene D, longifolene and (E)-caryophyllene) increased significantly following MeJA application, mainly in the root and stem. Four of the eight detected diterpenoids (abietate, levopimarate, palustrate and sandaracopimarate) increased in response to MeJA treatment, but only in root and stem tissue. This study provides the first description of the effects of MeJA applied to roots through the soil on the anatomy and terpene chemistry of a gymnosperm. This comprehensive inventory of terpenoids in P. menziesii, with and without MeJA treatment, may facilitate identification of terpenoid-related resistance traits. Potential practical applications of MeJA treatment of conifer roots as a pest management strategy are discussed.


IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation.
The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17-16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94-27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association.


Stakeholder-engaged process for refining the design of a clinical trial in home hospice.
Clinical trials in home hospice settings are important to build the evidence base for practice, but balancing the burden and benefit of clinical trial conduct for clinicians, patients, and family caregivers is challenging. A stakeholder-engaged process can help inform and refine key aspects of home hospice clinical trials. The aim of this study was to describe a stakeholder-engaged process to refine, design, and implement aspects of an educational intervention trial in home hospice, including recommendations for refining intervention content and delivery, recruitment and enrollment strategies, and content and frequency of outcome measurement. A panel of interprofessional (1 hospice administrator, 3 nurses, 2 physicians, 2 pharmacists) and 2 former family caregiver stakeholders was systematically selected and invited to participate based on expertise, representing 2 geographically distinct hospices who were participating in the clinical trial. Teleconferences followed a predetermined procedural sequence: 1. pre-meeting materials distribution and review; 2. pre-meeting email solicitation of concerns in response to materials; 3. teleconference with structured and guided discussion; and 4. documentation and distribution of minutes for accuracy review and future meeting guidance. Discussion topics were distinct for each panel meeting. Written reflections on the stakeholder engagement process were collected from panel members to further refine our process. Five initial biweekly teleconferences resulted in recommendations for recruitment strategy, enrollment process, measurement frequency, patient inclusion, and primary care physician notification of the patient's trial involvement. The panel continues to participate in quarterly teleconferences to review progress and unexpected questions and concerns. Panelist reflections reveal personal and professional benefit from participation. An interprofessional stakeholder process is feasible and invaluable for developing home hospice intervention studies, contributing to better science, successful trial implementation, and relevant, valid outcomes. Clinicaltrials.gov, NCT03972163 , Registered June 3, 2019.


Pigmentary changes in a patient treated with imatinib.
Imatinib mesylate (STI 571; Gleevec; Novartis Pharmaceuticals, Basel, Switzerland) is an orally available tyrosine kinase inhibitor that targets a constitutively activated BCR-ABL tyrosine kinase with additional inhibitory effects on platelet derived growth factor (PDGF) receptors alpha and beta, and KIT. It has revolutionized the treatment of adult and pediatric patients with Philadelphia chromosome positive chronic myelogenous leukemia (CML) and is also FDA-approved for KIT-positive advanced gastrointestinal tumor (GIST) and dermatofibrosarcoma protuberans. A wide spectrum of dermatologic toxicities has been associated with this agent, among which a maculopapular rash is the most common event. In addition, a variety of pigmentary abnormalities of the skin and mucosal surfaces have been reported. Hypopigmentation is a well-recognized adverse effect. In contrast, paradoxical hyperpigmentation has only rarely been documented. In this case report we describe imatinib-induced cutaneous hyperpigmentation and graying of hair occurring in the same patient with dermatofibrosarcoma protuberans treated with imatinib.


Site-directed mutagenesis of N-linked glycosylation sites on the gamma-aminobutyric acid type A receptor alpha 1 subunit.
Oligonucleotide-directed mutagenesis was used to mutate the two potential sites for N-linked glycosylation on the rat gamma-aminobutyric acid (GABA)A receptor alpha 1 subunit. Wild-type (WT) or mutant alpha 1 subunits [asparagine to glutamine substitutions at position 10 (alpha 1Q10), 110 (alpha 1Q110), or both 10 and 110 (alpha 1Q10/110)] were coexpressed with beta 1 and gamma 2 subunits in Xenopus oocytes. Removal of either one or both potential sites for N-linked glycosylation resulted in expression, in Xenopus oocytes, of functional GABAA receptors with pharmacological properties similar to those observed for the WT receptor. WT and mutant alpha 1 subunits were co-transfected with beta 1 and gamma 2 subunits in human embryonic kidney 293 cells. WT and mutant alpha 1 subunits expressed in 293 cells were photoaffinity labeled with [3H]flunitrazepam. Co-transfection of alpha 1WT, alpha 1Q10, or alpha 1Q110 subunits in combination with beta 1 and gamma 2 GABAA receptor subunits resulted in the labeling of single bands, with approximate molecular masses of 54, 49, and 50 kDa, respectively. The decrease in molecular mass for both the alpha 1Q10 and alpha 1Q110 mutants suggests that both consensus sequences for N-linked glycosylation are used in 293 cells. Low levels of [3H]flunitrazepam binding prevented visualization of the alpha 1Q10/110 double mutant. The 293 cells transfected with either the alpha 1Q10 or alpha 1Q110 mutant in combination with beta 1 and gamma 2 subunits expressed significantly lower levels of [3H]Ro15-1788 binding, relative to WT levels. In addition, [3H]Ro15-1788 binding was undetectable in 293 cells expressing the alpha 1Q10/110 double mutant. When transfected 293 cells were grown at 30 zero, [3H]Ro15-1788 binding to alpha 1Q10 and alpha 1Q110 GABAA receptors was restored to levels comparable to that for WT receptors. [3H]Ro15-1788 binding to alpha 1Q10/110 was not reliably detected at 30 zero. Similar results were observed using [3H]muscimol. These data suggest that intracellular processing and transport of the glycosylation-deficient GABAA receptor alpha 1 subunit is temperature sensitive. Furthermore, the observed differences between the two expression systems may be accounted for by the typically lower temperature used for maintaining microinjected Xenopus oocytes. Thus, although glycosylation is not an absolute requirement for GABAA receptor expression, it has a profound effect on the processing of at least the alpha 1 receptor and its subsequent assembly into a mature receptor.


Hedgehog directly controls initiation and propagation of retinal differentiation in the Drosophila eye.
Patterning of the compound eye begins at the posterior edge of the eye imaginal disc and progresses anteriorly toward the disc margin. The advancing front of ommatidial differentiation is marked by the morphogenetic furrow (MF). Here we show by clonal analysis that Hedgehog (Hh), secreted from two distinct populations of cells has two distinct functions: It was well documented that Hh expression in the differentiating photoreceptor cells drives the morphogenetic furrow. Now we show that, in addition, Hh, secreted from cells at the posterior disc margin, is absolutely required for the initiation of patterning and predisposes ommatidial precursor cells to enter ommatidial assembly later. These two functions of Hh in eye patterning are similar to the biphasic requirement for Sonic Hh in patterning of the ventral neural tube in vertebrates. We show further that Hh induces ommatidial development in the absence of its secondary signals Wingless (Wg) and Dpp and that the primary function of Dpp in MF initiation is the repression of wg, which prevents ommatidial differentiation. Our results show that the regulatory relationships between Hh, Dpp, and Wg in the eye are similar to those found in other imaginal discs such as the leg disc despite obvious differences in their modes of development.


