Imaging of peripheral vascular malformations - current concepts and future perspectives.
Vascular Malformations belong to the spectrum of orphan diseases and can involve all segments of the vascular tree: arteries, capillaries, and veins, and similarly the lymphatic vasculature. The classification according to the International Society for the Study of Vascular Anomalies (ISSVA) is of major importance to guide proper treatment. Imaging plays a crucial role to classify vascular malformations according to their dominant vessel type, anatomical extension, and flow pattern. Several imaging concepts including color-coded Duplex ultrasound/contrast-enhanced ultrasound (CDUS/CEUS), 4D computed tomography angiography (CTA), magnetic resonance imaging (MRI) including dynamic contrast-enhanced MR-angiography (DCE-MRA), and conventional arterial and venous angiography are established in the current clinical routine. Besides the very heterogenous phenotypes of vascular malformations, molecular and genetic profiling has recently offered an advanced understanding of the pathogenesis and progression of these lesions. As distinct molecular subtypes may be suitable for targeted therapies, capturing certain patterns by means of molecular imaging could enhance non-invasive diagnostics of vascular malformations. This review provides an overview of subtype-specific imaging and established imaging modalities, as well as future perspectives of novel functional and molecular imaging approaches. We highlight recent pioneering imaging studies including thermography, positron emission tomography (PET), and multispectral optoacoustic tomography (MSOT), which have successfully targeted specific biomarkers of vascular malformations.


Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects.
An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. Modafinil was well tolerated at a single oral dose of 200 mg. The most commonly reported adverse events were headache, fever, pharyngitis, and asthenia. There were no clinically meaningful differences with respect to the incidence rate of treatment-emergent adverse events among the young female, young male, and old male groups. Modafinil was rapidly absorbed after oral dosing and slowly cleared (t1/2 approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.


Evaluation of the antioxidant profile and cytotoxic activity of red propolis extracts from different regions of northeastern Brazil obtained by conventional and ultrasound-assisted extraction.
Propolis is a complex mixture of resinous and balsamic material collected from the exudates of plants, shoots, and leaves by bees. This study evaluated red propolis extracts obtained by conventional (ethanolic) extraction and ultrasound-assisted extraction of six samples from different regions of northeastern Brazil. The total phenolic compounds and flavonoids, in vitro antioxidant activity, concentration of formononetin and kaempferol and the cytotoxicity against four human tumor cell lines were determined for all twelve obtained extracts. Significant variations in the levels of the investigated compounds were identified in the red propolis extracts, confirming that the chemical composition varied according to the sampling region. The extraction method used also influenced the resulting propolis compounds. The highest concentration of the compounds of interest and the highest in vitro antioxidant activity were exhibited by the extracts obtained from samples from state of Alagoas. Formononetin and kaempferol were identified in all samples. The highest formononetin concentrations were identified in extracts obtained by ultrasound, thus indicating a greater selectivity for the extraction of this compound by this method. Regarding cytotoxic activity, for the HCT-116 line, all of the extracts showed an inhibition of greater than 90%, whereas for the HL-60 and PC3 lines, the minimum identified was 80%. In general, there was no significant difference (p>0.05) in the antiproliferative potential when comparing the extraction methods. The results showed that the composition of Brazilian red propolis varies significantly depending on the geographical origin and that the method used influences the resulting compounds that are present in propolis. However, regardless of the geographical origin and the extraction method used, all the red propolis samples studied presented great biological potential and high antioxidant activity. Furthermore, the ultrasound-assisted method can be efficiently applied to obtain extracts of red propolis more quickly and with high concentration of biomarkers of interest.


Biophysical feedback mediates effects of invasive grasses on coastal dune shape.
Vegetation at the aquatic-terrestrial interface can alter landscape features through its growth and interactions with sediment and fluids. Even similar species may impart different effects due to variation in their interactions and feedbacks with the environment. Consequently, replacement of one engineering species by another can cause significant change in the physical environment. Here we investigate the species-specific ecological mechanisms influencing the geomorphology of U.S. Pacific Northwest coastal dunes. Over the last century, this system changed from open, shifting sand dunes with sparse vegetation (including native beach grass, Elymus mollis), to densely vegetated continuous foredune ridges resulting from the introduction and subsequent invasions of two nonnative grass species (Ammophila arenaria and Ammophila breviligulata), each of which is associated with different dune shapes and sediment supply rates along the coast. Here we propose a biophysical feedback responsible for differences in dune shape, and we investigate two, non-mutually exclusive ecological mechanisms for these differences: (1) species differ in their ability to capture sand and (2) species differ in their growth habit in response to sand deposition. To investigate sand capture, we used a moveable bed wind tunnel experiment and found that increasing tiller density increased sand capture efficiency and that, under different experimental densities, the native grass had higher sand capture efficiency compared to the Ammophila congeners. However, the greater densities of nonnative grasses under field conditions suggest that they have greater potential to capture more sand overall. We used a mesocosm experiment to look at plant growth responses to sand deposition and found that, in response to increasing sand supply rates, A. arenaria produced higher-density vertical tillers (characteristic of higher sand capture efficiency), while A. breviligulata and E. mollis responded with lower-density lateral tiller growth (characteristic of lower sand capture efficiency). Combined, these experiments provide evidence for a species-specific effect on coastal dune shape. Understanding how dominant ecosystem engineers, especially nonnative ones, differ in their interactions with abiotic factors is necessary to better parameterize coastal vulnerability models and inform management practices related to both coastal protection ecosystem services and ecosystem restoration.


Paclitaxel and carboplatin with amifostine in advanced, recurrent, or refractory endometrial adenocarcinoma: a phase II study of the Southwest Oncology Group.
To evaluate the response rate and progression free and overall survival of patients with advanced endometrial cancer treated with paclitaxel, carboplatin and amifostine. To evaluate the toxicity of amifostine when used in combination with carboplatin and paclitaxel. Forty-seven eligible patients (median age: 66; range 45-82) with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/M2) and amifostine (740 mg/M2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity. There were 4 CRs (8%) (2 confirmed, 2 unconfirmed) and 15 PRs (32%) (9 confirmed, 6 unconfirmed) for a total response rate of 40% (95% confidence interval [CI], 26% to 56%). The median progression-free survival (PFS) was 7 months (95% CI, 6-9 months) and a 6-month PFS rate of 64% (95% CI, 50% to 78%). The median overall survival was 14 months (95% CI, 12 to 17 months). Toxicity was tolerable. While 79% of patients developed Grade 3/4 neutropenia (30% Grade 3, 49% Grade 4), there were no episodes of Grade 4 febrile neutropenia and one episode of infection with grades 3-4 neutropenia. The combination of paclitaxel and carboplatin with amifostine was well reasonably tolerated in this cohort. The regimen demonstrated significant activity in endometrial cancer, comparable to other multi-agent chemotherapy programs in terms of response rate and survival, and with a favorable toxicity profile.


Mucinous cystic neoplasm of the liver (MCN-L): a rare presentation and review of the literature.
Mucinous cystic neoplasms of the liver (MCN-L, (previously referred to as cystadenomas or cystadenocarcinoma) are rare cystic tumors that occur within the liver parenchyma, or less frequently, in the extrahepatic bile ducts. They are reported to account for <5% of all liver cysts. The differential diagnosis of MCN-L includes intraductal papillary neoplasm of the bile duct (IPNB), intrahepatic cholangiocarcinoma with cystic change, echinococcal cyst, and a simple cyst. Invasive MCNs can only be differentiated from non-invasive MCNs by microscopic evaluation for the presence of ovarian-type stroma. Intraoperative biopsy and frozen section(s) are essential to differentiate MCNs from other cystic liver lesions. The treatment of choice is complete excision and can result in excellent survival with initial correct diagnosis. But its rare presentation and insufficient recognition frequently lead to an incorrect initial or delayed diagnosis or misdiagnosis.


Coalitions of relatives and reproductive skew in cooperatively breeding white-winged choughs.
We used DNA fingerprinting to examine reproductive skew in cooperatively breeding white-winged choughs, Corcorax melanorhamphos, which live in groups of up to 20 individuals. Before a severe drought, groups that had been stable for multiple years were characterized by long-term monogamy involving a single breeding pair (high skew). After the drought, new groups formed from the amalgamation of multiple individuals and coalitions of relatives. At most one member of each faction succeeded in breeding, such that skew was dependent on the number of unrelated factions, and not group size. In the new groups, dominant males and females with supporting relatives were always successful. Whereas most females without support also gained breeding positions, many males without family support failed to breed. Thus subordinates gain indirect fitness by first helping related males to secure a breeding position, and then helping to raise their young. Our study demonstrates the advantage of operating in coalitions, and suggests that the acquisition of future allies may be a major benefit of helping behaviour in this species.


Floret development of durum wheat in response to nitrogen availability.
In Mediterranean durum wheat production, nitrogen (N) fertilization may be important to stabilize and increase yields. Wheat yield responses to N fertilization are usually related to grains per m(2), which in turn is the consequence of processes related to floret development (floret initiation followed by floret death/survival) during stem elongation. The literature is rather scarce in terms of the relevance of floret developmental dynamics, determining the final number of grains in general terms and in particular regarding responsiveness to N. The aim of this study was to determine whether durum wheat responses to N under different water regimes are related to the dynamics of development of floret primordia to produce fertile florets. During the 2006-2007 and 2007-2008 growing seasons, experiments with a factorial combination of two N levels (0 and 100 or 250 kg N ha(-1)) and two levels of water availability (rainfed and irrigated) were carried out (although the water regime was only effective in the second season). The response of yield was largely a consequence of that in grain number per spike. Floret initiation was similar for both N levels in each experiment and water regime, for which the survival of a higher proportion of initiated florets was critical in the response of the crop. The diminished rate of floret abortion during the late part of stem elongation in response to N was associated with a slightly accelerated rate of floret development which allowed a higher proportion of the primordia initiated to reach the stage of fertile floret by flowering.