The Polonium brief: a hidden history of cancer, radiation, and the tobacco industry.
The first scientific paper on polonium-210 in tobacco was published in 1964, and in the following decades there would be more research linking radioisotopes in cigarettes with lung cancer in smokers. While external scientists worked to determine whether polonium could be a cause of lung cancer, industry scientists silently pursued similar work with the goal of protecting business interests should the polonium problem ever become public. Despite forty years of research suggesting that polonium is a leading carcinogen in tobacco, the manufacturers have not made a definitive move to reduce the concentration of radioactive isotopes in cigarettes. The polonium story therefore presents yet another chapter in the long tradition of industry use of science and scientific authority in an effort to thwart disease prevention. The impressive extent to which tobacco manufacturers understood the hazards of polonium and the high executive level at which the problem and potential solutions were discussed within the industry are exposed here by means of internal documents made available through litigation.


Trends in the thermal stability of two-dimensional covalent organic frameworks.
Two-dimensional covalent organic frameworks (2D COFs) are synthetically diverse, layered macromolecules. Their covalent lattices are thought to confer high thermal stability, which is typically evaluated with thermogravimetric analysis (TGA). However, TGA measures the temperature at which volatile degradation products are formed and is insensitive to changes of the periodic structure of the COF. Here, we study the thermal stability of ten 2D COFs using a combination of variable-temperature X-ray diffraction, TGA, diffuse reflectance infrared spectroscopy, and density functional theory calculations. We find that 2D COFs undergo a general two-step thermal degradation process. At the first degradation temperature, 2D COFs lose their crystallinity without chemical degradation. Then, at higher temperatures, they chemically degrade into volatile byproducts. Several trends emerge from this exploration of 2D COF stability. Boronate ester-linked COFs are generally more thermally stable than comparable imine-linked COFs. Smaller crystalline lattices are more robust to thermal degradation than chemically similar larger lattices. Finally, pore-functionalized COFs degrade at significantly lower temperatures than their unfunctionalized analogues. These trends offer design criteria for thermally resilient 2D COF materials. These findings will inform and encourage a broader exploration of mechanical deformation in 2D networks, providing a necessary step towards their practical use.


Sport injuries aligned to peak height velocity in talented pubertal soccer players.
In young athletes, demands of sports are superimposed on normal growth and maturation. It has been suggested that this causes a temporarily increased vulnerability for injuries. We followed 26 talented soccer players (mean age 11.9±0.84 years) longitudinally for 3 years around their adolescent growth spurt, called Peak Height Velocity, to identify differences in number of traumatic and overuse injuries and days missed due to injuries. Peak Height Velocity was calculated according to the Maturity Offset Protocol. The number of injuries was calculated for each player per year. A repeated measurement analysis showed that athletes had significantly more traumatic injuries in the year of Peak Height Velocity (1.41) than in the year before Peak Height Velocity (0.81). A moderate effect size of 0.42 was found for the difference in number of overuse injuries per player per year before (0.81) and after Peak Height Velocity (1.41), respectively. Finally, a moderate effect size of 0.55 was found for difference between days missed due to injuries before (7.27 days per player per year) and during Peak Height Velocity (15.69 days per player per year). Adolescent growth spurt seems to result in increased vulnerability for traumatic injuries. Afterwards athletes seem to be susceptible to overuse injuries.


Prevention of thromboxane A2 receptor-mediated pulmonary hypertension by a nonpeptide angiotensin II type 1 receptor antagonist.
Losartan is a potent, nonpeptide, angiotensin II type 1 receptor antagonist. We investigated the possibility that losartan may interact with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors. We measured changes in mean systemic (MS) and pulmonary (MP) arterial pressures (AP) as well as in hematocrit induced by the TxA2 analog, U-46619 (9, 11-dideoxy-9 alpha, 11 alpha-methanoepoxy PGF2 alpha, during pharmacological blockade of either TxA2/PGH2 receptors or the renin-angiotensin system. In anesthetized, open chest rats, U-46619 dose dependently increased MPAP whereas MSAP presented a biphasic evolution. The U-446619 (1.25 micrograms/kg)-increased MPAP (52.4 +/- 12.1%; P < .005) was dose dependently inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 ([1S-[1 alpha,2 alpha (5z),3 alpha, 4 alpha]]-7- [3-[[2-[(phenylamino)-carbonyl)hydrazino]methyl]-7-oxabiacyclo [2.2.1]hept-2-yl]-5-heptenoic acid) (10.6 +/- 2 and 2.1 +/- 1.4% at 0.63 and 2.5 mg/kg, respectively; both P < .05 vs. U-46619 in control rats). Losartan dose dependently reduced this increase (45.5 +/- 5.8 and 11.9 +/- 1.8% at 2.5 and 10 mg/kg, respectively; P = N.S. and P < .05 vs. U-46619 in control rats) whereas chronic suppression of angiotensin II generation by the converting-enzyme inhibitor enalapril (10 mg/kg/day per os for 4-5 days) did not affect this response. None of these treatments significantly reduced the U-46619-associated increase in MSAP. Moreover, the angiotensin II-evoked increases in MSAP and MPAP were suppressed by pretreatment with losartan but not with SQ 29,548.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence and outcomes of multimorbidity in South Asia: a systematic review.
To systematically review the studies of prevalence, patterns and consequences of multimorbidity reported from South Asia. Systematic review. South Asia. Articles were retrieved from two electronic databases (PubMed and Embase) and from the relevant references lists. Methodical data extraction according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines was followed. English-language studies published between 2000 and March 2015 were included. Studies addressing prevalence, consequences and patterns of multimorbidity in South Asia. Articles documenting presence of two or more chronic conditions were included in the review. The quality and risk of bias were assessed using STROBE criteria. Two reviewers independently assessed studies for eligibility, extracted data and assessed study quality. Due to heterogeneity in methodologies among reported studies, only narrative synthesis of the results was carried out. Of 11,132, 61 abstracts were selected and 13 were included for final data synthesis. The number of health conditions analysed per study varied from 7 to 22, with prevalence of multimorbidity from 4.5% to 83%. The leading chronic conditions were hypertension, arthritis, diabetes, cardiac problems and skin diseases. The most frequently reported outcomes were increased healthcare utilisation, lowered physical functioning and quality of life, and psychological distress. Our study, a comprehensive mapping of multimorbidity research in South Asia, reveals the insufficient volume of work carried out in this domain. The published studies are inadequate to provide an indication of the magnitude of multimorbidity in these countries. Research into clinical and epidemiological aspects of multimorbidity is warranted to build up scientific evidence in this geographic region. The wide heterogeneity observed in the present review calls for greater methodological rigour while conducting these epidemiological studies. CRD42013005456.


Liver transplantation for alcoholic liver disease.
Orthotopic liver transplantation (OLT) for individuals with alcoholic liver disease (ALD) remains controversial. This review was designed to evaluate the survival, recidivism, and rehabilitation of the alcoholic liver transplant recipient in a single transplant center. Between 10/86 and 11/92 203 liver transplants were performed in 179 patients. In 42 patients (23%) the primary etiologic diagnosis was ALD (36 males, 6 females, median age 47 yr). All ALD patients were evaluated preoperatively by social service, psychiatry, and medical psychology, in addition to hepatology and transplant surgery. A minimum abstinence period of 3-6 months was encouraged, although exceptions were made for cases of extreme medical urgency in which a good prognosis for abstinence was predicted. In OLT recipients with ALD, actuarial survival at 1, 2, and 3 yr was 74%, 71%, and 71%, respectively, compared to 71%, 71%, and 69% for all OLT recipients. One- and two-year survival was 85% in the most recently transplanted 86 patients, 20 of whom (23%) had ALD with 1- and 2-yr survival of 84% (N.S.). Recidivism was monitored postoperatively by interviews with the patient and family, supplemented by random urine and serum toxicology. Of the 29 survivors, 2 (7%) returned temporarily to alcohol use but are presently abstinent. Although none of the ALD patients in this study was able to work prior to OLT, 76% of the survivors at least 4 months post-transplantation were employed. Although our experience is small, our results suggest that OLT is appropriate therapy for carefully selected patients with end-stage liver failure due to ALD. The multi-disciplinary approach to preoperative evaluation of the alcoholic liver transplant candidate is effective in determining those patients committed to abstinence after a successful transplant.


Contribution of vasogenic and cellular edema to traumatic brain swelling measured by diffusion-weighted imaging.
The contribution of brain edema to brain swelling in cases of traumatic brain injury remains a critical problem. The authors believe that cellular edema, the result of complex neurotoxic events, is the major contributor to brain swelling and that vasogenic edema, secondary to blood-brain barrier compromise, may be overemphasized. The objective of this study, therefore, was to quantify temporal water content changes and document the type of edema that forms during the acute and late stages of edema development following closed head injury (CHI). The measurement of brain water content was based on magnetic resonance imaging-determined values of tissue longitudinal relaxation time (T1-weighted imaging) and their subsequent conversion to percentage of water, whereas the differentiation of edema formation (cellular vs. vasogenic) was based on the measurement of the apparent diffusion coefficient (ADC) by diffusion-weighted imaging. A new impact-acceleration model was used to induce CHI. Thirty-six adult Sprague-Dawley rats were separated into two groups: Group I, control (six animals); and Group II, trauma (30 animals). Fast ADC measurements (localized, single-voxel) were obtained sequentially (every minute) up to 1 hour postinjury. The T1-weighted images, used for water content determination, and the diffusion-weighted images (ADC measurement with conventional diffusion-weighted imaging) were obtained at the end of the 1st hour postinjury and on Days 1, 3, 7, 14, 28, and 42 in animals from the trauma and control groups. In the animals subjected to trauma, the authors found a significant increase in ADC (10 +/- 5%) and brain water content (1.3 +/- 0.9%) during the first 60 minutes postinjury. This is consistent with an increase in the volume of extracellular fluid and vasogenic edema formation as a result of blood-brain barrier compromise. This transient increase, however, was followed by a continuing decrease in ADC that began 40 to 60 minutes postinjury and reached a minimum value on Days 7 to 14 (10 +/- 3% reduction). Because the water content of the brain continued to increase during the first 24 hours postinjury (1.9 +/- 0.9%), it is suggested that the decreased ADC indicated cellular edema formation, which started to develop soon after injury and became dominant between 1 and 2 weeks postinjury. The study provides supportive evidence that cellular edema is the major contributor to posttraumatic swelling in diffuse CHI and defines the onset and duration of the increase in cellular volume.


Achieving secondary prevention low-density lipoprotein particle concentration goals using lipoprotein cholesterol-based data.
Epidemiologic studies suggest that LDL particle concentration (LDL-P) may remain elevated at guideline recommended LDL cholesterol goals, representing a source of residual risk. We examined the following seven separate lipid parameters in achieving the LDL-P goal of <1000 nmol/L goal for very high risk secondary prevention: total cholesterol to HDL cholesterol ratio, TC/HDL, <3; a composite of ATP-III very high risk targets, LDL-C<70 mg/dL, non-HDL-C<100 mg/dL and TG<150 mg/dL; a composite of standard secondary risk targets, LDL-C<100, non-HDL-C<130, TG<150; LDL phenotype; HDL-C ≥ 40; TG<150; and TG/HDL-C<3. We measured ApoB, ApoAI, ultracentrifugation lipoprotein cholesterol and NMR lipoprotein particle concentration in 148 unselected primary and secondary prevention patients. TC/HDL-C<3 effectively discriminated subjects by LDL-P goal (F = 84.1, p<10(-6)). The ATP-III very high risk composite target (LDL-C<70, nonHDL-C<100, TG<150) was also effective (F = 42.8, p<10(-5)). However, the standard secondary prevention composite (LDL-C<100, non-HDL-C<130, TG<150) was also effective but yielded higher LDL-P than the very high risk composite (F = 42.0, p<10(-5)) with upper 95% confidence interval of LDL-P less than 1000 nmol/L. TG<150 and TG/HDL-C<3 cutpoints both significantly discriminated subjects but the LDL-P upper 95% confidence intervals fell above goal of 1000 nmol/L (F = 15.8, p = 0.0001 and F = 9.7, p = 0.002 respectively). LDL density phenotype neared significance (F = 2.85, p = 0.094) and the HDL-C cutpoint of 40 mg/dL did not discriminate (F = 0.53, p = 0.47) alone or add discriminatory power to ATP-III targets. A simple composite of ATP-III very high risk lipoprotein cholesterol based treatment targets or TC/HDL-C ratio <3 most effectively identified subjects meeting the secondary prevention target level of LDL-P<1000 nmol/L, providing a potential alternative to advanced lipid testing in many clinical circumstances.