Gastrotomy closure using bioabsorbable plugs in a canine model.
The repair of gastric perforation commonly involves simple suture closure using an open or laparoscopic approach. An endolumenal approach using prosthetic materials may be beneficial. The role of bioprosthetics in this instance has not been thoroughly investigated, thus the authors evaluated the feasibility of gastric perforation repair using a bioabsorbable device and quantified gross and histological changes at the injury site. Twelve canines were anesthetized and underwent open gastrotomy. A 1-cm-diameter perforation was created in the anterior wall of the stomach and plugged with a bioabsorbable device. Intralumenal pH was recorded. Canines were sacrificed at one, four, six, eight, and 12 weeks. The stomach was explanted followed by gross and histological examination. The injury site was examined. The relative ability of the device to seal the perforation was recorded, as were postoperative changes. Tissue samples were analyzed for gross and microscopic tissue growth and compared to normal gastric tissue in the same animal as an internal control. A scoring system of -2 to +2 was used to measure injury site healing (-2= leak, -1= no leak and minimal ingrowth, 0= physiologic healing, +1= mild hypertrophic tissue, +2= severe hypertrophic tissue). In all canines, the bioprosthesis successfully sealed the perforation without leak under ex vivo insufflation. At one week, the device maintained its integrity but there was no tissue ingrowth. Histological healing score was -1. At 4-12 weeks, gross examination revealed a healed injury site in all animals. The lumenal portion of the plug was completely absorbed. The gross and histological healing score ranged from -1 to +1. The application of a bioabsorbable device results in durable closure of gastric perforation with physiologic healing of the injury site. This method of gastrotomy closure may aid in the evolution of advanced endoscopic approaches to perforation closure of hollow viscera.


Multiple stressors in agricultural streams: a mesocosm study of interactions among raised water temperature, sediment addition and nutrient enrichment.
Changes to land use affect streams through nutrient enrichment, increased inputs of sediment and, where riparian vegetation has been removed, raised water temperature. We manipulated all three stressors in experimental streamside channels for 30 days and determined the individual and pair-wise combined effects on benthic invertebrate and algal communities and on leaf decay, a measure of ecosystem functioning. We added nutrients (phosphorus+nitrogen; high, intermediate, natural) and/or sediment (grain size 0.2 mm; high, intermediate, natural) to 18 channels supplied with water from a nearby stream. Temperature was increased by 1.4°C in half the channels, simulating the loss of upstream and adjacent riparian shade. Sediment affected 93% of all biological response variables (either as an individual effect or via an interaction with another stressor) generally in a negative manner, while nutrient enrichment affected 59% (mostly positive) and raised temperature 59% (mostly positive). More of the algal components of the community responded to stressors acting individually than did invertebrate components, whereas pair-wise stressor interactions were more common in the invertebrate community. Stressors interacted often and in a complex manner, with interactions between sediment and temperature most common. Thus, the negative impact of high sediment on taxon richness of both algae and invertebrates was stronger at raised temperature, further reducing biodiversity. In addition, the decay rate of leaf material (strength loss) accelerated with nutrient enrichment at ambient but not at raised temperature. A key implication of our findings for resource managers is that the removal of riparian shading from streams already subjected to high sediment inputs, or land-use changes that increase erosion or nutrient runoff in a landscape without riparian buffers, may have unexpected effects on stream health. We highlight the likely importance of intact or restored buffer strips, both in reducing sediment input and in maintaining cooler water temperatures.


Retinal Microvasculature Is Associated With Long-Term Survival in the General Adult Dutch Population.
Retinal vascular diameters are associated with (sub)clinical cardiovascular disease and short-term cardiovascular mortality, but their association with long-term mortality is uncertain. We studied the association of retinal vascular diameters with cause-specific mortality in the general adult Dutch population during 25 years of follow-up. From 1990 to 1993, arteriolar and venular diameters were measured semiautomatically on digitized images in 5674 persons (mean age 68.0 years, 59% women) from the population-based Rotterdam study. Follow-up for mortality was complete till March 2015. Associations between vascular diameters and mortality were examined using Cox proportional hazards models, adjusting for age, sex, cardiovascular risk factors, and the fellow vessel diameter. During 85 770 person-years (mean±SD: 15.1±6.67), 3794 (66.8%) persons died, of whom 1034 due to cardiovascular causes. We found that narrower arterioles and wider venules were associated with higher risk of mortality (adjusted hazard ratio [95% confidence interval] per SD decrease 1.04 [1.00-1.08] and increase 1.07 [1.03-1.12], respectively). For arterioles, these associations were strongest for cardiovascular mortality, whereas venules showed consistent associations for cardiovascular and noncardiovascular mortality. Importantly, these associations remained unchanged after excluding the first 10 years of follow-up as immortal person-time. We found evidence for effect modification with stronger associations in persons <70 years (venules only) and smokers (P value for interaction<0.01). We replicated our findings in another independent cohort from the Rotterdam Study of 3106 persons with 19 880 person-years of follow-up and 144 deaths (hazard ratio for venules 1.22 [1.00-1.49]). Markers of retinal microvasculature are associated with long-term mortality in the general adult Dutch population.


Using digital story telling to assess health students' knowledge of interprofessional roles in the care of the older adult.
Digital story telling (DST) is an innovative way to allow students to assess the care needs of an older adult and creates an opportunity for interdisciplinary involvement. Traditionally, a single healthcare discipline approach is used by higher education institutions for preclinical training in the care of the older adult. Interprofessional learning (IPL) is generally not integrated well into the health professional curricula of Australian Universities. To explore the use of Mask-Ed as a way of eliciting students understanding of their roles in patient care and to determine readiness for IPL in a cohort of health students prior to clinical placement. An online survey of students prior to their first clinical placement was undertaken. The survey incorporated a digital story of a Mask-Ed character and the readiness for IPL scale. Students recognised the importance of IPL. However, only 25% of students had an advanced understanding of their own roles and no student showed an advanced understanding of the other disciplines roles in the care of the older adult. In this study, DST using Mask-Ed assisted with students' understanding of interprofessional roles in the care of the older adult. Our findings demonstrated that IPL is important, and this was further enhanced by the use of Mask-Ed simulation.


Improving T-cell therapy for relapsed EBV-negative Hodgkin lymphoma by targeting upregulated MAGE-A4.
Patients with Hodgkin lymphoma (HL) relapsing after hematopoietic stem cell transplant have limited options for long-term cure. We have shown that infused cytotoxic T cells (CTL) targeting Epstein Barr virus (EBV)-derived proteins induced complete remissions in EBV(+) HL patients. A limitation of this approach is that up to 70% of relapsed HL tumors are EBV-negative. For these patients, an alternative is to target the cancer/testis antigen MAGE-A4 present in EBV antigen-negative HL tumors. Furthermore, epigenetic modification by clinically available demethylating agents can enhance MAGE-A4 expression in previously MAGE-negative tumors. We explored the feasibility of combining adoptive T cell therapy with epigenetic modification of tumor antigen expression. We further characterized MAGE-A4-specific T-cell phenotype and function, and examined the effects of the epigenetic modifying drug decitabine on these T cells. Cytotoxic T cells were generated specifically recognizing MAGE-A4 expressed by autologous HL targets and tumor cell lines. Decitabine-previously shown to increase tumor antigen expression in HL-did not compromise MAGE-A4-specific T-cell phenotype and function. In patients treated with decitabine, expanded MAGE-A4-specific T cells had a broader antitumor T cell repertoire, consistent with increased antigen stimulation in vivo. Adoptive transfer of MAGE-A4-specific T cells, combined with epigenetic modifying drugs to increase expression of the protein, may improve treatment of relapsed HL.


Presence of the aphid, Chaetosiphon fragaefolii, on strawberry in Argentina.
Seasonal abundance of the strawberry aphid complex under different agronomic practices in the outskirts of La Plata, Argentina was studied on strawberry, Fragaria x ananassa Duchesne (Rosales: Rosaceae). Aphid densities were low in strawberry fields in which insecticides and fungicides were used. In addition to Aphis gossypii, Aphis fabae, Mysus persicae and Macrosiphum euphorbiae, the aphid, Chaetosiphon fragaefolii (Cockerell) (Homoptera: Aphididae), was recorded for the first time in this horticultural area. Life history and some demographic parameters were calculated for C. fragaefolii. The mean duration of nymphal stages was 10.44 days, the oviposition period was 11.8 days, and the mean number of nymph/female/day was 2.4 +/- 0.3. Demographic parameters analyzed included the net reproductive rate R(o) = 14.55 +/- 0.096 nymph/female, generation time T=16.91 +/- 0.035 days, and the intrinsic rate of increase r(m) = 0.158 +/- (0.004). No parasites were found associated with C. fragaefolli. The pathogenic fungus, Entomophthora planchoniana Cornu (Zygomycetes: Entomophthorales) was the main mortality factor. Although aphids are not the main pests in strawberry fields, C. fragaefolii can be a serious problem because it can transmit several virus diseases of strawberry. Greater knowledge of life history traits and mortality factors of this species is needed in order to design appropriate control strategies.


Mitochondrial dysfunction during in vitro hepatocyte steatosis is reversed by omega-3 fatty acid-induced up-regulation of mitofusin 2.
We examined the effects and mechanisms of omega-3 polyunsaturated fatty acid (PUFA) administration on mitochondrial morphology and function in an in vitro steatotic hepatocyte model created using HepG2 cells. Reverse transcriptase polymerase chain reaction and Western blot analyses were performed to determine the expression levels of mitofusin 2 (Mfn2), and immunofluorescent MitoTracker Mitochondrion-Selective Probes were used to detect changes in mitochondrial morphology. Adenosine triphosphate (ATP) synthesis and reactive oxygen species (ROS) production were measured to assess mitochondrial function. Mitofusin 2 expression was significantly suppressed (P < .05), ATP levels were decreased (P < .05), ROS production was increased (P < .05), and the normal tubular network of mitochondria was fragmented into short rods or spheres. Model cells were incubated with eicosapentaenoic acid or docosahexaenoic acid at a final concentration of 50 μmol/L for 1 hour. Both eicosapentaenoic acid and docosahexaenoic acid increased the expression of Mfn2 (P < .01) and caused an increase in the length of mitochondrial tubules. The omega-3 PUFAs also increased the levels of ATP (P < .05) and decreased the ROS production (P < .05). However, these changes were not seen in Mfn2-depleted steatotic HepG2 cells, created by RNA interference before incubation with the omega-3 PUFAs. This study demonstrated that, in steatotic hepatocytes, omega-3 PUFAs may change mitochondrial morphology and have beneficial effects on recovery of mitochondrial function by increasing the expression of Mfn2.


Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials.
Patients with diffuse large B-cell lymphoma treated with first-line anthracycline-based immunochemotherapy and remaining in remission at 2 years have excellent outcomes. This study assessed overall survival (OS) stratified by progression-free survival (PFS) at 24 months (PFS24) using individual patient data from patients with DLBCL enrolled in multi-center, international randomized clinical trials as part of the Surrogate Endpoint for Aggressive Lymphoma (SEAL) Collaboration. PFS24 was defined as being alive and PFS24 after study entry. OS from PFS24 was defined as time from identified PFS24 status until death due to any cause. OS was compared with each patient's age-, sex-, and country-matched general population using expected survival and standardized mortality ratios (SMRs). A total of 5853 patients enrolled in trials in the SEAL database received rituximab as part of induction therapy and were included in this analysis. The median age was 62 years (range 18-92), and 56% were greater than 60 years of age. At a median follow-up of 4.4 years, 1337 patients (23%) had disease progression, 1489 (25%) had died, and 5101 had sufficient follow-up to evaluate PFS24. A total of 1423 assessable patients failed to achieve PFS24 with a median OS of 7.2 months (95% CI 6.8-8.1) after progression; 5-year OS after progression was 19% and SMR was 32.1 (95% CI 30.0-34.4). A total of 3678 patients achieved PFS24; SMR after achieving PFS24 was 1.22 (95% CI 1.09-1.37). The observed OS versus expected OS at 3, 5, and 7 years after achieving PFS24 was 93.1% versus 94.4%, 87.6% versus 89.5%, and 80.0% versus 83.7%, respectively. Patients treated with rituximab containing anthracycline-based immunochemotherapy on clinical trials who are alive without progression at 24 months from the onset of initial therapy have excellent outcomes with survival that is marginally lower but clinically indistinguishable from the age-, sex-, and country-matched background population for 7 years after achieving PFS24.


The chronically mentally ill in community facilities. A study of quality of life.
The quality of life of chronically mentally ill patients in acute wards in a district general hospital, a hostel ward and group homes was compared. Within the spectrum of care of these patients, the severity of psychopathology corresponded to their placement. Analysis, including adjustments for the influence of psychopathology, showed differences between the three types of facility. Although differences existed between all types of care, residents in group homes and the hostel ward shared more similarities in quality of life than those in the district general hospital. Problems of caring for the chronically mentally ill on acute wards are highlighted.


Diversity of transposable elements and repeats in a 600 kb region of the fly Calliphora vicina.
Transposable elements (TEs) are a very dynamic component of eukaryotic genomes with important implications (e.g., in evolution) and applications (e.g., as transgenic tools). They also represent a major challenge for the assembly and annotation of genomic sequences. However, they are still largely unknown in non-model species. Here, we have annotated the repeats and transposable elements present in a 600 kb genomic region of the blowfly Calliphora vicina (Diptera: Calliphoridae) which contains most of the achaete-scute gene complex of this species. This is the largest genomic region to be sequenced and analyzed in higher flies outside the Drosophila genus. We find that the repeat content spans at least 24% of the sequence. It includes 318 insertions classified as 3 LTR retrotransposons, 21 LINEs, 14 cut-and-paste DNA transposons, 4 helitrons and 33 unclassified repeats. This is the most detailed description of TEs and repeats in the Calliphoridae to date. This contribution not only adds to our knowledge about TE evolution but will also help in the annotation of repeats on Dipteran whole genome sequences.


The influence of aquariums on weight in individuals with dementia.
This study assessed whether individuals with dementia who observe aquariums increase the amount of food they consume and maintain body weight. The sample included 70 residents in dementia units within 3 extended care facilities in 2 states. The intervention included the introduction of an aquarium into each common dining area. A total increase of 196.9 g of daily food intake (25.0%) was noted from baseline to the end of the 10-week study. Resident body weight increased an average of 2.2 pounds during the study. Eight of 70 residents experienced a weight loss ((Equation is included in full-text article.)=1.89 lbs). People with advanced dementia responded to aquariums in their environment documenting that attraction to the natural environment is so innate that it survives dementia.


Reprogramming control of an allosteric signaling switch through modular recombination.
Many eukaryotic signaling proteins are composed of simple modular binding domains, yet they can display sophisticated behaviors such as allosteric gating and multi-input signal integration, properties essential for complex cellular circuits. To understand how such behavior can emerge from combinations of simple domains, we engineered variants of the actin regulatory protein N-WASP (neuronal Wiskott-Aldrich syndrome protein) in which the "output" domain of N-WASP was recombined with heterologous autoinhibitory "input" domains. Synthetic switch proteins were created with diverse gating behaviors in response to nonphysiological inputs. Thus, this type of modular framework can facilitate the evolution or engineering of cellular signaling circuits.


Salutogenesis as a theoretical framework for psychosocial rehabilitation: the case of the Clubhouse model.
Purpose: This study explored whether the holistic theory of salutogenesis may be a suitable theoretical framework for the Clubhouse model of psychosocial rehabilitation, a pioneer among psychosocial rehabilitation programmes.Methods: A systematic examination of elements of the Clubhouse model, as prescribed by the Clubhouse standards, was performed within the context of the theory of salutogenesis including its basic salutogenic orientation and the main concepts of sense of coherence and resistance resources.Results: We found that several standards and practices within the Clubhouse model can be understood as applications of salutogenesis. We have hypothesized that the Clubhouse model promotes peoples' sense of coherence and mental health. However, our investigation also showed that, to enhance the recovery of Clubhouse members, more explicitly incorporating some salutogenic principles, such as "appropriate challenges" and "active adaptation as the ideal in treatment", may benefit Clubhouse practice.Conclusions: The Clubhouse model of psychosocial rehabilitation is very consistent with the salutogenic orientation and main salutogenic concepts. The present study suggests that salutogenesis may be a suitable theoretical framework for the Clubhouse model and possibly in the psychosocial rehabilitation field in general.


Critical appraisal of technologies to assess electrical activity during atrial fibrillation: a position paper from the European Heart Rhythm Association and European Society of Cardiology Working Group on eCardiology in collaboration with the Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society and Computing in Cardiology.
We aim to provide a critical appraisal of basic concepts underlying signal recording and processing technologies applied for (i) atrial fibrillation (AF) mapping to unravel AF mechanisms and/or identifying target sites for AF therapy and (ii) AF detection, to optimize usage of technologies, stimulate research aimed at closing knowledge gaps, and developing ideal AF recording and processing technologies. Recording and processing techniques for assessment of electrical activity during AF essential for diagnosis and guiding ablative therapy including body surface electrocardiograms (ECG) and endo- or epicardial electrograms (EGM) are evaluated. Discussion of (i) differences in uni-, bi-, and multi-polar (omnipolar/Laplacian) recording modes, (ii) impact of recording technologies on EGM morphology, (iii) global or local mapping using various types of EGM involving signal processing techniques including isochronal-, voltage- fractionation-, dipole density-, and rotor mapping, enabling derivation of parameters like atrial rate, entropy, conduction velocity/direction, (iv) value of epicardial and optical mapping, (v) AF detection by cardiac implantable electronic devices containing various detection algorithms applicable to stored EGMs, (vi) contribution of machine learning (ML) to further improvement of signals processing technologies. Recording and processing of EGM (or ECG) are the cornerstones of (body surface) mapping of AF. Currently available AF recording and processing technologies are mainly restricted to specific applications or have technological limitations. Improvements in AF mapping by obtaining highest fidelity source signals (e.g. catheter-electrode combinations) for signal processing (e.g. filtering, digitization, and noise elimination) is of utmost importance. Novel acquisition instruments (multi-polar catheters combined with improved physical modelling and ML techniques) will enable enhanced and automated interpretation of EGM recordings in the near future.


Modulation of Cardiac Alternans by Altered Sarcoplasmic Reticulum Calcium Release: A Simulation Study.
Background: Cardiac alternans is an important precursor to arrhythmia, facilitating formation of conduction block, and re-entry. Diseased hearts were observed to be particularly vulnerable to alternans, mainly in heart failure or after myocardial infarction. Alternans is typically linked to oscillation of calcium cycling, particularly in the sarcoplasmic reticulum (SR). While the role of SR calcium reuptake in alternans is well established, the role of altered calcium release by ryanodine receptors has not yet been studied extensively. At the same time, there is strong evidence that calcium release is abnormal in heart failure and other heart diseases, suggesting that these changes might play a pro-alternans role. Aims: To demonstrate how changes to intracellular calcium release dynamics and magnitude affect alternans vulnerability. Methods: We used the state-of-the-art Heijman-Rudy and O'Hara-Rudy computer models of ventricular myocyte, given their detailed representation of calcium handling and their previous utility in alternans research. We modified the models to obtain precise control over SR release dynamics and magnitude, allowing for the evaluation of these properties in alternans formation and suppression. Results: Shorter time to peak SR release and shorter release duration decrease alternans vulnerability by improved refilling of releasable calcium within junctional SR; conversely, slow release promotes alternans. Modulating the total amount of calcium released, we show that sufficiently increased calcium release may surprisingly prevent alternans via a mechanism linked to the functional depletion of junctional SR during release. We show that this mechanism underlies differences between "eye-type" and "fork-type" alternans, which were observed in human in vivo and in silico. We also provide a detailed explanation of alternans formation in the given computer models, termed "sarcoplasmic reticulum calcium cycling refractoriness." The mechanism relies on the steep SR load-release relationship, combined with relatively limited rate of junctional SR refilling. Conclusion: Both altered dynamics and magnitude of SR calcium release modulate alternans vulnerability. In particular, slow dynamics of SR release, such as those observed in heart failure, promote alternans. Therefore, acceleration of intracellular calcium release, e.g., via synchronization of calcium sparks, may inhibit alternans in failing hearts and reduce arrhythmia occurrence.