Physical activity and fatigue in chronic obstructive pulmonary disease - A population based study.
In subjects with chronic obstructive pulmonary disease (COPD), symptoms of fatigue, concomitant heart disease and low physical activity levels are more frequently described than in subjects without COPD. However, there are no population-based studies addressing the relationship between physical activity, fatigue and heart disease in COPD. The aim was to compare physical activity levels among subjects with and without COPD in a population based study, and to evaluate if concomitant heart disease and fatigue was associated to physical activity. In this, 470 subjects with COPD and 659 subjects without COPD (non-COPD) participated in examinations including structured interview and spirometry. A ratio of the forced expiratory volume in one second (FEV1)/best of forced vital capacity (FVC) and vital capacity (VC) < 0.7 was used to define COPD. Physical activity was assessed with the International Physical Activity Questionnaire (IPAQ), and fatigue with the Functional Assessment of Chronic Illness Therapy - Fatigue scale (FACIT-F). The prevalence of low physical activity was higher among subjects with FEV1 < 80% predicted compared to non-COPD subjects (22.4% vs. 14.6%, p = 0.041). The factors most strongly associated with low physical activity in subjects with COPD were older age, OR 1.52, (95% CI 1.12-2.06), a history of heart disease, OR 2.11 (1.10-4.08), and clinically significant fatigue, OR 2.33 (1.31-4.13); while obesity was the only significant factor among non-COPD subjects, OR 2.26 (1.17-4.35). Physical activity levels are reduced when lung function is decreased below 80% of predicted, and the factors associated with low physical activity are different among subject with and without COPD. We propose that the presence of fatigue and heart disease are useful to evaluate when identifying subjects for pulmonary rehabilitation.


How I diagnose and treat venous thromboembolism in sickle cell disease.
The incidence of venous thromboembolism (VTE) in adult patients with sickle cell disease (SCD) is high. However, overlapping features between the clinical presentation of VTE and SCD complications and a low index of suspicion for thrombosis can influence patient management decisions. VTE in SCD can therefore present management challenges to the clinical hematologist. Herein, we present 3 distinct clinical vignettes that are representative of our clinical practice with SCD patients. These vignettes are discussed with specific reference to the hypercoagulable state in SCD patients, recent VTE diagnosis and anticoagulant therapy guidelines from the general population, and evaluation of the risk of bleeding as a result of long-term exposure to anticoagulant therapy. We examine current diagnostic and treatment options, highlight limitations of the existing clinical prognostic models that offer personalized guidance regarding the duration of anticoagulation, and propose a clinical approach to guide the decision to extend anticoagulation beyond 3 months.


Protective effect of betulinic acid against intracerebroventricular streptozotocin induced cognitive impairment and neuronal damage in rats: Possible neurotransmitters and neuroinflammatory mechanism.
The purpose of the study was to explore the therapeutic potential of Betulinic acid (BA) in streptozotocin (STZ) induced memory damage in experimental rats. STZ (3mg/kg bilaterally) as intracerebroventrical (icv) route was administered on day 1 and 3 in rats. Donepezil (5mg/kg/day po), used as standard, and BA (5, 10 and 15mg/kg/day po) were administered after 1h of 1st STZ infusion up to 21days. Object recognition task (ORT) for non-spatial, Morris water maze (MWM) for spatial and locomotor activity were performed to evaluate behavioral changes in rats. On 22nd day, animals were decapitated and hippocampus was separated to perform biochemical (AChE, LPO, GSH, nitrite), neuroinflammatory (TNF-α, IL-1β, and IL-6), neurotransmitters (NTs) (dopamine, norepinephrine and serotonin) analysis. STZ infusion significantly impaired memory as observed in MWM and ORT, increased oxidative stress, pro-inflammatory cytokine's level and altered NTs level. Moreover, BA demonstrated a neuroprotective effect in a dose-dependent manner. BA dose dependently (5, 10 and 15mg/kg) significantly restore STZ induced memory changes and pathological abnormalities in rat brain. The findings of the current study suggests that BA protect rat brain from STZ induced neuronal damage via acting through multiple mechanisms and would be used to curb cognitive decline associated with neurodegenerative disorders especially AD.


Carers' ambivalence in conflict situations with older persons.
The aim of this study was to illuminate the meaning of professional carers' experiences in caring situations when a conflict of interest arises with the older person receiving care. The findings reveal the complexity of the carers' ambivalence when facing a conflict of interest, weighing up between the older persons' right to self-determination and external demands. The carers are alone in their ambivalence, and the conclusion is that they need help and support to be more present in the encounter. The implication for this study is to focus on care as a person-centered practice and to focus on people as interdependent on support carers to maintain older people's right to self-determination in the relationship.


Dancing with multiple partners.
Transmembrane proteins, such as G protein-coupled receptors (GPCRs) and integrins, activate intracellular signaling pathways through interactions with downstream binding partners. Woodside discusses two examples in which GPCRs and integrins interact in a noncompeting manner with more than one partner. The specific GPCR described is the thrombin receptor, in experiments where G protein peptides selectively block signaling through a particular G protein that does not appear to inhibit coupling of the receptor to other G proteins. The second system described is the alphaIIbbeta3 integrin and its activation of the nonreceptor tyrosine kinase Syk. Syk appeared capable of interacting with both the integrin and intracellular domains of immune response receptors, because binding of Syk to the integrin was not inhibited by peptides based on the Syk binding site in immune response receptors. Thus, multiple, noncompeting binding partners add to the complexity of signal transduction outputs from a single receptor complex.


Digital orthodontic radiographic set versus cone-beam computed tomography: an evaluation of the effective dose.
The aim of this study was to compare the equivalent and effective doses of different digital radiographic methods (panoramic, lateral cephalometric and periapical) with cone-beam computed tomography (CBCT). Precalibrated thermoluminescent dosimeters were placed at 24 locations in an anthropomorphic phantom (Alderson Rando Phantom, Alderson Research Laboratories, New York, NY, USA), representing a medium sized adult. The following devices were tested: Heliodent Plus (Sirona Dental Systems, Bernsheim, Germany), Orthophos XG 5 (Sirona Dental Systems, Bernsheim, Germany) and i-CAT (Imaging Sciences International, Hatfield, PA, USA). The equivalent doses and effective doses were calculated considering the recommendations of the International Commission of Radiological Protection (ICRP) issued in 1990 and 2007. Although the effective dose of the radiographic set corresponded to 17.5% (ICRP 1990) and 47.2% (ICRP 2007) of the CBCT dose, the equivalent doses of skin, bone surface and muscle obtained by the radiographic set were higher when compared to CBCT. However, in some areas, the radiation produced by the orthodontic set was higher due to the complete periapical examination. Considering the optimization principle of radiation protection, i-CAT tomography should be used only in specific and justified circumstances. Additionally, following the ALARA principle, single periapical radiographies covering restricted areas are more suitable than the complete periapical examination.


Risk factors for house-entry by malaria vectors in a rural town and satellite villages in The Gambia.
In the pre-intervention year of a randomized controlled trial investigating the protective effects of house screening against malaria-transmitting vectors, a multi-factorial risk factor analysis study was used to identify factors that influence mosquito house entry. Mosquitoes were sampled using CDC light traps in 976 houses, each on one night, in Farafenni town and surrounding villages during the malaria-transmission season in The Gambia. Catches from individual houses were both (a) left unadjusted and (b) adjusted relative to the number of mosquitoes caught in four sentinel houses that were operated nightly throughout the period, to allow for night-to-night variation. Houses were characterized by location, architecture, human occupancy and their mosquito control activities, and the number and type of domestic animals within the compound. 106,536 mosquitoes were caught, of which 55% were Anopheles gambiae sensu lato, the major malaria vectors in the region. There were seven fold higher numbers of An. gambiae s.l. in the villages (geometric mean per trap night = 43.7, 95% confidence intervals, CIs = 39.5-48.4) than in Farafenni town (6.3, 5.7-7.2) and significant variation between residential blocks (p < 0.001). A negative binomial multivariate model performed equally well using unadjusted or adjusted trap data. Using the unadjusted data the presence of nuisance mosquitoes was reduced if the house was located in the town (odds ratio, OR = 0.11, 95% CIs = 0.09-0.13), the eaves were closed (OR = 0.71, 0.60-0.85), a horse was tethered near the house (OR = 0.77, 0.73-0.82), and churai, a local incense, was burned in the room at night (OR = 0.56, 0.47-0.66). Mosquito numbers increased per additional person in the house (OR = 1.04, 1.02-1.06) or trapping room (OR = 1.19, 1.13-1.25) and when the walls were made of mud blocks compared with concrete (OR = 1.44, 1.10-1.87). This study demonstrates that the risk of malaria transmission is greatest in rural areas, where large numbers of people sleep in houses made of mud blocks, where the eaves are open, horses are not tethered nearby and where churai is not burnt at night. These factors need to be considered in the design and analysis of intervention studies designed to reduce malaria transmission in The Gambia and other parts of sub-Saharan Africa.


Association of adenocarcinoma and squamous cell carcinoma of the esophagus with tobacco-related and other malignancies.
Little is known about the etiology of esophageal and gastric cardia adenocarcinoma (EGA), a cancer with one of the fastest-rising incidences in the developed world. To explore the etiology of this cancer, we conducted a retrospective cohort analysis using data from the Surveillance, Epidemiology and End Results Program of the United States National Cancer Institute to study EGA and esophageal squamous cell carcinoma (ESC), in association with cancers of other sites. Standardized incidence ratios, adjusted for age, sex, and time period, were calculated as a measure of the relative risk (RR) of developing a second primary cancer (EGA or ESC) following a given first primary site. We found a moderately elevated risk of EGA following cancers of the lung (RR = 1.9 in men and RR = 2.0 in women) and of the head and neck (RR = 2.1 in men and RR = 6.3 in women) and a strongly elevated risk of ESC following cancers of the lung (RR = 2.8 in men and RR = 5.1 in women) and of the head and neck (RR = 9.6 in men and RR = 38.8 in women). A significantly elevated risk following breast cancer in women was observed for both EGA (RR = 2.6; 95% confidence interval, 1.8-3.7) and ESC (RR = 1.4; 95% confidence interval, 1.1-1.9). We also found a significantly elevated risk of EGA following bladder (RR = 2.0), colorectal (RR = 1.7), and prostate (RR = 1.4) cancer in men and of ESC following colorectal cancer (RR = 1.7) in women in this study. The strong association with tobacco-related malignancies in this study reinforces the role of tobacco in the etiology of esophageal cancers, which appears stronger for squamous cell carcinoma than for adenocarcinoma and stronger in women than in men. The study also suggests a possible shared etiology between esophageal adenocarcinoma and colorectal cancer in men and provides new evidence about the association of both adenocarcinoma and squamous cell carcinoma of the esophagus with breast cancer in women. Findings of this study provide clues to the etiology of EGA and ESC.


Pro- and anti-inflammatory effects of sulforaphane on placental cytokine production.
Placental inflammation increases the risk of adverse pregnancy outcomes and possibly neurodevelopmental disorders in the offspring. Previous research suggests it may be possible to modulate the placental immune response to bacteria to favor an anti-inflammatory phenotype with dietary factors. Sulforaphane (SFN) is a dietary supplement with known anti-inflammatory activities, however, its effects on placental cytokine production are unclear. Therefore, we evaluated the effects of SFN on biomarkers of inflammation and neurodevelopment under basal conditions and a setting of mild infection. Placental explant cultures were established and treated with up to 10 μM SFN in the presence and absence of 107 CFU/ml heat-killed E. coli. Concentrations of IL-1β, TNF-α, IL-6, sgp130, HO-1 and BDNF in conditioned medium were quantified by immunoassay. SFN increased antioxidant HO-1 expression in the absence, but not the presence, of infection. SFN inhibited IL-1β and IL-10, but tended to promote, TNF-α production by bacteria-stimulated cultures. IL-6 and BDNF were inhibited by SFN irrespective of co-treatment with E.coli. A negative regulator of IL-6 signaling, sgp130, was increased by SFN under basal conditions, but not in E. coli-stimulated cultures. These results suggest that SFN has mixed effects on the placenta inhibiting both pro-inflammatory (IL-1β) and anti-inflammatory factors (IL-10) but promoting regulators of oxidative stress and inflammation (HO-1 and sgp130) in an infection-dependent manner.


The impacts of physical activity intervention on physical and cognitive outcomes in children with autism spectrum disorder.
This study examined the effects of a 12-week physical activity intervention on the motor skill proficiency and executive function of 22 boys (aged 9.08 ± 1.75 years) with autism spectrum disorder. In Phase I of the 12 weeks, 11 boys with autism spectrum disorder (Group A) received the intervention, whereas the other 11 boys with autism spectrum disorder (Group B) did not (true control, no intervention). The arrangement was reversed in Phase II, which lasted an additional 12 weeks. The Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and the Wisconsin Card Sorting Test were conducted three times for each participant (Group A, primary grouping: baseline (T1), post-assessment (T2), and follow-up assessment (T3); Group B, control grouping: T1-T2; intervention condition, T2-T3). The main findings were that both groups of children with autism spectrum disorder significantly exhibited improvements in motor skill proficiency (the total motor composite and two motor-area composites) and executive function (three indices of the Wisconsin Card Sorting Test) after 12 weeks of physical activity intervention. In addition, the effectiveness appeared to have been sustained for at least 12 weeks in Group A. The findings provide supporting evidence that physical activity interventions involving table tennis training may be a viable therapeutic option for treating children with autism spectrum disorder.