Deformation of stereolithographically produced surgical guides: an observational case series report.
Template-based computer-guided implant placement holds the promise of more precise and less traumatic placement of dental implants. Errors in the fabrication process of the surgical guide may lead to unfavorable clinical outcomes. This report discusses the potential of unintentional volumetric deformation of stereolithographically (SLA) produced surgical guides (NobelGuide, Nobel Biocare AB, Göteborg, Sweden) compared with the original scan denture. Three-dimensional radiographic data acquired by medical computerized tomography (CT) or cone beam CT (Newtom 3G, AFP Imaging Corporation, Elmsford, NY, USA) can be utilized in specialized software to develop treatment planning for dental implant placement. This information can then be transferred to the patient via a surgical guide. Stereolithography is a rapid prototyping process that can be used to create such a guide stent. Three cases are shown describing different levels of deformation of SLA-produced surgical guides. Unintentional deformation of SLA-produced surgical guides is possible. Deformation of surgical guides can create dissimilarity between the virtually planned position and the actual position of the implants. Incorrect setting of the ISO values for the segmentation of the scan denture has been found to be a factor in the deformation of SLA-produced surgical guides, although more, at this time known but also less understood, issues appear to be involved. Only one manufacturer's product is discussed; further research is warranted to determine if the discrepancies are process or product based. It might be prudent to closely evaluate the volumetric congruence of SLA-produced surgical stents before their clinical use to prevent undesired clinical outcomes.


The role of transcription in heterologous expression of polyketides in bacterial hosts.
Heterologous expression of biosynthetic pathways is an indispensable tool in the discovery, production, engineering, and characterization of bacterial polyketides and the complex enzymology involved in their biosynthesis. Ensuring transcription of polyketide biosynthetic gene clusters in heterologous hosts is a pressing problem. This review evaluates the two strategies used to ensure transcription. The first is a promoter replacement approach where promoters known to function in the heterologous host are inserted into the biosynthetic gene cluster. The second is an approach that relies on the heterologous host recognizing and utilizing promoters native to the gene cluster. Both have been successful methodologies and have different strengths and weaknesses, which are highlighted and discussed.


Stress relaxation and stress-strain characteristics of porcine amniotic membrane.
Recently, amniotic membrane (AM) as scaffold is accumulating much more attention in tissue engineering. It is well-known that the mechanical properties of the scaffold inevitably affect the biological process of the incorporated cells. This study investigates the stress relaxation and stress-strain characteristics of AM, which have not been sufficiently elucidated before. Porcine AM samples were prepared at four different AM regions and at three different directions. Ramp-and-hold and stretch-to-rupture tests were conducted on a uniaxial tensile apparatus. A nonlinear viscoelastic model with two relaxation coefficients is proposed to fit the ramp-and-hold data. Rupture strain, rupture stress, and elastic modulus of the linear portion of the stress-strain curve are used to characterize the strength properties of the AM. Sample direction has no significant effect on the mechanical properties of the AM. Samples at the ventral region has the maximum rupture strength and elastic modulus, respectively, 2.29±0.99MPa and 6.26±2.69MPa. The average of the relaxation coefficient for the fast and slow relaxation phases are 12.8±4.4s and 37.0±7.7s, respectively. AM is a mechanically isotropic and heterogeneous material. The nonlinear viscoelastic model is suitable to model the AM viscoelasticity and potential for other biological tissues.


The scope of plastic surgery.
To ascertain junior doctors' awareness of the scope of public-sector plastic surgery practice. A 12-part questionnaire asked the respondents to name, from a list, the specialty they felt was best equipped to manage patients with specific conditions. The data demonstrate that perception of the scope of plastic and reconstructive surgery is grossly limited. Although plastic surgeons were associated with reconstructive procedures, they were not necessarily identified as primary surgeons for procedures that they commonly perform. A significant number of respondents believed that plastic surgeons are seldom the first line of referral, and are more involved in cases with aesthetic rather than functional sequelae. These findings should be regarded with concern, particularly in light of the fact that these doctors will be responsible for carrying the burden of primary care delivery in South Africa and for referrals to secondary and tertiary levels of care. The study motivates for increased exposure to plastic surgery during undergraduate and postgraduate medical training.


Posttraumatic stress disorder symptom structure in injured children: functional impairment and depression symptoms in a confirmatory factor analysis.
To examine the factor structure of posttraumatic stress disorder (PTSD) symptoms in children and adolescents who have experienced an acute single-incident trauma, associations between PTSD symptom clusters and functional impairment, and the specificity of PTSD symptoms in relation to depression and general distress. Examined PTSD symptom structure in two samples of children (8 to 17 years of age) assessed an average of 6 months after unintentional injury: (1) a combined dataset of 479 children assessed with a PTSD symptom checklist, and (2) a sample of 204 children assessed via a standardized clinical interview. We evaluated the fit of six alternative models for the factor structure of PTSD symptoms, and the association of PTS symptom clusters with indicators of functional impairment. We then evaluated three models for the structure of PTSD and depression symptoms jointly, to examine specificity of PTSD versus general distress or mood symptoms. In both samples, the DSM-IV 3-factor model fit the data reasonably well. Two alternative four-factor models fit the data very well: one that separates effortful avoidance from emotional numbing, and one that separates PTSD-specific symptoms from general emotional distress. Effortful avoidance and dysphoria symptoms were most consistently associated with impairment. The best-fitting model for PTSD and depression symptom clusters had three factors: PTSD-specific, depression-specific, and general dysphoria symptoms. The DSM-IV model for PTSD symptom categories was a reasonable fit for these child data, but several alternative models fit equally well or better, and suggest potential improvements to the current diagnostic criteria for PTSD in children.


Clinicopathological features, treatment and outcome of Omani patients with localised prostate cancer.
Objectives: To report the outcomes of Omani men diagnosed with localised prostate cancer (PCa), as PCa incidence is increasing in developing countries and there are scarce data regarding clinicopathological features and outcomes of PCa from the Arab world. Patients and methods: All men diagnosed with localised PCa between January 2006 and December 2017, and treated at a university hospital in Oman were included in the study. Data included demographic information, clinical, laboratory, pathological and radiological features at presentation, treatment modalities, and survival outcomes. Patients were followed until April 2019 or until death for disease-free survival (DFS) and overall survival (OS) whichever came first. Survival rates were estimated using the method of Kaplan and Meier. Univariate and multivariate analysis and Cox regression analyses were performed to study factors affecting DFS and OS. Results: Out of 239 men diagnosed with PCa over the study period, only 47 had localised disease (19.7%). The median age was 69 years. The majority (53.2%) had a Gleason score of ≥8 and a median (range) PSA level of 23.71 (range 0.6 - 452.9)ng/mL. In all, 16 patients received radical surgery, 17 received hormonal therapy along with definitive radiotherapy, while 15 were treated either with medical or surgical castration only. After a median follow-up of 43 months, the median DFS was 44.0 months. The median OS was not reached for the entire cohort. The 5- and 10-year OS rates were 84% and 57%, respectively Conclusion: Omani patients with localised PCa present with a high PSA level and a high Gleason score. Potentially curative treatments options, e.g. radical surgery and radiotherapy, are underutilised. The survival outcomes are similar to studies reported internationally. Abbreviations: (P)ADT: (primary) androgen-deprivation therapy; CAPRA: Cancer of the Prostate Risk Assessment; 3D: three-dimensional; DFS: disease-free survival; HDI: Human Development Index; Linacs, linear accelerators; NCCN: National Comprehensive Cancer Network; OS: overall survival; (m)(CR)PC: (metastatic) (castrate-resistant) prostate cancer; RP: radical prostatectomy; (IM)RT: (intensity modulated) radiotherapy; SQUH: Sultan Qaboos University Hospital.


Poly(vinyl alcohol) as a water protecting agent for silver nanoparticles: the role of polymer size and structure.
Chemical modification of silver nanoparticles (AgNPs) with a stabilizing agent, such as poly(vinyl alcohol) (PVA), plays an important role in shape-controlled seeded-growth and colloidal stability. However, theoretical aspects of the stabilizing mechanism of PVA are still poorly understood. To gain a better understanding of the role of PVA in water protecting effects for silver nanoparticles, we developed an atomistic model of a AgNP grafted with single-chain PVA of various lengths. Our model, designed for classical molecular dynamics (MD) simulations, approximates the AgNP as a quasi-spherical silver nanocrystal with 3.9 nm diameter and uses a united-atom representation for PVA with its polymer chain length varying from 220 up to 1540 repeating units. We found that PVA adsorbs onto the AgNP surface through multiple non-covalent interactions, among which non-covalent bonding of the hydroxyl groups plays a key role. The analysis of adsorption isotherms by using the Hill, Scatchard, and McGhee & von Hippel models exhibits evidence for positive binding cooperativity with the cooperativity parameter varying from 1.55 to 2.12. Our results indicate that the size of the PVA polymer rather than its structure plays a crucial role in providing water protecting effects for the AgNP core, varying from 40% up to 91%. The water-protecting efficiency was well approximated by the Langmuir-Freundlich equation, allowing us to predict that the saturated coverage of the nanoparticle of a given diameter of 3.9 nm should occur when the PVA molecular weight approaches 115 kDa, which corresponds to the number of vinyl alcohol monomers being equal to 3100 units.