The effect of modulated electro-hyperthermia on local disease control in HIV-positive and -negative cervical cancer women in South Africa: Early results from a phase III randomised controlled trial.
The global burden of cervical cancer remains high with the highest morbidity and mortality rates reported in developing countries. Hyperthermia as a chemo- and radiosensitiser has shown to improve treatment outcomes. This is an analysis of the local control results at six months post-treatment of patients enrolled in an ongoing study investigating the effects of the addition of modulated electro-hyperthermia (mEHT) to chemoradiotherapy for the treatment of HIV-positive and -negative cervical cancer patients in a low-resource setting. This ongoing Phase III randomised controlled trial, conducted at a state hospital in Johannesburg, South Africa, was registered with the appropriate ethics committee. After signing an informed consent, participants with FIGO stages IIB to IIIB squamous cell carcinoma of the cervix were randomised to receive chemoradiotherapy with/without mEHT using a secure online random-sampling tool (stratum: HIV status) accounting for age and stage. Reporting physicians were blind to treatment allocation. HIV-positive participants on antiretroviral treatment, or with a CD4 count >200cell/μL were included. mEHT was administered 2/weekly immediately before external beam radiation. The primary end point is local disease control (LDC) and secondary endpoints are toxicity; quality of life analysis; and two year survival. We report on six month LDC, including nodes visualised in the radiation field on 18F-FDG PET/CT (censored for six month survival), and six month local disease free survival (LDFS) (based on intention to treat). Trial status: Recruitment closed (ClinicalTrials.gov: NCT03332069). 271 participants were recruited between January 2014 and November 2017, of which 210 were randomised for trial and 202 were available for analysis at six months post-treatment (mEHT: n = 101; Control: n = 101). Six month LDFS was higher in the mEHT Group (n = 39[38.6%]), than in the Control Group (n = 20[19.8%]); p = 0.003). LDC was also higher in the mEHT Group (n = 40[45.5%]) than the Control Group (n = 20[24.1%]); (p = 0.003). Our results show that mEHT is effective as a chemo-radiosensitiser for cervical cancer, even in high risk a patients and resource-constrained settings.


Arthropod community structure in pastures of an island archipelago (Azores): looking for local-regional species richness patterns at fine-scales.
The arthropod species richness of pastures in three Azorean islands was used to examine the relationship between local and regional species richness over two years. Two groups of arthropods, spiders and sucking insects, representing two functionally different but common groups of pasture invertebrates were investigated. The local-regional species richness relationship was assessed over relatively fine scales: quadrats (= local scale) and within pastures (= regional scale). Mean plot species richness was used as a measure of local species richness (= alpha diversity) and regional species richness was estimated at the pasture level (= gamma diversity) with the 'first-order-Jackknife' estimator. Three related issues were addressed: (i). the role of estimated regional species richness and variables operating at the local scale (vegetation structure and diversity) in determining local species richness; (ii). quantification of the relative contributions of alpha and beta diversity to regional diversity using additive partitioning; and (iii). the occurrence of consistent patterns in different years by analysing independently between-year data. Species assemblages of spiders were saturated at the local scale (similar local species richness and increasing beta-diversity in richer regions) and were more dependent on vegetational structure than regional species richness. Sucking insect herbivores, by contrast, exhibited a linear relationship between local and regional species richness, consistent with the proportional sampling model. The patterns were consistent between years. These results imply that for spiders local processes are important, with assemblages in a particular patch being constrained by habitat structure. In contrast, for sucking insects, local processes may be insignificant in structuring communities.


The effect of microwave radiation on the stability and formation of gramicidin-A channels in lipid bilayer membranes.
The effects of microwaves on the single-channel kinetics of gramicidin-A channels in lipid bilayer membranes were examined. Attempts were made to separate thermal and athermal effects by accurate measurements of temperature at the site of the membrane and by relating the measured parameters to their previously characterized temperature dependence. It was found that microwave radiation does not affect single-channel conductance or channel life time to a degree that is significantly different from that expected of a purely thermal effect. On the other hand, the rate of channel formation is decreased during exposure, which is opposite to that expected of a purely thermal effect. The mechanism of this effect is discussed in terms of the dimerization process of channel formation.


Deriving competencies for mentors of clinical and translational scholars.
Although the importance of research mentorship has been well established, the role of mentors of junior clinical and translational science investigators is not clearly defined. The authors attempt to derive a list of actionable competencies for mentors from a series of complementary methods. We examined focus groups, the literature, competencies derived for clinical and translational scholars, mentor training curricula, mentor evaluation forms and finally conducted an expert panel process in order to compose this list. These efforts resulted in a set of competencies that include generic competencies expected of all mentors, competencies specific to scientists, and competencies that are clinical and translational research specific. They are divided into six thematic areas: (1) Communication and managing the relationship, (2) Psychosocial support, (3) Career and professional development, (4) Professional enculturation and scientific integrity, (5) Research development, and (6) Clinical and translational investigator development. For each thematic area, we have listed associated competencies, 19 in total. For each competency, we list examples that are actionable and measurable. Although a comprehensive approach was used to derive this list of competencies, further work will be required to parse out how to apply and adapt them, as well future research directions and evaluation processes.


Comparative genomic analysis of the Tribolium immune system.
Tribolium castaneum is a species of Coleoptera, the largest and most diverse order of all eukaryotes. Components of the innate immune system are hardly known in this insect, which is in a key phylogenetic position to inform us about genetic innovations accompanying the evolution of holometabolous insects. We have annotated immunity-related genes and compared them with homologous molecules from other species. Around 300 candidate defense proteins are identified based on sequence similarity to homologs known to participate in immune responses. In most cases, paralog counts are lower than those of Drosophila melanogaster or Anopheles gambiae but are substantially higher than those of Apis mellifera. The genome contains probable orthologs for nearly all members of the Toll, IMD, and JAK/STAT pathways. While total numbers of the clip-domain serine proteinases are approximately equal in the fly (29), mosquito (32) and beetle (30), lineage-specific expansion of the family is discovered in all three species. Sixteen of the thirty-one serpin genes form a large cluster in a 50 kb region that resulted from extensive gene duplications. Among the nine Toll-like proteins, four are orthologous to Drosophila Toll. The presence of scavenger receptors and other related proteins indicates a role of cellular responses in the entire system. The structures of some antimicrobial peptides drastically differ from those in other orders of insects. A framework of information on Tribolium immunity is established, which may serve as a stepping stone for future genetic analyses of defense responses in a nondrosophiline genetic model insect.


Impaction of durian seed in the larynx.
Common foreign bodies in adults include fish bones and improperly chewed meat A 72-year-old Malay gentleman was brought in by his son to the emergency department after he was seen gasping at home. The patient has an underlying history of stroke with neurological deficit include his gag reflex. According to family members, the patient had the symptom a day after he had allegedly consumed a piece of durian without removing its seed. Patient was then admitted to Intensive care Unit (ICU) for monitoring. His blood gas normalized and was extubated after 2 days in ICU before discharged home the next day.


Preoperative evaluation of biliary anatomy of donor in living donor liver transplantation by conventional nonenhanced magnetic resonance cholangiography.
Detailed preoperative evaluation of the biliary anatomy of the donor in living donor liver transplantation (LDLT) can minimize postoperative morbidity in the recipient and maximize safety for the donor. We prospectively evaluated the diagnostic accuracy and clinical usefulness of nonenhanced conventional magnetic resonance cholangiography (MRC) for depicting the biliary anatomy of LDLT donors. MRC and intraoperative cholangiography (IOC) examinations of 111 donors were performed between August 2005 and February 2006. We observed the classical branching pattern of the biliary system in 67 subjects (60.4%), with the remaining 44 subjects (39.6%) showing anatomical variations. MRC showed accurate anatomy of the biliary system, using IOC as the reference standard, in 98 (88.3%) subjects. MRC had a sensitivity in differentiating normal from variant anatomy of 95.5%, specificity of 95.2%, a positive predictive value of 96.8% and a negative predictive value of 93.3%. The agreement between MRC and IOC findings, as evaluated by kappa-value (0.865) was statistically significant (P<0.001). In conclusion, the diagnostic accuracy of conventional nonenhanced MRC is sufficient for this method to be used for the preoperative evaluation of biliary anatomy in LDLT donor candidates.


Qualitative analysis of the viability of autogenous fat grafts grafted in different environments of interstitial pressure. Preliminary results and description of a new experimental model in mini-pigs.
To evaluate the feasibility of an experimental model of autologous fat graft (AFG) in different interstitial pressure (IP) environments. Three mini-pigs(Minipig-BR) with age of 8 months (weight: 25-30 kg) were used. AFG were collected from the bucal fat pad, and grafted in the intramuscular pocket (biceps femoralis muscle). IP model was based on a fusiform ressection followed by primary closure "under tension". A blood pressure catheter located in the intramuscular region connected to a pressure module was applied to quantify IP. The mean operative time was 236 min (210 - 272 min). All the AFG and muscular segments were removed successfully. Average interstitial pressure CP and H were 3 and 10.6 mmHg respectively. The AFG were biopsied for histopathological analysis 30 days after graft. Hematoxylin-eosin staining and immunohistochemical analyzes (TNF-alpha, CD31 and Perilipine with monoclonal antibodies) were employed. The data show that minipigs model could be used as a recipient site for autologous fat graft techniques and allow the development of studies to explore the AFG intake and pathophysiology response.


What makes a good general practitioner: do patients and doctors have different views?
General practitioners (GPs) are expected to be responsive to patients' expectations, but patients and doctors may have different views on what constitutes good general practice care. To elicit areas of controversy as well as areas of mutual agreement between the opinions of patients and GPs with regard to good general practice care. A questionnaire, distributed to 850 patients and 400 GPs, measured which of 40 aspects of general practice care were given priority. A second questionnaire, distributed to 400 different GPs, measured the GPs' perception of the priorities of patients. The priority rank order of all 40 aspects was highly correlated for patients and GPs (0.72), as was the rank order of aspects for patients and the perception of them by GPs (0.71). Nevertheless, when comparing the priorities of patients and GPs, 23 out of 40 aspects differed significantly (P = 0.00125) in their rank number. Similarly, when comparing the priorities of patients with the perception of them by GPs, 23 aspects differed significantly. There is great similarity between the priorities of patients and those of GPs. GPs are quite capable of assessing most of the priorities of patients. However, potentially controversial areas of general practice care do exist.


Novel fibrin-fibronectin matrix accelerates mice skin wound healing.
Plasma fibrinogen (F1) and fibronectin (pFN) polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound healing. About 90% of plasma F1 has a homodimeric pair of γ chains (γγF1), and 10% has a heterodimeric pair of γ and more acidic γ' chains (γγ'F1). We have synthesized a novel fibrin matrix exclusively from a 1:1 (molar ratio) complex of γγ'F1 and pFN in the presence of highly active thrombin and recombinant Factor XIII (rFXIIIa). In this matrix, the fibrin nanofibers were decorated with pFN nanoclusters (termed γγ'F1:pFN fibrin). In contrast, fibrin made from 1:1 mixture of γγF1 and pFN formed a sporadic distribution of "pFN droplets" (termed γγF1+pFN fibrin). The γγ'F1:pFN fibrin enhanced the adhesion of primary human umbilical vein endothelium cells (HUVECs) relative to the γγF1+FN fibrin. Three dimensional (3D) culturing showed that the γγ'F1:pFN complex fibrin matrix enhanced the proliferation of both HUVECs and primary human fibroblasts. HUVECs in the 3D γγ'F1:pFN fibrin exhibited a starkly enhanced vascular morphogenesis while an apoptotic growth profile was observed in the γγF1+pFN fibrin. Relative to γγF1+pFN fibrin, mouse dermal wounds that were sealed by γγ'F1:pFN fibrin exhibited accelerated and enhanced healing. This study suggests that a 3D pFN presentation on a fibrin matrix promotes wound healing.


Local and global calcium signals associated with the opening of neuronal alpha7 nicotinic acetylcholine receptors.
Neuronal nicotinic acetylcholine receptors (nAChRs) are Ca(2+)-permeable ligand-gated channels widely expressed in the central and peripheral nervous system. One of the most Ca(2+) selective isoform is the homopentameric alpha7-nAChR implicated in schizophrenia. The activity of alpha7-nAChRs is usually recorded electrophysiologically, which limits the amount of information obtained. Here, we used fluorescence imaging to record Ca(2+) transients associated with activation of the alpha7-nAChR in neuroblastoma cells stably expressing human alpha7-nAChRs. Application of nicotine (50 microM) consistently evoked transient (30s), stereotyped Ca(2+) responses that were inhibited by the selective alpha7-nAChRs antagonists methyllycaconitine (MLA) and alpha-bungarotoxin, and greatly increased and prolonged by the allosteric modulator PNU-120596 (1 microM). Unexpectedly, brief (1-5s), repetitive Ca(2+) transients of sub-micrometric dimension were observed in filopodia of cells expressing alpha7-nAChR. PNU-120596 increased the frequency and slowed the decay kinetics of these miniature Ca(2+) elevations, which were insensitive to ryanodine, preserved during hyperpolarisation, and prevented by MLA, alpha-bungarotoxin, or Ca(2+) removal. Global Ca(2+) responses were also recorded in ganglion cells of embryo chicken retina during co-application of PNU-120596 and nicotine, together with whole-cell currents and brief current bursts. These data demonstrate that Ca(2+) signals generated by alpha7-nAChRs can be recorded optically both in cell lines and in intact tissues. The possibility to image miniature Ca(2+) signals enables to map the location of functional alpha7-nAChR channel clusters within cells and to analyze their single channel properties optically. Deciphering the rich pattern of intracellular Ca(2+) signals generated by the activity of the alpha7-nAChRs will reveal the physiological role of these receptor-channels.


The secreted Ipa complex of Shigella flexneri promotes entry into mammalian cells.
The bacterial pathogen Shigella flexneri causes bacillary dysentery in humans by invading coloncytes. Upon contact with epithelial cells, S. flexneri elicits localized plasma membrane projections sustained by long actin filaments which engulf the microorganism. The products necessary for Shigella entry include three secretory proteins: IpaB, IpaC, and IpaD. Extracellular IpaB and IpaC associate in a soluble complex, the Ipa complex. We have immunopurified this Ipa complex on latex beads and found that they were efficiently internalized into HeLa cells. Like S. flexneri entry, uptake of the beads bearing the Ipa complex was associated with membrane projections and polymerization of actin at the site of cell-bead interaction and was dependent on small Rho GTPases. These results indicate that a secreted factor can promote S. flexneri entry into epithelial cells.