Effect of dietary n-3 polyunsaturated fatty acids on the inducibility of ventricular tachycardia in patients with ischemic cardiomyopathy.
Increased consumption of fish and/or fish oil was associated with decreased risk of sudden cardiac death (SCD). The study aim was to evaluate the antiarrhythmic effect of dietary fish oil on the inducibility of ventricular tachycardia (VT) at high risk of SCD. Patients with coronary artery disease undergoing defibrillator implantation were recruited if sustained monomorphic VT could be induced by programmed extra stimuli at 2 cycle lengths. After the initial study, 12 patients consumed 3 g/d of encapsulated fish oil for approximately 6 weeks before a repeated electrophysiologic study. To control for fluctuations in the inducibility of VT, an additional 14 patients with no dietary manipulation were also studied. Aggressiveness of stimulation required to induce VT was ranked from least aggressive to most aggressive based on cycle length and number of extra stimuli, with noninducibility ranked highest. At the repeated electrophysiologic study, in the fish-oil group, 42% had no inducible VT, 42% required more aggressive stimulation to induce VT, 8% required identical stimulation, and 8% required less stimulation compared with 7%, 36%, 36%, and 21% in the control group, respectively. Overall, there was a change to noninducible or less inducible VT in the fish-oil group, but no change in the control group (p = 0.003 and p = 0.65, respectively; Wilcoxon's sign-rank test). In conclusion, dietary n-3 fatty acid supplementation decreased the inducibility of VT in patients at risk of SCD. These findings suggest that dietary fish oil can have an antiarrhythmic effect.


Immediate outcomes in early life epilepsy: A contemporary account.
Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts. Children with newly diagnosed epilepsy and onset <3 years were prospectively recruited through 17 US hospitals, from 2012 to 2015 and followed for 1 year after diagnosis. Short-term outcome included mortality, drug resistance, evolution of nonsyndromic epilepsy to infantile spasms (IS) and from IS to other epilepsies, and developmental decline. Multivariable analyses assessed the risk of each outcome. Seven hundred seventy-five children were recruited, including 408 (53%) boys. Median age at onset was 7.5 months (interquartile range (IQR): 4.2-16.5), and 509 (66%) had onset in the first year of life. Of 22 deaths that occurred within one year of epilepsy diagnosis, 21 were children with epilepsy onset in infancy (<12 months). Of 680 children followed ≥6 months, 239 (35%) developed drug-resistant seizures; 34/227 (15%) infants with nonsyndromic epilepsy developed IS, and 48/210 (23%) initially presenting with IS developed additional seizure types. One hundred of 435 (23%) with initially typical development or only mild/equivocal delays at seizure onset, had clear developmental impairment within one year after initial diagnosis. Each outcome had a different set of predictors; however, younger age and impaired development at seizure onset were broadly indicative of poorer outcomes. Type of epilepsy and early identification of underlying cause were not reliable predictors of these outcomes. Early-life epilepsies carry a high risk of poor outcome which is evident shortly after epilepsy diagnosis. Onset in infancy and developmental delay is associated with an especially high risk, regardless of epilepsy type. The likelihood of poor outcomes is worrisome regardless of specific clinical profiles.


The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats.
The angiotensin AT2 receptor modulates renal production of cyclic guanosine 3',5'-monophosphate (cGMP; J. Clin. Invest. 1996. 97:1978-1982). In the present study, we hypothesized that angiotensin II (Ang II) acts at the AT2 receptor to stimulate renal production of nitric oxide leading to the previously observed increase in cGMP. Using a microdialysis technique, we monitored changes in renal interstitial fluid (RIF) cGMP in response to intravenous infusion of the AT2 receptor antagonist PD 123319 (PD), the AT1 receptor antagonist Losartan, the nitric oxide synthase (NOS) inhibitor nitro--arginine-methyl-ester (-NAME), the specific neural NOS inhibitor 7-nitroindazole (7-NI), or Ang II individually or combined in conscious rats during low or normal sodium balance. Sodium depletion significantly increased RIF cGMP. During sodium depletion, both PD and -NAME caused a similar decrease in RIF cGMP. Combined administration of PD and -NAME decreased RIF cGMP to levels observed with PD or -NAME alone or during normal sodium intake. During normal sodium intake, Ang II caused a twofold increase in RIF cGMP. Neither PD nor -NAME, individually or combined, changed RIF cGMP. Combined administration of Ang II and either PD or -NAME produced a significant decrease in RIF cGMP compared with that induced by Ang II alone. Combined administration of Ang II, PD, and -NAME blocked the increase in RIF cGMP produced by Ang II alone. During sodium depletion, 7-NI decreased RIF cGMP, but the reduction of cGMP in response to PD alone or PD combined with 7-NI was greater than with 7-NI alone. During normal sodium intake, 7-NI blocked the Ang II-induced increase in RIF cGMP. PD alone or combined with 7-NI produced a greater inhibition of cGMP than did 7-NI alone. During sodium depletion, 7-NI (partially) and -NAME (completely) inhibited RIF cGMP responses to -arginine. These data demonstrate that activation of the renin- angiotensin system during sodium depletion increases renal nitric oxide production through stimulation by Ang II at the angiotensin AT2 receptor. This response is partially mediated by neural NOS, but other NOS isoforms also contribute to nitric oxide production by this pathway.


An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases.
RNA interference (RNAi) and antisense strategies provide experimental therapeutic agents for numerous diseases, including polyglutamine (polyQ) disorders caused by CAG repeat expansion. We compared the potential of different oligonucleotide-based strategies for silencing the genes responsible for several polyQ diseases, including Huntington's disease and two spinocerebellar ataxias, type 1 and type 3. The strategies included nonallele-selective gene silencing, gene replacement, allele-selective SNP targeting and CAG repeat targeting. Using the patient-derived cell culture models of polyQ diseases, we tested various siRNAs, and antisense reagents and assessed their silencing efficiency and allele selectivity. We showed considerable allele discrimination by several SNP targeting siRNAs based on a weak G-G or G-U pairing with normal allele and strong G-C pairing with mutant allele at the site of RISC-induced cleavage. Among the CAG repeat targeting reagents the strongest allele discrimination is achieved by miRNA-like functioning reagents that bind to their targets and inhibit their translation without substantial target cleavage. Also, morpholino analog performs well in mutant and normal allele discrimination but its efficient delivery to cells at low effective concentration still remains a challenge. Using three cellular models of polyQ diseases and the same experimental setup we directly compared the performance of different oligonucleotide-based treatment strategies that are currently under development. Based on the results obtained by us and others we discussed the advantages and drawbacks of these strategies considering them from several different perspectives. The strategy aimed at nonallele-selective inhibiting of causative gene expression by targeting specific sequence of the implicated gene is the easiest to implement but relevant benefits are still uncertain. The gene replacement strategy that combines the nonallele-selective gene silencing with the expression of the exogenous normal allele is a logical extension of the former and it deserves to be explored further. Both allele-selective RNAi approaches challenge cellular RNA interference machinery to show its ability to discriminate between similar sequences differing in either single base substitutions or repeated sequence length. Although both approaches perform well in allele discrimination most of our efforts are focused on repeat targeting due to its potentially higher universality.


High-intensity signals in the basal ganglia from gadolinium-enhanced T1-weighted MRI as an early change in toxoplasma encephalitis in an AIDS patient.
A 30-year-old Brazilian man hospitalized with AIDS developed a high-grade fever. Neither culture studies nor radiological examinations revealed the cause; small yet highly intense signals in the basal ganglia were detected upon gadolinium (Gd)-enhanced T1-weighted magnetic resonance imaging (MRI) of the head. This finding was equivocal at that time but obviously abnormal for his age. A week later, he developed a movement disorder in his right arm, speech apraxia, and a worsening disturbance of consciousness. Repeated Gd-enhanced T1-weighted MRI demonstrated incredible changes in the brain; enhanced lesions in the basal ganglia deteriorated over time, multiple nodular and ring-enhanced lesions were observed in almost the entire brain. A diagnosis of toxoplasma encephalitis (TE) was confirmed by the detection of Toxoplasma gondii DNA in the cerebrospinal fluid. After initiation of intravenous trimethoprim-sulfamethoxazole (TMP-SMX; 10 mg/kg/day of TMP and 50 mg/kg/day of SMX) treatment, his symptoms and radiological findings improved dramatically. Our case suggests that high-intensity signals seen in the basal ganglia of a Gd-enhanced T1-weighted MRI, even at the preclinical stage, is indicative of TE. Because the use of MRI in general has become more widespread, it is predicted that preclinical lesions of TE will be found in various clinical settings more frequently.


Statistical Model Based HPLC Analytical Method Adjustment Strategy to Adapt to Different Sets of Analytes in Complicated Samples.
On account of the complicated compositions of the products like traditional Chinese medicines (TCMs) and functional foods, it is a common practice to determine different sets of analytes in the same product for different purposes. To efficiently develop the corresponding HPLC methods, a statistical model based analytical method adjustment (SMB-AMA) strategy was proposed. In this strategy, the HPLC data acquired with design of experiments methodology were efficiently utilised to build the retention models for all the analytes and interferences shown in the chromatograms with multivariate statistical modelling methods. According to the set of analytes under research, Monte-Carlo simulations were conducted based on these retention models to estimate the probability of achieving adequate separations between all the analytes and their interferences. Then the analytical parameters were mathematically optimised to the point giving a high value of this probability to compose a robust HPLC method. Radix Angelica Sinensis (RAS) and its TCM formula with Folium Epimedii (FE) were taken as the complicated samples for case studies. The retention models for the compounds in RAS and FE were built independently with correlation coefficients all above 0.9799. The analytical parameters were tactfully adjusted to adapt to six cases of different sets of analytes and different sample matrices. In the validation experiments using the adjusted analytical parameters, satisfactory separations were acquired. The results demonstrated that the SMB-AMA strategy was able to develop HPLC methods rationally and rapidly in the adaption of different sets of analytes. Copyright © 2017 John Wiley & Sons, Ltd.