Marijuana use among patients with epilepsy at a tertiary care center.
The expansion of medical and recreational marijuana legalization facilitates patient access to cannabis, and many patients with epilepsy pursue marijuana as a treatment for seizures. We administered a nine-item survey on marijuana use to patients seen in an epilepsy clinic over a 9 month period at a tertiary care center in Oregon where recreational use was legalized in 2015. The majority of respondents (n = 39) reported cannabis use for the purpose of treating epilepsy (87.2%, n = 34), and strongly agreed (53.8%, n = 21) or agreed (28.2%, n = 11) that cannabis use improved seizure control. The most commonly selected cannabis strains were high cannabidiol (CBD) (30.8%, n = 12) or multiple types (30.8%, n = 12), with administration methods of smoking (66.7%, n = 26), edibles (48.7%, n = 19), and concentrates (43.6%, n = 17). More participants reported using marijuana with primarily CBD than primarily tetrahydrocannabinol (THC) or equal CBD:THC content, and very few women reported using marijuana with primarily THC compared with men (10% of female versus 47% of male respondents). Only 2 of 39 participants were able to give an exact dosage used in milligrams. Medical and recreational dispensaries were the most common cannabis sources, followed by homegrown and friends/family members. Although pharmaceutical CBD extract is now Food and Drug Administration (FDA)-approved for certain epilepsy types, access remains limited. Further research is needed to understand recreational cannabis use among patients with epilepsy while clinical research for pharmaceutical cannabis products continues.


Molecular Signatures of Non-typeable Haemophilus influenzae Lung Adaptation in Pediatric Chronic Lung Disease.
Non-typeable Haemophilus influenzae (NTHi), an opportunistic pathogen of the upper airways of healthy children, can infect the lower airways, driving chronic lung disease. However, the molecular basis underpinning NTHi transition from a commensal to a pathogen is not clearly understood. Here, we performed comparative genomic and transcriptomic analyses of 12 paired, isogenic NTHi strains, isolated from the nasopharynx (NP) and bronchoalveolar lavage (BAL) of 11 children with chronic lung disease, to identify convergent molecular signatures associated with lung adaptation. Comparative genomic analyses of the 12 NP-BAL pairs demonstrated that five were genetically identical, with the remaining seven differing by only 1 to 3 mutations. Within-patient transcriptomic analyses identified between 2 and 58 differentially expressed genes in 8 of the 12 NP-BAL pairs, including pairs with no observable genomic changes. Whilst no convergence was observed at the gene level, functional enrichment analysis revealed significant under-representation of differentially expressed genes belonging to Coenzyme metabolism, Function unknown, Translation, ribosomal structure, and biogenesis Cluster of Orthologous Groups categories. In contrast, Carbohydrate transport and metabolism, Cell motility and secretion, Intracellular trafficking and secretion, and Energy production categories were over-represented. This observed trend amongst genetically unrelated NTHi strains provides evidence of convergent transcriptional adaptation of NTHi to pediatric airways that deserves further exploration. Understanding the pathoadaptative mechanisms that NTHi employs to infect and persist in the lower pediatric airways is essential for devising targeted diagnostics and treatments aimed at minimizing disease severity, and ultimately, preventing NTHi lung infections and subsequent chronic lung disease in children.


Poison Control and the Drug Information Center: the Palestinian experience.
The Palestinian Poison Control and Drug Information Center was established in 2006 to provide up-to-date information on medications and to help in the early diagnosis and management of poisoning cases. To summarize the activities carried out by the PCDIC in the past 2 years. Documented inquires received at the PCDIC were analyzed and the Center's activities were extracted from the files. During the first 2 years of the Center's existence, 323 enquiries were received, mainly (67.2%)from physicians; 70% of the calls were from the city of Nablus. Unintentional poisoning was the leading type of call (62.8%) followed by suicidal poisoning (20.7%). Medications were the major category of toxicants encountered (48.9%), followed by pesticides (23.5%). In 67.9% of the cases, the calls were initiated before any treatment was provided. The advice provided by the PCDIC was based on the nature of the call. During these 2 years the PCDIC has conducted both academic and non-academic activities. The Center introduced the concept of poison prevention weeks in Palestine and has conducted two so far. The PCDIC has published several articles in the fields of toxicology, rational drug use, complementary and herbal therapy, pharmacoepidemiology, and self-medication. Documentation of all enquiries is mandatory for analysis, evaluation, comparative purposes and quality assurance. More information campaigns are needed to encourage people to use the services provided by the PCDIC.


Hepatitis E Virus Does Not Contribute to Hepatic Decompensation Among Patients With Advanced Chronic Hepatitis C.
Hepatitis E (HEV) can cause acute-on-chronic liver failure in persons with pre-existing liver disease. We investigated whether HEV infection contributes to hepatic decompensation in patients with previously stable, advanced chronic hepatitis C. We performed a case-control study using stored serum samples from subjects enrolled in the randomized phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial (n = 1050; mean age, 51 y; 70% male; 40% with cirrhosis at baseline). Cases were subjects who developed hepatic decompensation within a 24-week period. Controls (3 per case) were subjects without hepatic decompensation matched for fibrosis stage and followed up for a similar period. A serum sample obtained within 6 months after the decompensation event in cases and the same follow-up period in controls were tested for anti-HEV IgG. Subjects with a positive result had a baseline sample similarly tested for anti-HEV IgG. We measured levels of anti-HEV IgM and HEV RNA in blood samples from incident cases. Of the 1050 subjects analyzed, 314 (30%) experienced a clinical event. Of the 314 subjects who experienced decompensation as defined, 89 (28%) were tested for anti-HEV, along with 267 controls (without decompensation). Similar proportions of cases and controls tested positive for anti-HEV (22.5% and 20.6%, respectively; P = .70). Ten incident HEV infections were identified-4 in cases (4.5%) and 6 in controls (2.2%) (P = .28). HEV RNA was not detected in blood samples from the 10 incident infections. Only 2 of the 4 incident infections among cases were related temporally to the decompensation event. HEV does not appear to be a significant cause of hepatic decompensation among persons with previously stable, advanced chronic hepatitis C in the United States.


Saliency detection based on biological plausibility of hypercomplex Fourier spectrum contrast.
This Letter proposes a novel saliency detection method based on biological plausibility of a hypercomplex Fourier spectrum contrast algorithm. The proposed algorithm takes into consideration not only simulation of simple cortical cells in the receptive field of humans but also the texture-color feature global spectrum contrast of an image. First, we utilize log-Gabor filters to mimic simple cortical cells in the receptive field of humans. Two complex numbers of texture colors are acquired through feature maps in hue, saturation, and value color space by log-Gabor. Second, we build the hypercomplex number using these representations of feature maps. Finally, the salient object is detected by spectrum contrast in the hypercomplex Fourier domain. Experimental results show that the proposed algorithm outperforms the state-of-the-art methods.