Are live bird markets reservoirs of avian influenza?
Live bird markets (LBM) are essential for marketing poultry in many developing countries, and they are a preferred place for many people to purchase poultry for consumption throughout the world. Live bird markets are typically urban and have a permanent structure in which birds can be housed until they are sold. Live bird markets bring together a mixture of bird species that meet the preferences of their customers and that are commonly produced by multiple suppliers. The mixture of species, the lack of all-in-all-out management, and multiple suppliers are all features that make LBM potential sources of avian influenza viruses (AIV), especially for their supply flocks. Live bird markets have been linked to many outbreaks of avian influenza internationally and in the United States. Avian influenza virus is endemic in many, but not all, LBM systems. For instance, AIV has not been isolated from the Southern California LBM system since December 2005, although the risk of new introductions remains. The California LBM system is much smaller than the New York system, handles fewer birds, and has fewer bird suppliers, which, combined with recent avian influenza prevention and control plans, have enabled it to be AIV free for nearly 3 yr.


Sequential acquisition of T cells and antibodies to nontyphoidal Salmonella in Malawian children.
Salmonella Typhimurium (STm) remain a prominent cause of bacteremia in sub-Saharan Africa. Complement-fixing antibodies to STm develop by 2 years of age. We hypothesized that STm-specific CD4⁺ T cells develop alongside this process. Eighty healthy Malawian children aged 0-60 months were recruited. STm-specific CD4⁺ T cells producing interferon γ, tumor necrosis factor α, and interleukin 2 were quantified using intracellular cytokine staining. Antibodies to STm were measured by serum bactericidal activity (SBA) assay, and anti-STm immunoglobulin G antibodies by enzyme-linked immunosorbent assay. Between 2006 and 2011, STm bacteremias were detected in 449 children <5 years old. STm-specific CD4⁺ T cells were acquired in infancy, peaked at 14 months, and then declined. STm-specific SBA was detectable in newborns, declined in the first 8 months, and then increased to a peak at age 35 months. Acquisition of SBA correlated with acquisition of anti-STm-lipopolysaccharide (LPS) immunoglobulin G (r = 0.329 [95% confidence interval, .552-.062]; P = .01) but not anti-STm-outer membrane protein or anti-STm-flagellar protein (FliC). Acquisition of STm-specific CD4⁺ T cells in early childhood is consistent with early exposure to STm or cross-reactive protein antigens priming this T-cell development. STm-specific CD4⁺ T cells seem insufficient to protect against invasive nontyphoidal Salmonella disease, but sequential acquisition of SBA to STm LPS is associated with a decline in its incidence.


Field performance of self-siphon sediment cleansing set for sediment removal in deep CSO chamber.
This paper presents a study of the self-siphon sediment cleansing set (SSCS), a system designed to remove sediment from the deep combined sewer overflow (CSO) chamber during dry-weather periods. In order to get a better understanding of the sediment removal effectiveness and operational conditions of the SSCS system, we carried out a full-scale field study and comparison analysis on the sediment depth changes in the deep CSO chambers under the conditions with and without the SSCS. The field investigation results demonstrated that the SSCS drains the dry-weather flow that accumulated for 50-57 min from the sewer channel to the intercepting system in about 10 min. It is estimated that the bed shear stress in the CSO chamber and sewer channel is improved almost 25 times on average. The SSCS acts to remove the near bed solids with high pollution load efficiently. Moreover, it cleans up not only the new sediment layer but also part of the previously accumulated sediment.


Use of yoga in outpatient eating disorder treatment: a pilot study.
Individuals with restrictive eating disorders present with co-morbid psychiatric disorders and many attempt to control symptoms using strenuous exercises that increase caloric expenditure. Yoga offers a safe avenue for the engagement in physical activity while providing an outlet for disease-associated symptoms. This study sought to examine use of yoga practice in an outpatient setting and its impact on anxiety, depression and body image disturbance in adolescents with eating disorders. Twenty adolescent girls were recruited from an urban eating disorders clinic who participated in weekly yoga classes at a local studio, in addition to standard multidisciplinary care. Yoga instructors underwent training regarding this patient population. Participants completed questionnaires focused on anxiety, depression and body image disturbance prior to the first class, and following completion of 6 and 12 classes. In participants who completed the study, a statistically significant decrease in anxiety, depression, and body image disturbance was seen, including: Spielberger State anxiety mean scores decreased after the completion of 7-12 yoga classes [47 (95%CI 42-52) to 42 (95%CI 37-47), adj. p = 0.0316]; as did the anorexia nervosa scale [10 (95% CI 7-12) vs. 6 (95%CI 4-8), adj. p = .0004], scores on Beck depression scales [18 (95%CI 15-22) to 10 (95%CI 6-14), adj. p = .0001], and weight and shape concern scores [16 (95%CI 12-20) to 12 (95%CI 8-16), adj. p =0.0120] and [31 (95%CI 25-37) to 20 (95%CI 13-27), adj. p = 0.0034], respectively. No significant changes in body mass index were seen throughout the trial. Yoga practice combined with outpatient eating disorder treatment were shown to decrease anxiety, depression, and body image disturbance without negatively impacting weight. These preliminary results suggest yoga to be a promising adjunct treatment strategy, along with standard multidisciplinary care. However, whether yoga should be endorsed as a standard component of outpatient eating disorder treatment merits further study.


Computational simulation of the effects of oxygen on the electronic states of hydrogenated 3C-porous SiC.
A computational study of the dependence of the electronic band structure and density of states on the chemical surface passivation of cubic porous silicon carbide (pSiC) was performed using ab initio density functional theory and the supercell method. The effects of the porosity and the surface chemistry composition on the energetic stability of pSiC were also investigated. The porous structures were modeled by removing atoms in the [001] direction to produce two different surface chemistries: one fully composed of silicon atoms and one composed of only carbon atoms. The changes in the electronic states of the porous structures as a function of the oxygen (O) content at the surface were studied. Specifically, the oxygen content was increased by replacing pairs of hydrogen (H) atoms on the pore surface with O atoms attached to the surface via either a double bond (X = O) or a bridge bond (X-O-X, X = Si or C). The calculations show that for the fully H-passivated surfaces, the forbidden energy band is larger for the C-rich phase than for the Si-rich phase. For the partially oxygenated Si-rich surfaces, the band gap behavior depends on the O bond type. The energy gap increases as the number of O atoms increases in the supercell if the O atoms are bridge-bonded, whereas the band gap energy does not exhibit a clear trend if O is double-bonded to the surface. In all cases, the gradual oxygenation decreases the band gap of the C-rich surface due to the presence of trap-like states.


Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients.
Killer cell immunoglobulin-like receptor (KIR) genes encode for activating and inhibitory surface receptors, which are correlated with the regulation of Natural Killer (NK) cell cytotoxic activity. Reduced NK cell cytotoxic activity has been consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients, and KIR haplotypes and allelic polymorphism remain to be investigated. The aim of this article was to conduct a pilot study to examine KIR genotypes, haplotypes, and allelic polymorphism in CFS/ME patients and nonfatigued controls (NFCs). Comparison of KIR and allelic polymorphism frequencies revealed no significant differences between 20 CFS/ME patients and 20 NFCs. A lower frequency of the telomeric A/B motif (P < 0.05) was observed in CFS/ME patients compared with NFCs. This pilot study is the first to report the differences in the frequency of KIR on the telomeric A/B motif in CFS/ME patients. Further studies with a larger CFS/ME cohort are required to validate these results.


Physician-diagnosed depression as a correlate of hospitalizations in patients receiving long-term hemodialysis.
Hospital admissions consume a large proportion of costs for the end-stage renal disease (ESRD) program in the United States. We investigated whether a physician diagnosis of depression increases the risk for hospitalization or death in patients with ESRD receiving long-term hemodialysis (HD), independent of medical comorbidities. Centralized Veterans Affairs (VA) databases were used to identify a population-based prevalence cohort of 1,588 male patients with ESRD receiving long-term HD in VA facilities between September 1, 2000, and September 30, 2000. International Classification of Diseases, Ninth Revision, codes were used to identify comorbidities and depression diagnosis. Negative binomial regression models were used to examine the association between depression diagnosis and number of hospitalizations and cumulative hospital days in a 2-year observation period. Logistic regression models were used to investigate the association between depression diagnosis and hospitalization, death, and death or hospitalization. The prevalence of physician-diagnosed depression was 14.7%. Patients with a depression diagnosis were more likely to be white and have more comorbidities. Depression diagnosis was associated with increased hospital days (rate ratio for adjusted model, 1.31; 95% confidence interval, 1.04 to 1.66) and increased number of hospitalizations (rate ratio for adjusted model, 1.30; 95% confidence interval, 1.11 to 1.52). Depression diagnosis was not statistically associated with death or the composite of death or hospitalization in adjusted models. Physician-diagnosed depression was associated significantly with both increased hospitalization rate and length of stay in patients with ESRD receiving outpatient HD in VA facilities, independent of demographics and comorbidities. Prospective studies should be conducted to assess whether treatment of depression will decrease hospitalization in these patients.


Mutations at position 184 of human immunodeficiency virus type-1 reverse transcriptase affect virus titer and viral DNA synthesis.
Methionine at position 184 of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) was changed to valine, isoleucine, threonine, or alanine in an HIV-1-based vector. The vectors were analyzed for replication capacity and for resistance to the nucleoside analog 2',3'-dideoxy-3'thiacytidine (3TC) using a single-cycle assay. Viruses containing the valine or isoleucine mutations were highly resistant to 3TC and replicated almost as well as the wild-type virus. The virus containing the threonine mutation was resistant to 3TC, but replicated about 30% as well as the wild-type. The alanine mutation conferred partial resistance to 3TC, but replicated poorly. The amounts of viral DNA synthesized decreased in 3TC-treated cells when the cells were infected with wild-type virus and the M184A mutant. The effect of these mutations on the generation of the ends of the linear viral DNA was determined using the sequence of the 2-LTR circle junctions. The M184T mutation increased the proportion of 2-LTR circle junctions containing a tRNA insertion, suggesting that the mutation affected the RNase H activity of RT.


Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression.
Neuroligins (NLGNs) are cell adhesion molecules that are important for proper synaptic formation and functioning, and are critical regulators of the balance between neural excitation/inhibition (E/I). Mutations in NLGNs have been linked to psychiatric disorders in humans involving social dysfunction and are related to similar abnormalities in animal models. Chronic stress increases the likelihood for affective disorders and has been shown to induce changes in neural structure and function in different brain regions, with the hippocampus being highly vulnerable to stress. Previous studies have shown evidence of chronic stress-induced changes in the neural E/I balance in the hippocampus. Therefore, we hypothesized that chronic restraint stress would lead to reduced hippocampal NLGN-2 levels, in association with alterations in social behavior. We found that rats submitted to chronic restraint stress in adulthood display reduced sociability and increased aggression. This occurs along with a reduction of NLGN-2, but not NLGN-1 expression (as shown with western blot, immunohistochemistry, and electron microscopy analyses), throughout the hippocampus and detectable in different layers of the CA1, CA3, and DG subfields. Furthermore, using synthetic peptides that comprise sequences in either NLGN-1 (neurolide-1) or NLGN-2 (neurolide-2) involved in the interaction with their presynaptic partner neurexin (NRXN)-1, intra-hippocampal administration of neurolide-2 led also to reduced sociability and increased aggression. These results highlight hippocampal NLGN-2 as a key molecular substrate regulating social behaviors and underscore NLGNs as promising targets for the development of novel drugs for the treatment of dysfunctional social behaviors.


Y-chromosome lineages in São Tomé e Príncipe islands: evidence of European influence.
The Y-chromosome haplogroup composition of the population of São Tomé e Príncipe (STP) archipelago was analyzed using 25 biallelic markers and compared with populations of different origins from Europe, Africa, and the Middle East. Two main Y-chromosome haplogroups were found: E3a, very common among sub-Saharans accounts for 84.2% of the paternal lineages and R1b, typical of West Eurasia, represents 8.7% of the overall male population. Nevertheless, we detected in the population of STP a significant heterogeneous distribution of R1b among the two main ethnic groups of the archipelago: Forros (10.3%) and Angolares (6.6%). Together, haplogroups known to be prevalent in West Eurasia reach 12.5% of the chromosomes analyzed unequally distributed among the two groups: Forros present 17.7% while Angolares display only 8.2% of west Eurasian haplogroups. Our findings suggest that, despite its sub-Saharan genetic background, a relevant contribution of European paternal lineages is present in nowadays STP population. This influence has shown to be stronger in Forros than in Angolares, which could be explained by the social isolation that these have last experienced through their history.


[A Case of Ascending Colon Cancer with Synchronous Liver Metastases and Peritoneal Dissemination].
The patient was a 73-year-old man with ascending colon cancer and synchronous liver metastases. A right hemicolectomy with a lymph node dissection was performed for the primary lesion. The resected specimen revealed a KRAS codon 12 mutation. After 6 courses of chemotherapy with capecitabine, oxaliplatin, and bevacizumab(Bv), we performed a partial hepatectomy and resection of the peritoneal dissemination. A computed tomography(CT)scan 5 months later revealed the recurrence of the liver metastases. After 8 courses of chemotherapy with 5-fluorouracil, Leucovorin, irinotecan, and Bv, we performed a partial hepatectomy. CT scan after 13 months revealed a recurrence in the peritoneal dissemination in the Douglas pouch and the right subphrenic space; therefore, we performed a low anterior resection and resection of the peritoneal dissemination with curative intent. CT scan after 19 months revealed a recurrence in the right subphrenic dissemination, a lung metastasis, and pleural dissemination. Chemotherapy with 5-fluorouracil, Leucovorin, and Bv was administered for 2 years and 5 months. After 5 years and 9 months of the primary operation, the patient is alive. Recently, we have focused on the mechanism of multidrug resistance through NAD(P)H: quinone oxidoreductase-1(NQO1)overexpression, which can be used to determine the role of an enzyme in sensitivity to toxicity and carcinogenesis. In this case, the pathological examination of the resected specimen revealed NQO1 negative expression. In conclusion, NQO1 may play a significant role in chemotherapy resistance in colorectal cancer patients.


Peritoneal perforation is less a complication than an expected event during transanal endoscopic microsurgery: experience from 194 consecutive cases.
Indications for transanal endoscopic microsurgery (TEM) have been extended to technically challenging tumors, which may be associated with an increased risk of peritoneal perforation (PP). The aim of the present study was to investigate the occurrence, management and outcome of PP in patients having TEM. All the patients who had TEM for rectal adenoma or adenocarcinoma in our unit were included. Patients in whom PP occurred (Group A) were compared to those without PP (Group B). From 2007 to 2015, 194 TEM (116 men, median age 66 [range 21-100] years) were divided into Groups A (n = 28, 14%) and B (n = 166). The latter group included four patients, in whom a laparoscopy did not confirm suspicion of PP made during TEM. In 2 of 28 patients (7%), the diagnosis of PP was made postoperatively during reoperation for peritonitis. For the 26 other patients (93%), routine exploratory laparoscopy was performed with suture of the peritoneal defect on the pouch of Douglas in 24 cases and a rectal suture alone in 2 cases. Independent predictive factors for PP were: distance from the anal verge >10 cm (OR = 3.6), circumferential tumor (OR = 3.0) and anterior location (OR = 2.7). Hospital stay was significantly longer in Group A (7.5 [3-31] days) than in Group B (4 [1-38] days; p < 0.0001), whereas there was no significant difference regarding postoperative morbidity and recurrence rate. Our results suggested that PP is not a very rare event during TEM, especially in anterior, circumferential and/or high rectal tumors. Laparoscopic treatment of PP is feasible and safe. The occurrence of PP is not associated with poor oncologic results.


A review of ethics for the radiologic technologist.
Radiologic technology students learn ethical theory, ethical principles and the Code of Ethics. However, over time, the concepts may fade from the radiologic technologist's memory. Periodic review of the ethical concepts and the American Registry of Radiologic Technologists Standards of Ethics are important to maintain a clear understanding of ethical expectations of the radiologic technologist. This article provides examples of potential ethical violations to illustrate each principle in the Code of Ethics and each tenet in the Rules of Ethics. The examples are intended to help readers think about and relate to situations they may encounter. This article is a Directed Reading. Your access to Directed Reading quizzes for continuing education credit is determined by your CE preference. For access to other quizzes, go to www.asrt.org/store.


A high spatiotemporal study of somatic exocytosis with scanning electrochemical microscopy and nanoITIES electrodes.
Extra-synaptic exocytosis is an essential component of cellular communication. A knowledge gap exists in the exocytosis of the non-redox active transmitter acetylcholine. Using the nano-interface between two immiscible electrolyte solutions and scanning electrochemical microscopy (SECM), a high resolution spatiotemporal study of acetylcholine exocytosis is shown from an individual neuronal soma. The nanoelectrode was positioned ∼140 nm away from the release sites on the soma using an SECM. The quantitative study enables the obtaining of key information related to cellular communication, including extracellular concentration of the neurotransmitter, cellular permeability, Ca2+ dependence on somatic release, vesicle density, number of molecules released and the release dynamics. Measurements were achieved with a high signal to noise ratio of 6-19. The released neurotransmitter with a concentration of 2.7 (±1.0) μM was detected at the nanoelectrodes with radii of 750 nm to 860 nm.


Physician predictors of mammographic accuracy.
The association between physician experience and the accuracy of screening mammography in community practice is not well studied. We identified characteristics of U.S. physicians associated with the accuracy of screening mammography. Data were obtained from the Breast Cancer Surveillance Consortium and the American Medical Association Master File. Unadjusted mammography sensitivity and specificity were calculated according to physician characteristics. We modeled mammography sensitivity and specificity by multivariable logistic regression as a function of patient and physician characteristics. All statistical tests were two-sided. We studied 209 physicians who interpreted 1,220,046 screening mammograms from January 1, 1995, through December 31, 2000, of which 7143 (5.9 per 1000 mammograms) were associated with breast cancer within 12 months of screening. Each physician interpreted a mean of 6011 screening mammograms (95% confidence interval [CI] = 4998 to 6677), including a mean of 34 (95% CI = 28 to 40) from women diagnosed with breast cancer. The mean sensitivity was 77% (range = 29%-97%), and the mean false-positive rate was 10% (range = 1%-29%). After adjustment for the patient characteristics of those whose mammograms they interpreted, physician characteristics were strongly associated with specificity. Higher specificity was associated with at least 25 years (versus less than 10 years) since receipt of a medical degree (for physicians practicing for 25-29 years, odds ratio [OR] = 1.54, 95% CI = 1.14 to 2.08; P = .006), interpretation of 2500-4000 (versus 481-750) screening mammograms annually (OR = 1.30, 95% CI = 1.06 to 1.59; P = .011) and a high focus on screening mammography compared with diagnostic mammography (OR = 1.59, 95% CI = 1.37 to 1.82; P<.001). Higher overall accuracy was associated with more experience and with a higher focus on screening mammography. Compared with physicians who interpret 481-750 mammograms annually and had a low screening focus, physicians who interpret 2500-4000 mammograms annually and had a high screening focus had approximately 50% fewer false-positive examinations and detected a few less cancers. Raising the annual volume requirements in the Mammography Quality Standards Act might improve the overall quality of screening mammography in the United States.


Domestic cats infected with lion or puma lentivirus develop anti-feline immunodeficiency virus immune responses.
Attenuated live viral strains have afforded significant protection against virus challenge in HIV vaccine models. Although both cellular and humoral immunity are assumed to be vital for protection, specific parameters consistently associated with control of infection have been elusive. Our previous studies have shown that lentiviruses from 2 nondomestic feline species--lion (Pathera leo) and puma (Felis concolor)--persistently but nonpathogenetically infect domestic cats (Felis domestica). Moreover, infection with either the puma lentivirus (PLV) or lion lentivirus (LLV) conferred partial protection against superinfection with virulent feline immunodeficiency virus (FIV), the feline equivalent of HIV. To determine whether domestic cats infected by the lentiviruses of pumas or lions generate cross-reactive immune responses, we infected groups of 5 domestic cats with PLV, LLV, or a sham control and then monitored virus load, hematologic parameters, antibody protection, proliferative responses, and the ability of blood mononuclear cells to inhibit LLV, PLV, and FIV replication in vitro. All cats inoculated with LLV or PLV developed persistent infection, and low-level cell-associated viremia has been previously described. Infected cats also generated robust antibody titers and lymphocytes that proliferated in response to viral antigens and downregulated PLV, LLV, and FIV replication in vitro. This latter activity was CD8 cell associated for PLV and LLV inhibition but not for FIV inhibition. Thus, cats infected with the phylogenetically more ancient and less pathogenic feline lentiviruses generated humoral and cell-mediated immune responses reactive against both the homologous viruses and the heterologous FIV of domestic cats, which correlated with decreased viral load. These results are analogous to protection studies with attenuated primate immunodeficiency viruses and provide a system by which to examine adaptation, interference, and cross protection among lentiviruses.


Cinnoline derivatives as human neutrophil elastase inhibitors.
Compounds that can effectively inhibit the proteolytic activity of human neutrophil elastase (HNE) represent promising therapeutics for treatment of inflammatory diseases. We present here the synthesis, structure-activity relationship analysis, and biological evaluation of a new series of HNE inhibitors with a cinnoline scaffold. These compounds exhibited HNE inhibitory activity but had lower potency compared to N-benzoylindazoles previously reported by us. On the other hand, they exhibited increased stability in aqueous solution. The most potent compound, 18a, had a good balance between HNE inhibitory activity (IC50 value = 56 nM) and chemical stability (t1/2 = 114 min). Analysis of reaction kinetics revealed that these cinnoline derivatives were reversible competitive inhibitors of HNE. Furthermore, molecular docking studies of the active products into the HNE binding site revealed two types of HNE inhibitors: molecules with cinnolin-4(1H)-one scaffold, which were attacked by the HNE Ser195 hydroxyl group at the amido moiety, and cinnoline derivatives containing an ester function at C-4, which is the point of attack of Ser195.


Implementing HIV-1 genotypic resistance testing in antiretroviral therapy programs in Africa: needs, opportunities, and challenges.
Tremendous progress has been made with the scale-up of antiretroviral therapy in Africa, with an estimated seven million people now receiving antiretroviral therapy in the region. The long-term success of antiretroviral therapy programs depends on appropriate strategies to deal with potential threats, one of which is the emergence and spread of antiretroviral drug resistance. Whilst public health surveillance forms the mainstay of the World Health Organization approach to antiretroviral drug resistance, there is likely to be increasing demand for access to drug resistance testing as programs mature and as HIV clinical management becomes more complex. African-owned research initiatives have helped to develop affordable resistance testing appropriate for use in the region, and have developed delivery models for resistance testing at different levels of the public health system. Some upper-middle-income countries such as Botswana and South Africa have introduced drug resistance testing for selected patient groups to guide clinical management. The scale-up of resistance testing will require substantial expansion of clinical and laboratory capacity in the region, but the expertise and resources exist in Africa to support this. The long-term population health impact and cost-effectiveness of resistance testing in the region will also require further investigation.


Antifungal effect of dairy propionibacteria--contribution of organic acids.
Large amounts of food and feed are lost every year due to spoilage by moulds and yeasts. Biopreservation, i.e. the use of microorganisms as preservatives instead of chemicals, has gained increased interest. Lactic acid bacteria and propionibacteria might be particularly useful due to their important role in many food fermentations. Knowledge of the antifungal effects of the organic acids produced by these bacteria is necessary to understand their inhibitory activity. We evaluated the antifungal activity of the type strains of five dairy propionibacteria, Propionibacterium acidipropionici, P. jensenii, P. thoenii, P. freudenreichii subsp. freudenreichii and P. freudenreichii subsp. shermanii against eight food- and feedborne moulds and yeasts. A dual culture system assayed the inhibitory activity on three different agar media, sodium lactate (SL), de Man Rogosa Sharp (MRS) and MRS without acetate (MRS-ac). The amounts of organic acids produced during growth of propionibacteria in liquid SL, MRS and MRS-ac were also determined. The minimal inhibitory concentration (MIC) values of propionic, acetic and lactic acid were established for all fungi at pH 3, 5 and 7. Propionic acid, followed by acetic acid, was the most potent antifungal acid. Inhibition at pH 7 generally required concentrations above 500 mM for all three acids, at pH 5 the MIC values for propionic and acetic acids were 20-120 mM and above 500 mM for lactic acid. At pH 3, the MIC values were, with one exception, below 10 mM for both propionic and acetic acid and above 160 mM for lactic acid. The yeast Pichia anomala was the fungus most resistant to organic acids. The propionibacteria exhibited a pronounced species variation in antifungal activity on MRS (+/-acetate) agar, with P. thoenii being the most potent. Four of the five propionibacteria species produced more propionic and acetic acid in liquid SL medium than in MRS (+/-acetate) broth. However, when SL agar was used as the growth medium, none of the propionibacteria inhibited fungal growth.


Availability and affordability of cardiovascular disease medicines and their effect on use in high-income, middle-income, and low-income countries: an analysis of the PURE study data.
WHO has targeted that medicines to prevent recurrent cardiovascular disease be available in 80% of communities and used by 50% of eligible individuals by 2025. We have previously reported that use of these medicines is very low, but now aim to assess how such low use relates to their lack of availability or poor affordability. We analysed information about availability and costs of cardiovascular disease medicines (aspirin, β blockers, angiotensin-converting enzyme inhibitors, and statins) in pharmacies gathered from 596 communities in 18 countries participating in the Prospective Urban Rural Epidemiology (PURE) study. Medicines were considered available if present at the pharmacy when surveyed, and affordable if their combined cost was less than 20% of household capacity-to-pay. We compared results from high-income, upper middle-income, lower middle-income, and low-income countries. Data from India were presented separately given its large, generic pharmaceutical industry. Communities were recruited between Jan 1, 2003, and Dec 31, 2013. All four cardiovascular disease medicines were available in 61 (95%) of 64 urban and 27 (90%) of 30 rural communities in high-income countries, 53 (80%) of 66 urban and 43 (73%) of 59 rural communities in upper middle-income countries, 69 (62%) of 111 urban and 42 (37%) of 114 rural communities in lower middle-income countries, eight (25%) of 32 urban and one (3%) of 30 rural communities in low-income countries (excluding India), and 34 (89%) of 38 urban and 42 (81%) of 52 rural communities in India. The four cardiovascular disease medicines were potentially unaffordable for 0·14% of households in high-income countries (14 of 9934 households), 25% of upper middle-income countries (6299 of 24,776), 33% of lower middle-income countries (13,253 of 40,023), 60% of low-income countries (excluding India; 1976 of 3312), and 59% households in India (9939 of 16,874). In low-income and middle-income countries, patients with previous cardiovascular disease were less likely to use all four medicines if fewer than four were available (odds ratio [OR] 0·16, 95% CI 0·04-0·57). In communities in which all four medicines were available, patients were less likely to use medicines if the household potentially could not afford them (0·16, 0·04-0·55). Secondary prevention medicines are unavailable and unaffordable for a large proportion of communities and households in upper middle-income, lower middle-income, and low-income countries, which have very low use of these medicines. Improvements to the availability and affordability of key medicines is likely to enhance their use and help towards achieving WHO's targets of 50% use of key medicines by 2025. Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.


Single-Particle Tracking of Human Immunodeficiency Virus Type 1 Productive Entry into Human Primary Macrophages.
Macrophages are one of the major targets of human immunodeficiency virus (HIV-1), but the viral entry pathway remains poorly understood in these cells. Noninvasive virus labeling and single-virus tracking are effective tools for studying virus entry. Here, we constructed a quantum dot (QD)-encapsulated infectious HIV-1 particle to track viral entry at a single-particle level in live human primary macrophages. QDs were encapsulated in HIV-1 virions by incorporating viral accessory protein Vpr-conjugated QDs during virus assembly. With the HIV-1 particles encapsulating QDs, we monitored the early phase of viral infection in real time and observed that, during infection, HIV-1 was endocytosed in a clathrin-mediated manner; the particles were translocated into Rab5A-positive endosomes, and the core was released into the cytoplasm by viral envelope-mediated endosomal fusion. Drug inhibition assays verified that endosome fusion contributes to HIV-1 productive infection in primary macrophages. Additionally, we observed that a dynamic actin cytoskeleton is critical for HIV-1 entry and intracellular migration in primary macrophages. HIV-1 dynamics and infection could be blocked by multiple different actin inhibitors. Our study revealed a productive entry pathway in macrophages that requires both endosomal function and actin dynamics, which may assist in the development of inhibitors to block the HIV entry in macrophages.


Home environment relationships with children's physical activity, sedentary time, and screen time by socioeconomic status.
Children in households of lower socioeconomic status (SES) are more likely to be overweight/obese. We aimed to determine if home physical activity (PA) environments differed by SES and to explore home environment mediators of the relation of family SES to children's PA and sedentary behavior. Participants were 715 children aged 6 to 11 from the Neighborhood Impact on Kids (NIK) Study. Household SES was examined using highest educational attainment and income. Home environment was measured by parent report on a survey. Outcomes were child's accelerometer-measured PA and parent-reported screen time. Mediation analyses were conducted for home environment factors that varied by SES. Children from lower income households had greater media access in their bedrooms (TV 52% vs. 14%, DVD player 39% vs. 14%, video games 21% vs. 9%) but lower access to portable play equipment (bikes 85% vs. 98%, jump ropes 69% vs. 83%) compared to higher income children. Lower SES families had more restrictive rules about PA (2.5 vs. 2.0). Across SES, children watched TV/DVDs with parents/siblings more often than they engaged in PA with them. Parents of lower SES watched TV/DVDs with their children more often (3.1 vs. 2.5 days/week). Neither total daily and home-based MVPA nor sedentary time differed by SES. Children's daily screen time varied from 1.7 hours/day in high SES to 2.4 in low SES families. Media in the bedroom was related to screen time, and screen time with parents was a mediator of the SES--screen time relationship. Lower SES home environments provided more opportunities for sedentary behavior and fewer for PA. Removing electronic media from children's bedrooms has the potential to reduce disparities in chronic disease risk.